1 00:00:05,660 --> 00:00:06,594 GOOD MORNING, I WOULD ALSO 2 00:00:06,594 --> 00:00:07,895 LIKE IT SAY GOOD AFTERNOON OR 3 00:00:07,895 --> 00:00:10,198 EVENING TO SOME OF OUR 4 00:00:10,198 --> 00:00:11,633 PARTICIPANTS WHO MAY LIVE IN 5 00:00:11,633 --> 00:00:16,504 DEFINITE PART OF THE GLOBE. 6 00:00:16,504 --> 00:00:18,306 WOW, SO GOOD TO SEE YOU ALL 7 00:00:18,306 --> 00:00:19,574 HERE. 8 00:00:19,574 --> 00:00:23,211 WELCOME TO THE 2 DAY WORKSHOP 9 00:00:23,211 --> 00:00:24,379 PROGENITOR RESILIENCE AND THE 10 00:00:24,379 --> 00:00:26,214 EARLY ONSET OF CHRONIC LUNG 11 00:00:26,214 --> 00:00:27,982 DISEASE HOSTED BY THE DIVISION 12 00:00:27,982 --> 00:00:30,818 OF LUNG DISEASE AT THE NATIONAL 13 00:00:30,818 --> 00:00:32,720 HEART, LUNG AND BLOOD INSTITUTE 14 00:00:32,720 --> 00:00:39,961 OF THE NATIONAL 15 00:00:39,961 --> 00:00:40,662 INSTITUTE OF 16 00:00:40,662 --> 00:00:40,895 HEALTH. 17 00:00:40,895 --> 00:00:48,436 ON BEHALF OF OUR DIRECTOR OF 18 00:00:48,436 --> 00:00:49,303 DIVISION, DR. MATUTE-BELLO, AND 19 00:00:49,303 --> 00:00:51,639 THE REST OF THE TEAM, I WOULD 20 00:00:51,639 --> 00:00:54,342 LIKE TO WELCOME YOU TO TODAY'S 21 00:00:54,342 --> 00:00:54,909 PRESENTATIONS. 22 00:00:54,909 --> 00:01:02,784 I AM DR. LU, PROGRAM DIRECTOR 23 00:01:02,784 --> 00:01:04,419 OBSTRUCTIVE LUNG DISEASE BRANCH 24 00:01:04,419 --> 00:01:06,721 OF THE NHLBI, I AM HAPPY TO 25 00:01:06,721 --> 00:01:09,457 REPORT THAT MORE THAN 400 PEOPLE 26 00:01:09,457 --> 00:01:10,525 REGISTERED FOR THIS WORKSHOP. 27 00:01:10,525 --> 00:01:14,162 I AM SURE THEY ARE NOT COMING AT 28 00:01:14,162 --> 00:01:15,463 THE SAME TIMES BUT I'M SURE THEY 29 00:01:15,463 --> 00:01:18,633 ARE COMING IN AND OUT, SO IN 30 00:01:18,633 --> 00:01:20,401 TOTAL WE HAVE 400 REGISTRATIONS. 31 00:01:20,401 --> 00:01:21,669 THANK YOU AGAIN. 32 00:01:21,669 --> 00:01:23,404 THIS WORKSHOP IS ALSO BEING LIVE 33 00:01:23,404 --> 00:01:30,144 STREAMED AT THE NIH VIDEOCAST 34 00:01:30,144 --> 00:01:30,845 AND RECORDED. 35 00:01:30,845 --> 00:01:36,317 RECORDINGS WILL BE AVAILABLE IN 36 00:01:36,317 --> 00:01:40,388 THE NIH VIDEOCAST ONLINE 1 WEEK 37 00:01:40,388 --> 00:01:46,828 WITHIN TODAY . 38 00:01:46,828 --> 00:01:52,500 OUR ACTING DIRECTOR 39 00:01:52,500 --> 00:01:54,001 DR. MATUTE-BELLOS, PLANNED TO BE 40 00:01:54,001 --> 00:01:59,574 HERE, HOWEVER, HE HAS ANOTHER 41 00:01:59,574 --> 00:02:01,209 COMMITMENT WHICH HE HAS -- 42 00:02:01,209 --> 00:02:02,243 ABSOLUTELY HAS TO ATTEND. 43 00:02:02,243 --> 00:02:04,178 SO I'M SURE YOU UNDERSTAND THAT. 44 00:02:04,178 --> 00:02:07,381 NOW, I WOULD LIKE TO THANK OUR 45 00:02:07,381 --> 00:02:08,416 CO-CHAIRS FOR THEIR 46 00:02:08,416 --> 00:02:10,718 EXTRAORDINARY LEADERSHIP IN 47 00:02:10,718 --> 00:02:11,385 PLANNING THIS WORKSHOP. 48 00:02:11,385 --> 00:02:15,289 I WOULD ALSO LIKE TO EXPRESS OUR 49 00:02:15,289 --> 00:02:16,824 GRATITUDE TO THE DIVERSE PANEL 50 00:02:16,824 --> 00:02:19,660 OF MODERATORS AND SPEAKERS FOR 51 00:02:19,660 --> 00:02:21,329 YOUR INSIGHT AND THE 52 00:02:21,329 --> 00:02:23,131 CONTRIBUTION TO THIS IMPORTANT 53 00:02:23,131 --> 00:02:23,331 EVENT. 54 00:02:23,331 --> 00:02:26,234 I WANT TO THANK OUR AUDIENCE, 55 00:02:26,234 --> 00:02:28,803 PARTICULARLY THOSE WHO OVERCOME 56 00:02:28,803 --> 00:02:30,972 CHALLENGING TIME ZONE 57 00:02:30,972 --> 00:02:31,472 DIFFERENCES. 58 00:02:31,472 --> 00:02:36,844 I WOULD ALSO LIKE TO THANK NHLBI 59 00:02:36,844 --> 00:02:38,246 WORKSHOP SUPPORT TEAM FOR THEIR 60 00:02:38,246 --> 00:02:39,947 ASSISTNESS, AND LAST BUT NOT 61 00:02:39,947 --> 00:02:43,084 LEAST, I WOULD LIKE TO THANK OUR 62 00:02:43,084 --> 00:02:47,455 LEADERSHIP, DIVISION LEADERSHIP 63 00:02:47,455 --> 00:02:50,591 AND MY CO-LEAD DR. KRISTI GOMEZ, 64 00:02:50,591 --> 00:02:51,726 AND OTHER COMMITTEE MEMBERS FOR 65 00:02:51,726 --> 00:02:57,031 THEIR SUPPORT AND CONTRIBUTIONS. 66 00:02:57,031 --> 00:02:57,832 PARTICULARLY, THE DIVISION OF 67 00:02:57,832 --> 00:03:00,268 LUNG DISEASE IS COMMITTED TO 68 00:03:00,268 --> 00:03:04,071 ADVANCING RESEARCH THAT NOT ONLY 69 00:03:04,071 --> 00:03:05,807 ADDRESSES THE COST, DIAGNOSIS, 70 00:03:05,807 --> 00:03:07,875 PREVENTION ASK TREATMENT OF LUNG 71 00:03:07,875 --> 00:03:10,411 DISEASE AND SLEEP DISORDERS BUT 72 00:03:10,411 --> 00:03:12,013 ALSO EXPLORED INNOVATIVE 73 00:03:12,013 --> 00:03:14,582 APPROACH TO PROMOTE RESILIENCE 74 00:03:14,582 --> 00:03:18,219 OF LUNG TISSUE IN ITS CELLULAR 75 00:03:18,219 --> 00:03:20,188 COMPONENT AND PRESERVE LUNG 76 00:03:20,188 --> 00:03:20,555 [INDISCERNIBLE]. 77 00:03:20,555 --> 00:03:22,924 BY UNDERSTANDING THE CURRENT 78 00:03:22,924 --> 00:03:26,260 RESILIENCE OF PROGENITOR CELLS 79 00:03:26,260 --> 00:03:27,895 WE UNCOVER NOVEL PATHWAYS FOR 80 00:03:27,895 --> 00:03:29,630 MITIGATION OF THE EARLY ONSET 81 00:03:29,630 --> 00:03:30,798 AND PROGRESSION OF CHRONIC LUNG 82 00:03:30,798 --> 00:03:34,769 DISEASE . 83 00:03:34,769 --> 00:03:36,470 THAT BEING SAID THE OVERARCHING 84 00:03:36,470 --> 00:03:39,073 GOAL OF THIS WORKSHOP IS TO 85 00:03:39,073 --> 00:03:44,779 BRING TOGETHER MULTIDISCIPLINARY 86 00:03:44,779 --> 00:03:46,547 RESEARCHERS, INCLUDING PROMINENT 87 00:03:46,547 --> 00:03:48,182 MAGAZINE SCIENTISTS AND STEM 88 00:03:48,182 --> 00:03:49,350 CELL AND PROGENITOR SCIENTISTS 89 00:03:49,350 --> 00:03:51,886 TO DISCUSS THE CURRENT STATE OF 90 00:03:51,886 --> 00:03:53,754 SCIENCE AND IDENTIFY CRUCIAL 91 00:03:53,754 --> 00:03:56,090 RECENT GAPS, CHALLENGES, 92 00:03:56,090 --> 00:03:56,858 OPPORTUNITIES AND KEY QUESTIONS 93 00:03:56,858 --> 00:04:02,830 IN THE AREA OF LUNG PROGENITOR 94 00:04:02,830 --> 00:04:04,332 CELL RESILIENCE AND IMPLICATIONS 95 00:04:04,332 --> 00:04:05,967 IN THE EARLY ONSET AND 96 00:04:05,967 --> 00:04:10,137 PROGRESSION OF CHRONIC LUNG 97 00:04:10,137 --> 00:04:13,241 DISEASE INCLUDING MECHANISMS AND 98 00:04:13,241 --> 00:04:14,609 POTENTIAL PROGENITOR BASED 99 00:04:14,609 --> 00:04:15,843 BIOMARKERS AND THERAPEUTIC 100 00:04:15,843 --> 00:04:16,077 TARGETS. 101 00:04:16,077 --> 00:04:19,747 WE BELIEVE THIS WORKSHOP IS 102 00:04:19,747 --> 00:04:24,919 TIMELY, AND IS ALIGNED WITH 103 00:04:24,919 --> 00:04:26,787 NHLBI'S STRATEGIC OBJECTIVES. 104 00:04:26,787 --> 00:04:27,855 THANK YOU FOR YOUR 105 00:04:27,855 --> 00:04:28,222 [INDISCERNIBLE]. 106 00:04:28,222 --> 00:04:30,725 WE LOOK FORWARD TO A SUCCESSFUL 107 00:04:30,725 --> 00:04:33,828 WORKSHOP AND YOUR ACTIONABLE 108 00:04:33,828 --> 00:04:34,195 RECOMMENDATIONS. 109 00:04:34,195 --> 00:04:40,234 NOW, LET ME WELCOME MY CO-LEAD 110 00:04:40,234 --> 00:04:41,535 DR. KRISTI GOMEZ TO SAY A FEW 111 00:04:41,535 --> 00:04:43,170 WORDS AND INTRODUCE OUR 112 00:04:43,170 --> 00:04:45,373 INCREDIBLE CO CHAIRS, THANK YOU. 113 00:04:45,373 --> 00:04:49,577 KRISTI TAKE IT AWAY. 114 00:04:49,577 --> 00:04:54,248 >> THANK YOU SO MUCH QING, THIS 115 00:04:54,248 --> 00:04:54,715 IS EXCITING. 116 00:04:54,715 --> 00:04:57,051 GOOD MORNING AND WELCOME TO THE 117 00:04:57,051 --> 00:04:59,654 WORKSHOP, I AM CHRISTIAN GOMEZ 118 00:04:59,654 --> 00:05:01,822 PROGRAM OFFICER AT THE DIVISION 119 00:05:01,822 --> 00:05:03,491 OF LUNG DECS IN NHLBI. 120 00:05:03,491 --> 00:05:04,892 IT'S A PLEASURE TO BE HERE WITH 121 00:05:04,892 --> 00:05:09,096 YOU TODAY AS WE DELVE INTO THE 122 00:05:09,096 --> 00:05:09,797 CRITICAL ISSUES SURROUNDING 123 00:05:09,797 --> 00:05:10,998 CHRONIC LUNG DECS WITH A 124 00:05:10,998 --> 00:05:13,200 PARTICULAR FOCUS ON ENHANCING 125 00:05:13,200 --> 00:05:15,069 RESILIENCE IN PROGENITOR CELLS. 126 00:05:15,069 --> 00:05:17,038 I AM HONORED TO INTRODUCE OUR 127 00:05:17,038 --> 00:05:19,874 CO-CHAIRS FOR THIS WORKSHOP WHO 128 00:05:19,874 --> 00:05:21,542 WILL BRING EXCEPTIONAL EXPERTISE 129 00:05:21,542 --> 00:05:24,478 AND INSIGHT INTO THIS VITAL AREA 130 00:05:24,478 --> 00:05:25,613 OF RESEARCH. 131 00:05:25,613 --> 00:05:33,120 FIRST WE HAVE DR. RAVI KALHAN, 132 00:05:33,120 --> 00:05:34,021 WITH THE NORTHWESTERN UNIVERSITY 133 00:05:34,021 --> 00:05:38,492 FINE BERG SCHOOL OF MEDICINE, 134 00:05:38,492 --> 00:05:40,127 DR. KALHAN IS FOCUSING ON 135 00:05:40,127 --> 00:05:41,729 EPIDEMIOLOGY AND MANAGEMENT OF 136 00:05:41,729 --> 00:05:43,464 THESE CONDITIONS, HIS WORK 137 00:05:43,464 --> 00:05:45,499 EMPHASIZES EARLY DETECTION AND 138 00:05:45,499 --> 00:05:47,435 INTERVENTION WITH AN INTEREST IN 139 00:05:47,435 --> 00:05:50,304 HOW ENHANCING THE RESILIENCE OF 140 00:05:50,304 --> 00:05:55,242 LUNG TISSUES CAN ALTER THE 141 00:05:55,242 --> 00:05:55,676 DISEASE TRAJECTORY. 142 00:05:55,676 --> 00:05:57,211 HIS CONTRIBUTIONS HAVE BEEN 143 00:05:57,211 --> 00:05:58,245 INSTRUMENTAL IN ADVANCING OUR 144 00:05:58,245 --> 00:06:00,414 UNDERSTANDING OF HOW TO FORTIFY 145 00:06:00,414 --> 00:06:02,049 THE BODY'S NATURAL DEFENSES 146 00:06:02,049 --> 00:06:06,253 AGAINST CHRONIC LUNG DISEASES. 147 00:06:06,253 --> 00:06:08,522 JOIN DR. KALHAN, AND 148 00:06:08,522 --> 00:06:10,124 DR. [INDISCERNIBLE] A RENOUNCED 149 00:06:10,124 --> 00:06:11,726 RESEARCHER IN IMMUNOLOGY AND 150 00:06:11,726 --> 00:06:12,426 RESPIRATORY DISEASES. 151 00:06:12,426 --> 00:06:15,096 HE IS AT THE FOREFRONT OF 152 00:06:15,096 --> 00:06:17,131 EXPLORING CELLULAR AND MOLECULAR 153 00:06:17,131 --> 00:06:20,668 MECHANISMS THAT CONTRIBUTE TO 154 00:06:20,668 --> 00:06:21,602 CHRONIC LUNG DECS. 155 00:06:21,602 --> 00:06:22,970 HIS RESEARCH DELVES INTO THE 156 00:06:22,970 --> 00:06:24,572 RESILIENCE OF THE NEW SYSTEM AND 157 00:06:24,572 --> 00:06:27,108 IN THE DIRECTION WITH LUNG 158 00:06:27,108 --> 00:06:28,709 PROGENITOR CELLS, AIMING TO 159 00:06:28,709 --> 00:06:32,880 DISCOVER NOVEL THERAPEUTIC 160 00:06:32,880 --> 00:06:35,182 TARGETS BY APPLYING 161 00:06:35,182 --> 00:06:36,450 [INDISCERNIBLE] TECHNIQUES SUCH 162 00:06:36,450 --> 00:06:38,619 AS [INDISCERNIBLE], SEEKS TO 163 00:06:38,619 --> 00:06:40,788 STRENGTHENS THE RESILIENCE OF 164 00:06:40,788 --> 00:06:42,823 LUNG TISSUE, ULTIMATELY 165 00:06:42,823 --> 00:06:44,058 IMPROVING OUTCOMES FOR PATIENTS 166 00:06:44,058 --> 00:06:45,092 WITH LUNG DECS. 167 00:06:45,092 --> 00:06:46,527 TOGETHER OUR CO-CHAIRS BRING A 168 00:06:46,527 --> 00:06:49,230 WEALTH OF EXPERTISE AND A SHARED 169 00:06:49,230 --> 00:06:50,164 VISION ON ENHANCING RESILIENCE 170 00:06:50,164 --> 00:06:52,266 AS A NEEDS TO COMBAT THE EARLY 171 00:06:52,266 --> 00:06:54,668 ONSET OF CHRONIC LUNG DISEASES. 172 00:06:54,668 --> 00:06:58,739 THEIR LEADERSHIP WILL GUIDE US 173 00:06:58,739 --> 00:07:01,475 TOGETHER TOWARDS MINIMAL 174 00:07:01,475 --> 00:07:02,309 DISCUSSIONS, MEANINGFUL 175 00:07:02,309 --> 00:07:03,310 DISCUSSIONS AND SOLUTIONS. 176 00:07:03,310 --> 00:07:05,046 THANKS, YOU ALL FOR JOINING US 177 00:07:05,046 --> 00:07:05,246 TODAY. 178 00:07:05,246 --> 00:07:07,448 I LOOK FORWARD TO THE 179 00:07:07,448 --> 00:07:09,216 COLLABORATIVE EFFORTS AND 180 00:07:09,216 --> 00:07:10,151 VALUABLE EXCHANGES THAT WILL 181 00:07:10,151 --> 00:07:11,419 TAKE PLACE DURING THE WORKSHOP 182 00:07:11,419 --> 00:07:14,855 AS WE WORK TOGETHER TO BUILD A 183 00:07:14,855 --> 00:07:17,691 MORE RESILIENT FUTURE FOR LUNG 184 00:07:17,691 --> 00:07:18,059 HEALTH. 185 00:07:18,059 --> 00:07:26,700 RAVI AND JOSE, TAKE IT AWAY. 186 00:07:26,700 --> 00:07:28,302 >> THANK YOU VERY MUCH 187 00:07:28,302 --> 00:07:30,738 DR. GOMEZ, AND DR. LU FOR THE 188 00:07:30,738 --> 00:07:31,539 NICE INTRODUCTION. 189 00:07:31,539 --> 00:07:34,542 I WILL KEEP MY OPENING REMARKS 190 00:07:34,542 --> 00:07:37,411 BRIEF, JUST TO HELP INTRODUCE 191 00:07:37,411 --> 00:07:41,882 RAVI HERE TO SET THE STAGE. 192 00:07:41,882 --> 00:07:44,185 I ACTUALLY FIRST MET RAVI IN THE 193 00:07:44,185 --> 00:07:46,420 PLANNING OF THIS SYMPOSIUM AND I 194 00:07:46,420 --> 00:07:49,123 WAS WONDERING, YOU KNOW KIND OF 195 00:07:49,123 --> 00:07:50,157 HOW CHRISTIAN AND QING HAD 196 00:07:50,157 --> 00:07:54,662 THOUGHT TO BRING US TOGETHER. 197 00:07:54,662 --> 00:07:56,497 AND IN THE EVOLUTION OF THE 198 00:07:56,497 --> 00:07:57,965 PLANNING FOR THIS, IT BECAME 199 00:07:57,965 --> 00:07:59,567 CLEAR THERE'S A VERY INTERESTING 200 00:07:59,567 --> 00:08:04,472 GAP TO EXPLORE BETWEEN TAKING AN 201 00:08:04,472 --> 00:08:05,106 EPIDEMIOLOGICAL AND POPULATION 202 00:08:05,106 --> 00:08:08,375 HEALTH VIEW ON THESE ISSUES OF 203 00:08:08,375 --> 00:08:10,444 CHRONIC LUNG DISEASES AND TYING 204 00:08:10,444 --> 00:08:13,013 IT TO THE EMERGENT WORK ON OUR 205 00:08:13,013 --> 00:08:14,215 UNDERSTANDING OF LUNG PROGENITOR 206 00:08:14,215 --> 00:08:16,984 CELLS AND HOW THEY CAN HELP US 207 00:08:16,984 --> 00:08:18,686 TO UNDERSTAND AND HOPEFULLY 208 00:08:18,686 --> 00:08:21,122 BUILD A MORE RESILIENT LUNG 209 00:08:21,122 --> 00:08:22,490 ECOSYSTEM. 210 00:08:22,490 --> 00:08:26,193 NOW, THE WORD RESILIENT MAY BE 211 00:08:26,193 --> 00:08:27,495 NEW FOR ME, MAYBE NEW FOR OTHERS 212 00:08:27,495 --> 00:08:31,532 IN THE AUDIENCE AND I THINK THE 213 00:08:31,532 --> 00:08:33,134 IDEA OF RESILIENCE IS SOMETHING 214 00:08:33,134 --> 00:08:35,236 WE WILL HAVE TO CAREFULLY 215 00:08:35,236 --> 00:08:37,538 EXPLORE OVER THE NEXT COUPLE OF 216 00:08:37,538 --> 00:08:39,974 DAYS, BOTH IN TERMS OF HOW WE 217 00:08:39,974 --> 00:08:41,609 ALL USE THE WOORDER AND HOW WE 218 00:08:41,609 --> 00:08:44,378 DEFINE IT AND THE MOLECULAR AND 219 00:08:44,378 --> 00:08:45,880 CELLULAR AND SCALING BACK OUT TO 220 00:08:45,880 --> 00:08:47,414 WHAT IT ACTUALLY MEANS TO NOT 221 00:08:47,414 --> 00:08:49,350 ONLY REBUILD THE LUNGS BUT ALSO 222 00:08:49,350 --> 00:08:50,851 RESILIENT COMMUNITY WHEN IS IT 223 00:08:50,851 --> 00:08:54,355 COMES TO LUNG HEALTH. 224 00:08:54,355 --> 00:08:59,827 SO I CAN GIVE A FEW INTRODUCTORY 225 00:08:59,827 --> 00:09:00,861 NOTES ON RAVI. 226 00:09:00,861 --> 00:09:10,271 SO RAVI IS CURRENTLY THE LOUIS 227 00:09:10,271 --> 00:09:15,242 SISM SON, AT THE FINESCHOOL 228 00:09:15,242 --> 00:09:17,077 MESSAGE AND FOCUSED ON LIFE 229 00:09:17,077 --> 00:09:18,345 COURSE TRANSITIONS FROM 230 00:09:18,345 --> 00:09:19,413 RESPIRATORY HEALTH TO CHRONIC 231 00:09:19,413 --> 00:09:20,581 LUNG DISEASE, OF COURSE 232 00:09:20,581 --> 00:09:22,183 SOMETHING VERY CENTRAL FOR THIS 233 00:09:22,183 --> 00:09:32,726 WORKSHOP HERE, AND TO HELP US -- 234 00:10:10,531 --> 00:10:14,868 I WILL HAND IT OVER TO DR. RAVI 235 00:10:14,868 --> 00:10:16,637 KALHAN TO GIVE THE BRIEF KEY 236 00:10:16,637 --> 00:10:18,038 NOTE HERE TO SET THE STAGE FOR 237 00:10:18,038 --> 00:10:19,940 THE WORKSHOP. 238 00:10:19,940 --> 00:10:20,874 SO PLEASE, RAVI. 239 00:10:20,874 --> 00:10:23,744 >> THANKS SO MUCH JOSE AND 240 00:10:23,744 --> 00:10:24,812 CHRISTIAN AND QING AND GIVING ME 241 00:10:24,812 --> 00:10:27,481 THE OPPORTUNITY TO CO-CHAIR AND 242 00:10:27,481 --> 00:10:28,182 GIVING OPENING FRAMEWORK AROUND 243 00:10:28,182 --> 00:10:29,817 HOW WE CAN THINK ABOUT 244 00:10:29,817 --> 00:10:31,986 RESILIENCE IN THE CONTEXT OF 245 00:10:31,986 --> 00:10:32,786 CHRONIC LUNG DISEASE. 246 00:10:32,786 --> 00:10:36,724 THE NEXT SLIDE WOULD BE GREAT. 247 00:10:36,724 --> 00:10:38,792 SO THIS IS A LITTLE BIT OF A 248 00:10:38,792 --> 00:10:40,261 TALL ORDER TO DEFINE RESILIENCE 249 00:10:40,261 --> 00:10:44,064 WHICH I THINK IS A CRITICAL STEP 250 00:10:44,064 --> 00:10:44,898 TO PROMOTE RESPIRATORY HEALTH. 251 00:10:44,898 --> 00:10:47,901 I KIND OF FEEL LIKE A CLINICAL 252 00:10:47,901 --> 00:10:49,270 EPIDEMIOLOGIST AND A SEA OF 253 00:10:49,270 --> 00:10:50,437 DISCOVERY SCIENTISTS SO I WILL 254 00:10:50,437 --> 00:10:51,905 ASPIRE TO GIVE YOU A FRAMEWORK 255 00:10:51,905 --> 00:10:53,607 FOR WHY WE NEED TO THINK ABOUT 256 00:10:53,607 --> 00:10:56,710 THIS CLINICALLY, HOW WE CAN 257 00:10:56,710 --> 00:10:57,711 DEFINE RESPIRATORY HEALTH AND 258 00:10:57,711 --> 00:11:00,481 THEN SHIFT OUR 2-DAY 259 00:11:00,481 --> 00:11:05,653 CONVERSATION TOWARD RESILIENCE. 260 00:11:05,653 --> 00:11:06,687 NEXT SLIDE. 261 00:11:06,687 --> 00:11:08,455 SO WHEN WE DEFINE RESILIENCE, IT 262 00:11:08,455 --> 00:11:09,757 SEEMS TO ME THIS TAKES A FEW 263 00:11:09,757 --> 00:11:12,059 STEPS AND WE'RE GOING TO TRY TO 264 00:11:12,059 --> 00:11:13,927 ACCELERATE SOME OF THESE STEPS 265 00:11:13,927 --> 00:11:14,161 QUICKLY. 266 00:11:14,161 --> 00:11:19,366 SO 1 IS HOW DO WE ACTUALLY 267 00:11:19,366 --> 00:11:19,933 DEFINE RESPIRATORY HEALTH. 268 00:11:19,933 --> 00:11:21,001 WE NEED TO ASK THE QUESTION 269 00:11:21,001 --> 00:11:23,570 WHETHER IT'S POSSIBLE TO PROMOTE 270 00:11:23,570 --> 00:11:24,271 RESPIRATORY HEALTH. 271 00:11:24,271 --> 00:11:25,906 IN MY TIME AS A PULMONARY 272 00:11:25,906 --> 00:11:27,508 POSITION, AND IN NIGH TRAINING 273 00:11:27,508 --> 00:11:29,243 WE'VE OFTEN THOUGHT ABOUT 274 00:11:29,243 --> 00:11:30,511 RESPIRATORY HEALTH AS SOMETHING 275 00:11:30,511 --> 00:11:32,413 THAT ONLY GETS WORSE ACROSS THE 276 00:11:32,413 --> 00:11:33,147 LIFE COURSE. 277 00:11:33,147 --> 00:11:36,216 PEOPLE KIND OF PEAK 1 FUNCTION 278 00:11:36,216 --> 00:11:36,784 AND THEN DECLINE. 279 00:11:36,784 --> 00:11:39,019 I'M GOING TO TRY TO HELP 280 00:11:39,019 --> 00:11:40,154 UNDERSTAND WHAT RESPIRATORY 281 00:11:40,154 --> 00:11:41,622 INVESTIGATORS THINK ABOUT 282 00:11:41,622 --> 00:11:42,323 RESILIENCE TO DATE. 283 00:11:42,323 --> 00:11:44,158 THE ANSWER IS THERE HASN'T BEEN 284 00:11:44,158 --> 00:11:45,559 THAT MUCH THOUGHT FROM THE 285 00:11:45,559 --> 00:11:46,493 CLINICAL COMMUNITY ABOUT 286 00:11:46,493 --> 00:11:47,561 RESILIENCE AT LEAST, AND THEN 287 00:11:47,561 --> 00:11:48,829 ASK THE QUESTION, AND MAYBE SHOW 288 00:11:48,829 --> 00:11:50,331 A LITTLE BIT OF PRELIMINARY 289 00:11:50,331 --> 00:11:51,965 STUFF FROM OUR OWN WORK ABOUT 290 00:11:51,965 --> 00:11:54,401 HOW WE CAN ULTIMATELY DEVELOP 291 00:11:54,401 --> 00:11:58,238 BIOLOGIC DEFINITIONS AND TARGETS 292 00:11:58,238 --> 00:12:00,808 THAT DISTINGUISH SUSCEPTIBILITY 293 00:12:00,808 --> 00:12:04,211 FROM RESILIENCE. 294 00:12:04,211 --> 00:12:04,578 NEXT SLIDE. 295 00:12:04,578 --> 00:12:06,513 SO IF WE THINK ABOUT HOW LUNG 296 00:12:06,513 --> 00:12:08,615 FUNCTION AS BEEN CONCEPTUALIZED 297 00:12:08,615 --> 00:12:10,317 ACROSS PEOPLE'S LIFE COURSE, 298 00:12:10,317 --> 00:12:12,252 WE'VE OFTEN THOUGHT ABOUT 299 00:12:12,252 --> 00:12:12,986 TRAJECTORIES, PEOPLE DEVELOP 300 00:12:12,986 --> 00:12:14,688 THROUGH CHILDHOOD AND THEY REACH 301 00:12:14,688 --> 00:12:15,789 PEAK 1 FUNCTION, THAT'S OFTEN 302 00:12:15,789 --> 00:12:17,591 THOUGHT TO BE IN YOUNG 303 00:12:17,591 --> 00:12:19,126 ADULTHOOD, SOME PEOPLE REACH 304 00:12:19,126 --> 00:12:20,861 HIGHER PEAKS THAN OTHERS, THAT'S 305 00:12:20,861 --> 00:12:23,731 BEEN A POINT OF EMPHASIS IN THE 306 00:12:23,731 --> 00:12:24,665 COPD COMMUNITY LATELY THAT THERE 307 00:12:24,665 --> 00:12:26,200 MIGHT BE PEOPLE WHO HAVE 308 00:12:26,200 --> 00:12:28,035 RESILIENCE BASED ON BETTER LUNG 309 00:12:28,035 --> 00:12:28,869 DEVELOPMENT AND BETTER LUNG 310 00:12:28,869 --> 00:12:31,705 GROWTH THAN OTHERS WHO HAVE LESS 311 00:12:31,705 --> 00:12:34,174 PEAK LUNG FUNCTION. 312 00:12:34,174 --> 00:12:36,477 IT'S BEEN TAUGHT THAT AFTER 313 00:12:36,477 --> 00:12:37,745 MAXIMUM LUNG FUNCTION IS 314 00:12:37,745 --> 00:12:39,947 ACHIEVED WE HAVE AN UNRELENTING 315 00:12:39,947 --> 00:12:42,249 DECLINE IN LUNG FUNCTION, THINGS 316 00:12:42,249 --> 00:12:45,252 ONLY GET WORSE ACCORDING TO THE 317 00:12:45,252 --> 00:12:46,620 DECLINING FEATURES OF 318 00:12:46,620 --> 00:12:47,654 RESPIRATORY HEALTH, BUT THERE 319 00:12:47,654 --> 00:12:48,989 ARE SOME WHO PRESERVE IT MORE 320 00:12:48,989 --> 00:12:51,625 THAN OTHERS, SOME HAVE A DECLINE 321 00:12:51,625 --> 00:12:57,364 THAT DESCENDS TOWARDS DISEASE 322 00:12:57,364 --> 00:12:57,965 ALATHE [INDISCERNIBLE] DISEASE 323 00:12:57,965 --> 00:12:58,399 IN LUNG FUNCTION. 324 00:12:58,399 --> 00:12:59,833 I THINK WE NEED TO SPEND A 325 00:12:59,833 --> 00:13:02,136 LITTLE MORE TIME THINKING ABOUT 326 00:13:02,136 --> 00:13:05,839 THE INTERMEDIATE PHENOTYPE OF 327 00:13:05,839 --> 00:13:06,707 IMPAIRED RESPIRATORY HEALTH. 328 00:13:06,707 --> 00:13:09,109 THAT IS THOSE PEOPLE SEEM TO BE 329 00:13:09,109 --> 00:13:11,912 TILTING IN YELLOW HERE AWAY FROM 330 00:13:11,912 --> 00:13:12,613 IDEAL RESPIRATORY HEALTH, WHAT'S 331 00:13:12,613 --> 00:13:15,115 THE BEST THEY'RE GOING TO BE IN 332 00:13:15,115 --> 00:13:18,852 THEIR LIFE AND WHETHER WE CAN 333 00:13:18,852 --> 00:13:21,822 ACTUALLY INTERSECT THOSE PEOPLE 334 00:13:21,822 --> 00:13:32,266 BY PROMOTING RESILIENCE WHETHER 335 00:13:32,266 --> 00:13:34,668 WE CAN EXPERIENCE IT OR THOSE 336 00:13:34,668 --> 00:13:36,270 WHO EXPERIENCE LUNG IT BUT THEY 337 00:13:36,270 --> 00:13:38,839 DEVIATE ABOUT YOU WE CAN START 338 00:13:38,839 --> 00:13:39,807 TO RESTORE LUNG FUNCTION. 339 00:13:39,807 --> 00:13:43,277 I AM A COPD DOCTOR, I THINK WE 340 00:13:43,277 --> 00:13:44,211 SHOULD DELIVER THE BEST 341 00:13:44,211 --> 00:13:45,646 TREATMENTS TO PEOPLE LIVING WITH 342 00:13:45,646 --> 00:13:45,879 COPD. 343 00:13:45,879 --> 00:13:47,548 I THINK IT WOULD BE BETTER IF WE 344 00:13:47,548 --> 00:13:49,516 COULD INTERCEPT THEIR 345 00:13:49,516 --> 00:13:50,250 UNFAVORABLE TRAJECTORYINGS 346 00:13:50,250 --> 00:13:52,286 BEFORE THEY DESCENDED TOWARD THE 347 00:13:52,286 --> 00:13:53,120 DEVELOPMENT OF EMPHYSEMA AND 348 00:13:53,120 --> 00:13:56,423 THAT'S SORT OF A KEY PARADIGM IN 349 00:13:56,423 --> 00:14:01,328 PROMOTING RESPIRATORY HEALTH. 350 00:14:01,328 --> 00:14:02,129 NEXT SLIDE, PLEASE. 351 00:14:02,129 --> 00:14:04,131 SO WHO'S DONE THIS BEFORE, WELL 352 00:14:04,131 --> 00:14:04,832 CARDIOVASCULAR PEOPLE DO THIS 353 00:14:04,832 --> 00:14:07,835 ALL THE TIME AND THEY TALK A LOT 354 00:14:07,835 --> 00:14:08,569 ABOUT IDEAL CARDIOVASCULAR 355 00:14:08,569 --> 00:14:10,971 HEALTH THROUGH A BALANCE OF 356 00:14:10,971 --> 00:14:11,972 HEALTH PROMOTION, WITH DEC 357 00:14:11,972 --> 00:14:12,906 INTERCEPTION AND BY HEALTH 358 00:14:12,906 --> 00:14:15,008 PROMOTION, THEY THINK ABOUT 359 00:14:15,008 --> 00:14:17,077 BEHAVIORS QUIT SMOKING, BE 360 00:14:17,077 --> 00:14:19,012 ACTIVE, EAT HEALTHY, LOSE SOME 361 00:14:19,012 --> 00:14:20,814 WEIGHT AND THEN THEY THINK ABOUT 362 00:14:20,814 --> 00:14:21,982 HOW TO INTERCEPT DISEASE FOR 363 00:14:21,982 --> 00:14:24,485 THOSE WHO WHO HAVE INDICATORS OF 364 00:14:24,485 --> 00:14:25,185 AWN UNFAVORABLE TRAJECTORY, ALL 365 00:14:25,185 --> 00:14:27,287 OF WHICH HAVE BEEN INFORMED BY 366 00:14:27,287 --> 00:14:29,923 DISCOVERY DEC THROUGH, YOU KNOW 367 00:14:29,923 --> 00:14:32,626 A CENTURY NOW. 368 00:14:32,626 --> 00:14:33,193 CONTROLLING CHOLESTEROL, 369 00:14:33,193 --> 00:14:34,495 MANAGING BLOOD PRESSURE, AND 370 00:14:34,495 --> 00:14:35,329 REDUCING BLOOD SUGAR BECAUSE 371 00:14:35,329 --> 00:14:37,297 THESE ARE THINGS ON THE CAUSAL 372 00:14:37,297 --> 00:14:39,600 PATHWAY TOWARDS DISEASE THAT CAN 373 00:14:39,600 --> 00:14:40,400 ACTUALLY BE INTERCEPTED. 374 00:14:40,400 --> 00:14:42,703 I WILL HAZARD TO SAY WE CAN 375 00:14:42,703 --> 00:14:45,005 PROMOTE HEALTH IN LUNG DEC BY 376 00:14:45,005 --> 00:14:47,007 TELLING PEOPLE TO STOP SMOKING, 377 00:14:47,007 --> 00:14:49,176 WE HAVE DEFICIENT INFORMATION IN 378 00:14:49,176 --> 00:14:50,010 EPIDEMIOLOGIC STUDIESAs WELL 379 00:14:50,010 --> 00:14:51,612 AS DISCOVERY PROGRAMS TO SOME 380 00:14:51,612 --> 00:14:52,679 EXTENT ABOUT ALL THE OTHER 381 00:14:52,679 --> 00:14:56,583 THINGS WE CAN DO TO TRY TO 382 00:14:56,583 --> 00:14:59,419 PROMOTE RES PERATTORY HEALTH 383 00:14:59,419 --> 00:15:03,457 AND DWEPT DEVIATIONS FROM IDEAL 384 00:15:03,457 --> 00:15:04,992 RESPIRATORY HEALTH. 385 00:15:04,992 --> 00:15:05,292 NEXT SLIDE. 386 00:15:05,292 --> 00:15:06,727 SO HOW CAN WE THINK ABOUT TARGET 387 00:15:06,727 --> 00:15:09,363 POPULATIONS IN WHICH WE CAN 388 00:15:09,363 --> 00:15:10,397 PROMOTE REZONING PIRATTORY 389 00:15:10,397 --> 00:15:10,631 HEALTH? 390 00:15:10,631 --> 00:15:11,698 WELL THIS WOIS WORK THAT COMES 391 00:15:11,698 --> 00:15:14,935 FROM OUR GROUP WHERE WE USE A 392 00:15:14,935 --> 00:15:18,338 LARGE EPIDEMIOLOGICAL TODAY 393 00:15:18,338 --> 00:15:20,307 CALLED CARDIA, AN NHLBI 394 00:15:20,307 --> 00:15:22,175 SPONSORED COHORT THAT RECRUIT 395 00:15:22,175 --> 00:15:23,810 THE 18-30 YEAR-OLDS IN 1985 AND 396 00:15:23,810 --> 00:15:25,012 FOLLOWED THEM FOR NEARLY 40 397 00:15:25,012 --> 00:15:25,312 YEARS. 398 00:15:25,312 --> 00:15:27,748 WE ASKED THE QUESTION WHETHER WE 399 00:15:27,748 --> 00:15:29,383 COULD IDENTIFY SUSCEPTIBLE 400 00:15:29,383 --> 00:15:30,884 POPULATIONS, JUST BASED ON A 401 00:15:30,884 --> 00:15:34,021 SIMPLE THING, LIKE THE PRESENCE 402 00:15:34,021 --> 00:15:35,923 OF RESPIRATORY SYMPTOMS WHEN 403 00:15:35,923 --> 00:15:38,659 THEY ARE BUT MEAN AGE 25-27 404 00:15:38,659 --> 00:15:39,359 YEARS OLD. 405 00:15:39,359 --> 00:15:42,496 SO DO YOUNG ADULTS WITH 406 00:15:42,496 --> 00:15:43,196 RESPIRATORY SYMPTOMS DEMONSTRATE 407 00:15:43,196 --> 00:15:44,264 RISK FOR FUTURE DISEASE BECAUSE 408 00:15:44,264 --> 00:15:45,666 WE NEED TO IDENT PIE AND DEFINE 409 00:15:45,666 --> 00:15:49,670 LIKE I SAID BEFORE, WHAT IS 410 00:15:49,670 --> 00:15:50,604 IMPAIRED VERSUS IDEAL 411 00:15:50,604 --> 00:15:52,472 RESPIRATORY HEALTH BECAUSE IF WE 412 00:15:52,472 --> 00:15:53,507 WILL PROMOTE RESILIENCE, WE NEED 413 00:15:53,507 --> 00:15:55,342 TO UNDERSTAND THOSE DIFFERENCES, 414 00:15:55,342 --> 00:15:56,577 RIGHT? 415 00:15:56,577 --> 00:15:58,412 AND IT TURNED OUT THAT 416 00:15:58,412 --> 00:16:01,548 INDIVIDUALS WHO REPORTED 417 00:16:01,548 --> 00:16:05,385 RESPIRATORY SYMPTOMS AT MEAN AGE 418 00:16:05,385 --> 00:16:06,920 25 WERE AT INCREASED RISK WHEN 419 00:16:06,920 --> 00:16:12,225 FOLLOWED FORWARD FOR THE NEXT 420 00:16:12,225 --> 00:16:13,026 20-30 YEARS. 421 00:16:13,026 --> 00:16:14,494 INCREASED RISK FOR OBSTRUCTIVE 422 00:16:14,494 --> 00:16:15,495 LUNG PHYSIOLOGY AND IN THE CASE 423 00:16:15,495 --> 00:16:20,167 OF PEOPLE WHO REPORTED COUGH AND 424 00:16:20,167 --> 00:16:23,236 PHLEGM AT THAT AGE, WERE AT 425 00:16:23,236 --> 00:16:27,474 INCREASED RISK, 1.46 WAS THE 426 00:16:27,474 --> 00:16:30,744 ODDS RATIO, 1.5 FOR THE RATIOS 427 00:16:30,744 --> 00:16:32,946 OF BRONCHITIS OF HAVING CT 428 00:16:32,946 --> 00:16:34,247 EMSEEMA 25 YEARS LATER. 429 00:16:34,247 --> 00:16:36,450 SO THIS INDICATES TO ME THIS IS 430 00:16:36,450 --> 00:16:38,018 A SUSCEPTIBLE POPULATION WHO 431 00:16:38,018 --> 00:16:41,455 MIGHT COMPRISE PART OF A 432 00:16:41,455 --> 00:16:43,357 DEFINITION OF IMPAIRED 433 00:16:43,357 --> 00:16:44,992 RESPIRATORY HEALTH WHO SHOULD BE 434 00:16:44,992 --> 00:16:55,502 TARGETED FOR HEALTH PROMOTION. 435 00:16:55,936 --> 00:16:56,436 NEXT SLIDE. 436 00:16:56,436 --> 00:17:00,273 WHO ELSE IS AT RISK FOR RESPIRAT 437 00:17:00,273 --> 00:17:03,010 ORY DISEASE WHO ARE TARGETED 438 00:17:03,010 --> 00:17:03,577 POPULATIONS? 439 00:17:03,577 --> 00:17:06,480 WELL THOSE IN DISADVANTAGE 440 00:17:06,480 --> 00:17:09,416 NEIGHBORHOODS, WE LOOKEDDA THE 441 00:17:09,416 --> 00:17:11,718 PEOPLE MEAN AGE 28-40, AND 442 00:17:11,718 --> 00:17:12,419 FOLLOWED THEM 15-20 YEARS 443 00:17:12,419 --> 00:17:16,023 FORWARD AND PEOPLE WHO LIVED IN 444 00:17:16,023 --> 00:17:16,690 DISADVANTAGED NEIGHBORHOODS, 445 00:17:16,690 --> 00:17:18,492 INDEPENDENT OF BOTH THEIR 446 00:17:18,492 --> 00:17:21,294 INDIVIDUAL INCOME, AND THEIR 447 00:17:21,294 --> 00:17:22,362 CUMULATIVE PACK THEY'RE SMOKING 448 00:17:22,362 --> 00:17:24,998 WERE INDEED AT GREATER RISK FOR 449 00:17:24,998 --> 00:17:26,066 FUTURE DEVELOPMENT OF EMPHYSEMA 450 00:17:26,066 --> 00:17:34,708 AS WELL AS FUTURE DEVELOPMENT 451 00:17:34,708 --> 00:17:35,742 WITH SPIROMETRY, ANOTHER GROUP 452 00:17:35,742 --> 00:17:37,811 WHO HAVE AT RISK FOR FUTURE 453 00:17:37,811 --> 00:17:38,879 DISEASE AND MAYBE IMPORTANT 454 00:17:38,879 --> 00:17:40,981 PEOPLE TO TARGET FOR RESPIRATORY 455 00:17:40,981 --> 00:17:42,182 HEALTH PROMOTION AND 456 00:17:42,182 --> 00:17:45,686 INTERVENTIONS THAT FOSTER 457 00:17:45,686 --> 00:17:46,353 RESILIENCE. 458 00:17:46,353 --> 00:17:46,653 NEXT SLIDE. 459 00:17:46,653 --> 00:17:49,122 NOW OF COURSE NEIGHBORHOOD 460 00:17:49,122 --> 00:17:50,991 DISADVANTAGE IS AN INTEGRATIVE 461 00:17:50,991 --> 00:17:53,760 MEASURE RIGHT, OF RISK? 462 00:17:53,760 --> 00:17:55,395 IT INVOLVES INCREASED EXPOSURE 463 00:17:55,395 --> 00:17:58,598 TO BIOMASS FUEL, RISK FACTORS, 464 00:17:58,598 --> 00:18:00,033 ASINERATES ARE HIGHER IN -- 465 00:18:00,033 --> 00:18:02,335 ASTHMA RATES ARE HIGHER IN 466 00:18:02,335 --> 00:18:05,205 INDIVIDUAL NEIGHBORHOODS. 467 00:18:05,205 --> 00:18:07,240 INDIVIDUALS BORN PREMATURELY MAY 468 00:18:07,240 --> 00:18:08,809 EXPERIENCE THIS, EARLY LIFE MAY 469 00:18:08,809 --> 00:18:11,278 IMPACT THIS, IMPAIRED GROWTH MAY 470 00:18:11,278 --> 00:18:13,346 EXPERIENCE THIS, AND WE NEED TO 471 00:18:13,346 --> 00:18:18,452 DIVE DEEPER IN HOW THESE FOSTER 472 00:18:18,452 --> 00:18:19,152 DEVIATIONS FROM RESPIRATORY 473 00:18:19,152 --> 00:18:19,386 HEALTH. 474 00:18:19,386 --> 00:18:22,956 BUT IF WE THINK ABOUT 475 00:18:22,956 --> 00:18:24,491 URBANIZATION GLOBALLY, THE 476 00:18:24,491 --> 00:18:25,759 SOCIOECONOMIC DIVIDES THAT 477 00:18:25,759 --> 00:18:27,227 EMERGE, THERE'S A TREMENDOUS 478 00:18:27,227 --> 00:18:28,161 POPULATION WHO WILL REQUIRE OUR 479 00:18:28,161 --> 00:18:31,031 THINK BEING HOW TO INTERVENE 480 00:18:31,031 --> 00:18:32,666 UPON AND PROMOTE RESPIRATORY 481 00:18:32,666 --> 00:18:36,903 HEALTH. 482 00:18:36,903 --> 00:18:37,704 NEXT SLIDE, PLEASE. 483 00:18:37,704 --> 00:18:39,406 SO I WAS TALKING ABOUT BEFORE 484 00:18:39,406 --> 00:18:40,841 HOW WE TAUGHT OUR MEDICAL 485 00:18:40,841 --> 00:18:42,209 STUDENTS AND TRAINEES FOR A LONG 486 00:18:42,209 --> 00:18:44,845 TIME THERE THERE'S THIS 487 00:18:44,845 --> 00:18:45,445 UNRELENTING DECLINE IN LUNG 488 00:18:45,445 --> 00:18:47,380 FUNCTION AND WHEN I WAS SORT OF 489 00:18:47,380 --> 00:18:49,483 EARLIER ON IN MY CAREER, I WAS 490 00:18:49,483 --> 00:18:51,017 LIKE, MAN, IF THAT'S THOUGHT TO 491 00:18:51,017 --> 00:18:52,185 BE TRUE, WE'RE IN BIG TROUBLE 492 00:18:52,185 --> 00:18:55,756 BECAUSE IF YOU CAN'T PROMOTE 493 00:18:55,756 --> 00:18:57,357 RESPAIRATTORY HEALTH SORT OF ON 494 00:18:57,357 --> 00:18:58,425 THE FOUNDATIONAL IDEA THAT 495 00:18:58,425 --> 00:19:00,527 PEOPLE AREN'T GOING TO BUY-INTO 496 00:19:00,527 --> 00:19:02,462 THIS CONCEPT, SO WE ASKED A 497 00:19:02,462 --> 00:19:04,831 QUESTION IN CARDIA, WE ASK 498 00:19:04,831 --> 00:19:08,034 WHETHER PEOPLE WHO PRESERVE 499 00:19:08,034 --> 00:19:10,537 PHYSICAL FITNESS ACTUALLY HAVE 500 00:19:10,537 --> 00:19:12,472 RESILIENCE, IE THEY EXPERIENCE 501 00:19:12,472 --> 00:19:14,875 LESS LUNG FUNCTION DECLINE AND 502 00:19:14,875 --> 00:19:19,679 IT TURNED OUT THEY DID. 503 00:19:19,679 --> 00:19:23,283 IT TURNS OUT, FITNESS EXPERIENCE 504 00:19:23,283 --> 00:19:24,417 LESS LUNG FUNCTION DECLINE 505 00:19:24,417 --> 00:19:25,352 INDEPENDENT OF WHETHER THEY 506 00:19:25,352 --> 00:19:26,620 SMOKE, INDEPENDENT OF WHETHER 507 00:19:26,620 --> 00:19:28,421 THEY GAIN WEIGHT, INDEPENDENT OF 508 00:19:28,421 --> 00:19:30,657 WHERE THEY LIVE AND A VARIETY OF 509 00:19:30,657 --> 00:19:31,792 OTHER CO VARIANTS. 510 00:19:31,792 --> 00:19:34,127 SO INDEED, PERHAPS WE DO HAVE 511 00:19:34,127 --> 00:19:34,928 STRATEGIES TO PROMOTE RESILIENCE 512 00:19:34,928 --> 00:19:38,732 AND WE KNOW THAT EXERCISE AND 513 00:19:38,732 --> 00:19:40,467 FITNESS HAVE BENEFITS, 514 00:19:40,467 --> 00:19:42,068 ANTIINFLAMMATORY BENEFITS OR 515 00:19:42,068 --> 00:19:43,303 THESE GLOBALLY STATED BENEFITS, 516 00:19:43,303 --> 00:19:44,871 PERHAPS WE NEED TO THINK DEEPER 517 00:19:44,871 --> 00:19:46,173 ABOUT HOW TO UNDERSTAND THESE 518 00:19:46,173 --> 00:19:47,707 BENEFITS MORE SO IN THE LUNG, 519 00:19:47,707 --> 00:19:49,342 BUT REALLY I SAY THAT THIS IS A 520 00:19:49,342 --> 00:19:52,512 PARADIGM THAT THERE ARE THINGS 521 00:19:52,512 --> 00:19:55,182 THAT OCCUR THAT DO ATTENUATE 522 00:19:55,182 --> 00:19:55,982 THIS UNRELENTING LUNG FUNCTION 523 00:19:55,982 --> 00:20:00,554 DECLINE AND MAY BE ABLE TO 524 00:20:00,554 --> 00:20:02,155 PROMOTE RESPIRATORY HEALTH. 525 00:20:02,155 --> 00:20:02,455 NEXT SLIDE. 526 00:20:02,455 --> 00:20:04,457 SO IF I WERE TO SUM THIS UP AND 527 00:20:04,457 --> 00:20:05,792 THEN MOVE A LITTLE BIT FORWARD 528 00:20:05,792 --> 00:20:08,094 TO THINKING, A LITTLE BIT MORE 529 00:20:08,094 --> 00:20:09,496 ABOUT RESILIENCE AND 530 00:20:09,496 --> 00:20:11,064 SUSCEPTIBILITY, WE HAVE TO 531 00:20:11,064 --> 00:20:14,301 DEFINE AND UNDERSTAND AN 532 00:20:14,301 --> 00:20:16,169 INTERMEDIATE PHENOTYPE OF 533 00:20:16,169 --> 00:20:16,703 IMPAIRED RESPIRATORY HELT. 534 00:20:16,703 --> 00:20:18,605 ONE WAY IS TO THINK ABOUT LUNG 535 00:20:18,605 --> 00:20:19,539 FUNCTION, LUNG FUNCTION IS 536 00:20:19,539 --> 00:20:22,642 THOUGHT TO BE THE MOST WIDELY 537 00:20:22,642 --> 00:20:27,814 RECOGNIZED INDICATOR OF IDEAL, 538 00:20:27,814 --> 00:20:30,450 AKA RESILIENT, AKA IMPAIRED, AKA 539 00:20:30,450 --> 00:20:31,418 SUSCEPTIBLE RESPIRATORY HEALTH 540 00:20:31,418 --> 00:20:35,155 BUT IT'S MEASUREMENT OUTSIDE OF 541 00:20:35,155 --> 00:20:38,758 THE RESPIRATORY DISEASE IS 542 00:20:38,758 --> 00:20:39,025 DIFFICULT. 543 00:20:39,025 --> 00:20:40,160 WE DO THESE STUDIES OVER AND 544 00:20:40,160 --> 00:20:43,597 OVER AGAIN BUT NO 1 DOES THIS IN 545 00:20:43,597 --> 00:20:46,867 THE CLINICAL POSITIONS OF SINGLE 546 00:20:46,867 --> 00:20:51,471 RISK, AND SINGLE MEASUREMENT OF 547 00:20:51,471 --> 00:20:52,906 SO, IT DOESN'T TELL YOU WHETHER 548 00:20:52,906 --> 00:20:55,976 THEY TARTED LOW, HIGH, 549 00:20:55,976 --> 00:20:56,643 EXPERIENCING ACCELERATED 550 00:20:56,643 --> 00:20:56,877 DECLINE. 551 00:20:56,877 --> 00:21:00,280 SO WE REALLY DO NEED BIOMARKERS 552 00:21:00,280 --> 00:21:01,214 OF IMPAIRED RESPIRATORY HEALTH 553 00:21:01,214 --> 00:21:03,049 TO ALLOW FOR MORE EFFICIENT 554 00:21:03,049 --> 00:21:05,919 IDENT IIVES OF AT-RISK 555 00:21:05,919 --> 00:21:08,688 INDIVIDUALS, PROVIDE MECHANISTIC 556 00:21:08,688 --> 00:21:09,422 INSIGHTS INTO SUSCEPTIBILITY 557 00:21:09,422 --> 00:21:10,457 VERVERSUS RESILIENCE, AND WHAT 558 00:21:10,457 --> 00:21:11,925 WE CALL LUNG HEALTH ENDOTYPES 559 00:21:11,925 --> 00:21:15,061 AND PROVIDE A FRAMEWORK FOR THE 560 00:21:15,061 --> 00:21:16,763 INTERCEPTION OF CHRONIC LUNG 561 00:21:16,763 --> 00:21:20,367 DISEASE BEFORE IT'S CLINICALLY 562 00:21:20,367 --> 00:21:22,035 APPARENT. 563 00:21:22,035 --> 00:21:22,602 NEXT SLIDE. 564 00:21:22,602 --> 00:21:26,806 SO WHEN WE ASK CLINICAL 565 00:21:26,806 --> 00:21:27,874 INVESTIGATORS WHAT A RESILIENT 566 00:21:27,874 --> 00:21:29,142 PERSON IS, WE DON'T HAVE THAT 567 00:21:29,142 --> 00:21:32,746 MUCH INFORMATION BUT THERE IS AN 568 00:21:32,746 --> 00:21:37,217 IMPORTANT PAPER FROM ANITA O IN 569 00:21:37,217 --> 00:21:38,418 SPIROMICS WHERE THEY DEVELOPED 570 00:21:38,418 --> 00:21:39,119 IT YEARS AGO. 571 00:21:39,119 --> 00:21:40,921 WHERE THEY DEVELOPED A CONSENSUS 572 00:21:40,921 --> 00:21:43,523 DEFINITION RECARDING WHAT A 573 00:21:43,523 --> 00:21:45,992 RESILIENT SMOKER IS USING A 574 00:21:45,992 --> 00:21:47,427 MODIFIED DELPH I,A PROACH AND 575 00:21:47,427 --> 00:21:49,729 THEY CAME UP WITH THESE 576 00:21:49,729 --> 00:21:50,297 PARAMETERS. 577 00:21:50,297 --> 00:21:52,399 RESILIENCE IS NOT HAVING COUGH 578 00:21:52,399 --> 00:21:54,100 AND SPUTUM PRODUCTION, SHORTNESS 579 00:21:54,100 --> 00:21:56,870 OF BREATH, LINES UP WITH WHAT WE 580 00:21:56,870 --> 00:22:00,807 REPORTED IN CARDIA, NOT HAVING 581 00:22:00,807 --> 00:22:02,742 RESPIRATORY EXACERBATIONS THINGS 582 00:22:02,742 --> 00:22:04,244 THAT REQUIRED HEALTHCARE FOR 583 00:22:04,244 --> 00:22:06,346 CARTIC O STEROIDS OR 584 00:22:06,346 --> 00:22:08,181 ANTIBIOTICS, NOT HAVING 585 00:22:08,181 --> 00:22:09,816 EMPHYSEMA ON A CT SCAN AND NOT 586 00:22:09,816 --> 00:22:11,451 HAVING AIR TRAPPING ON A CT SCAN 587 00:22:11,451 --> 00:22:13,286 AND THEN NOT HAVING A HIGH 588 00:22:13,286 --> 00:22:14,587 ANNUAL RATE OF DECLEAN IN 1 589 00:22:14,587 --> 00:22:14,854 FUNCTION. 590 00:22:14,854 --> 00:22:16,389 SO IT'S THE ABSENCE OF A WHOLE 591 00:22:16,389 --> 00:22:17,090 LOT OF THINGS. 592 00:22:17,090 --> 00:22:20,660 THAT'S WHAT THEY USED AS THE 593 00:22:20,660 --> 00:22:22,862 DEFINITION FOR RESILIENCE. 594 00:22:22,862 --> 00:22:25,532 AND OF 892 SPIROMICS 595 00:22:25,532 --> 00:22:28,501 PARTICIPANTS WHO HAD NORMAL LUNG 596 00:22:28,501 --> 00:22:29,803 FUNCTION ONLY WOB 49 597 00:22:29,803 --> 00:22:30,737 QUALIFIEDAs RESILIENT AND 598 00:22:30,737 --> 00:22:34,975 AMONG HE'S PEOPLE THINKING 599 00:22:34,975 --> 00:22:36,076 BIOLOGICALLY, THEY DID HAVE 600 00:22:36,076 --> 00:22:40,046 LOWER LEVELS OF THESE 601 00:22:40,046 --> 00:22:42,415 NONSPECIFIC INFLAMMATORY 602 00:22:42,415 --> 00:22:43,850 MARKERS, TNH ALPHA FACTOR 1A AND 603 00:22:43,850 --> 00:22:46,686 THEY WERE LOWER IN RESILIENT 604 00:22:46,686 --> 00:22:48,288 VERSE US FAUN RESILIENT SMOKERS. 605 00:22:48,288 --> 00:22:52,125 NEXT SLIDE. 606 00:22:52,125 --> 00:22:54,127 I THINK WE NEED TO GET DEEPER ON 607 00:22:54,127 --> 00:22:54,828 THIS AND PERHAPS NOT ONLY 608 00:22:54,828 --> 00:22:57,030 KNOWLEDGE ABOUT THE ABSENCE OF 609 00:22:57,030 --> 00:22:59,232 THINGS LIKE EMPHYSEMA AND AIR 610 00:22:59,232 --> 00:23:00,033 TRAPPING, BUT THINK A LITTLE 611 00:23:00,033 --> 00:23:05,405 DEEPER ABOUT HOW WE CAN USE 612 00:23:05,405 --> 00:23:06,539 TECHNOLOGY TO UNDERSTAND EARLIER 613 00:23:06,539 --> 00:23:10,110 THINGS GOING ON IN THE LUNG AND 614 00:23:10,110 --> 00:23:11,011 CLINICAL POPULATION, SO 1 615 00:23:11,011 --> 00:23:12,779 POTENTIAL MAY BE TO USE CT 616 00:23:12,779 --> 00:23:15,048 IMAGING AND THIS IS JUST AN 617 00:23:15,048 --> 00:23:20,754 EXAMPLE OF WHAT OUR 618 00:23:20,754 --> 00:23:22,222 COLLABORATORS AT BRIGHAM AND 619 00:23:22,222 --> 00:23:23,023 UNIVERSITY OF WASHINGTON HAVE 620 00:23:23,023 --> 00:23:24,424 DEVELOPED BUT THEY HAVE THE 621 00:23:24,424 --> 00:23:26,393 ABILITY TO MAKE AN ENTIRE MAP 622 00:23:26,393 --> 00:23:27,594 USING A VARIETY OF FEATURES, 623 00:23:27,594 --> 00:23:30,196 SOME THAT ARE VISIBLE AND SOME 624 00:23:30,196 --> 00:23:32,999 ARE ATTENUATION BASED IN AN 625 00:23:32,999 --> 00:23:33,967 INTEGRATED WAY USING MACHINE 626 00:23:33,967 --> 00:23:34,234 LEARNING. 627 00:23:34,234 --> 00:23:36,102 AND THEY CAN E DENTIFY 628 00:23:36,102 --> 00:23:36,569 INTERESTING FEATURES. 629 00:23:36,569 --> 00:23:38,438 ONE OF THE FEATURES WE REPORTED 630 00:23:38,438 --> 00:23:39,606 ON A BIT, I DON'T HAVE TIME TO 631 00:23:39,606 --> 00:23:42,442 SHARE IT WITH YOU AND NORMAL ARK 632 00:23:42,442 --> 00:23:43,777 PEERING AREAS OF IATTENUATION. 633 00:23:43,777 --> 00:23:46,212 MAYBE WHAT COULD BE INDICATORS 634 00:23:46,212 --> 00:23:47,614 OF THE EARLIEST POINTS OF LUNG 635 00:23:47,614 --> 00:23:49,783 INJURY WERE WORKING HARD TO 636 00:23:49,783 --> 00:23:50,850 UNDERSTAND HOW THOSE POINTS 637 00:23:50,850 --> 00:23:53,720 EVOLVE OVER TIME USING CEREAL 638 00:23:53,720 --> 00:23:55,455 IMAGING AND CARDIA ACTUALLY TO 639 00:23:55,455 --> 00:23:58,024 SEE WHETHER THESE POINTS OF LUNG 640 00:23:58,024 --> 00:24:00,927 INJURY EVOLVE INTO VISUAL CHANGE 641 00:24:00,927 --> 00:24:01,761 OR WHETHER THEY RESOLVE. 642 00:24:01,761 --> 00:24:03,563 AND IF THEY DO RESOLVE, IT GIVES 643 00:24:03,563 --> 00:24:08,134 US A BETTER WAI TO THINK ABOUT 644 00:24:08,134 --> 00:24:09,769 WHO'S REWRILIENT VERSUS 645 00:24:09,769 --> 00:24:10,070 SUSCEPTIBLE. 646 00:24:10,070 --> 00:24:10,570 NEXT SLIDE. 647 00:24:10,570 --> 00:24:11,871 AT THE END OF THE DAY, THOUGH, I 648 00:24:11,871 --> 00:24:14,174 THINK WE'RE GOING TO HAVE TO FOR 649 00:24:14,174 --> 00:24:15,475 CLINICAL POPULATIONS USE 650 00:24:15,475 --> 00:24:17,877 BIOMARKERS, AND THINK ABOUT HOW 651 00:24:17,877 --> 00:24:20,013 TO DEFINE SUSCEPTIBILITY VERSUS 652 00:24:20,013 --> 00:24:20,513 RESILIENCE BIOLOGICALLY. 653 00:24:20,513 --> 00:24:24,017 SO WE STARTED TO DO THIS, AS 654 00:24:24,017 --> 00:24:25,919 PAPERS AND PRESS GABBY, AND 655 00:24:25,919 --> 00:24:27,520 FELLOW AND JUNIOR FACULTY MEMBER 656 00:24:27,520 --> 00:24:30,824 WITH ME AT UC DAVIS DID THIS 657 00:24:30,824 --> 00:24:32,325 WORK WHERE WE ACTUALLY TOOK 658 00:24:32,325 --> 00:24:35,261 ADVANTAGE OF THE LIFE COURSE 659 00:24:35,261 --> 00:24:38,665 TRAJECTORIES OF LUNG FUNCTION IN 660 00:24:38,665 --> 00:24:41,201 CARDIA, TO DEFINE THOSE 661 00:24:41,201 --> 00:24:41,768 EXPERIENCING LUNG FUNCTION 662 00:24:41,768 --> 00:24:47,707 DECLEAN AND THOSE WHO HAD 663 00:24:47,707 --> 00:24:48,842 RESILIENCE, IDEAL SUSTAINED 664 00:24:48,842 --> 00:24:49,676 RESPIRATORY HEALTH. 665 00:24:49,676 --> 00:24:52,412 WE TOOK THESE GROUPS OF PEOPLE 666 00:24:52,412 --> 00:24:59,853 AND WE CAN PROTEOMICS USING THE 667 00:24:59,853 --> 00:25:00,787 SOMA [INDISCERNIBLE], WHETHER WE 668 00:25:00,787 --> 00:25:05,325 COULD TRAIN A PROTEOMIC SCORE ON 669 00:25:05,325 --> 00:25:06,192 SUSCEPTIBLE VERSUS RESILIENCE 670 00:25:06,192 --> 00:25:09,762 AND INDEED, A NUMBER OF PROTEINS 671 00:25:09,762 --> 00:25:13,733 WERE FOUND TO BE ASSOCIATED WITH 672 00:25:13,733 --> 00:25:14,667 SUSCEPTIBILITY VERSUS 673 00:25:14,667 --> 00:25:16,169 RESILIENCE. 674 00:25:16,169 --> 00:25:19,038 WE THEN TOOK THIS PROTEOMIC 675 00:25:19,038 --> 00:25:21,574 SCORE, NEXT SLIDE, AND TESTED IT 676 00:25:21,574 --> 00:25:24,010 IN BOTH UK BIOBANK AND THE COPD 677 00:25:24,010 --> 00:25:27,313 GENE STUDY AND DOCUMENTED THAT 678 00:25:27,313 --> 00:25:28,781 AN INCREASED PROTEOMIC 679 00:25:28,781 --> 00:25:31,618 SUSCEPTIBILITY SCORE WAS 680 00:25:31,618 --> 00:25:34,387 ASSOCIATED WITH FUTURE POOR 681 00:25:34,387 --> 00:25:36,089 RESPIRATORY OUTCOMES, INCIDENCE 682 00:25:36,089 --> 00:25:39,259 IN THE UK BIOBANK, EXACERBATION 683 00:25:39,259 --> 00:25:42,262 AND RISK IN THE COPD GENE, NEXT 684 00:25:42,262 --> 00:25:44,797 SLIDE, AS WELL AS MORTALITY IN 685 00:25:44,797 --> 00:25:45,698 BOTH OF THOSE STUDIES. 686 00:25:45,698 --> 00:25:47,534 SOPHISTICATEDY WE THINK THIS IS 687 00:25:47,534 --> 00:25:48,301 A REALLY PRELIMINARY STEP 688 00:25:48,301 --> 00:25:49,435 FORWARD, TO THINK ABOUT HOW WE 689 00:25:49,435 --> 00:25:51,938 CAN FIND WHAT WE MIGHT THINK OF 690 00:25:51,938 --> 00:25:53,573 AS A CHOLESTEROL LIKE INDICATOR 691 00:25:53,573 --> 00:25:54,774 FOR THE LUNG. 692 00:25:54,774 --> 00:25:56,943 THOSE, A BIOMARKER THAT'S ON 693 00:25:56,943 --> 00:26:00,113 CAUSAL PATHWAY THAT THINKS ABOUT 694 00:26:00,113 --> 00:26:00,980 SUSCEPTIBILITY TO LUNG INJURY 695 00:26:00,980 --> 00:26:05,552 AND FUTURE DISEASE AND THE 696 00:26:05,552 --> 00:26:07,754 ABSENCE OF SUSCEPTIBILITY, I. E. 697 00:26:07,754 --> 00:26:08,054 RESILIENCE. 698 00:26:08,054 --> 00:26:09,756 WE NEED TO DO MUCH MORE WORK TO 699 00:26:09,756 --> 00:26:10,857 UNDERSTAND WHETHER THOSE 700 00:26:10,857 --> 00:26:13,593 BIOMARKERS, WHETHER FROM THE 701 00:26:13,593 --> 00:26:14,494 PROTEOMIC DORPHY PLATFORM ARE 702 00:26:14,494 --> 00:26:15,929 EXPRESSED IN LUNG TISSUE, HOW 703 00:26:15,929 --> 00:26:17,664 THEY RELITE TO SORT OF THE 704 00:26:17,664 --> 00:26:18,631 CAUSAL PATHWAY TOWARDS DISEASE, 705 00:26:18,631 --> 00:26:20,833 WHETHER THE ABSENCE IN THE LUNG 706 00:26:20,833 --> 00:26:22,502 TISSUE IS ACTUALLY INDICATIVE OF 707 00:26:22,502 --> 00:26:23,570 RESILIENCE AND ALL SORTS OF 708 00:26:23,570 --> 00:26:25,205 OTHER THINGS BUT THIS IS AN 709 00:26:25,205 --> 00:26:26,239 INTERESTING FRAMEWORK WE THINK 710 00:26:26,239 --> 00:26:28,541 TO TAKE POPULATION DORPHY AND 711 00:26:28,541 --> 00:26:32,278 APPLY IT TO BIOLOGIC DORPHY 712 00:26:32,278 --> 00:26:33,313 SCIENCE. 713 00:26:33,313 --> 00:26:34,047 NEXT SLIDE. 714 00:26:34,047 --> 00:26:35,381 SO THAT KIND OF WRAPS UP WHAT I 715 00:26:35,381 --> 00:26:36,683 WANT TO SAY IN SETTING THE 716 00:26:36,683 --> 00:26:37,517 FRAMEWORK BUT I WILL LEAVE YOU 717 00:26:37,517 --> 00:26:38,551 WITH A FEW QUESTIONS. 718 00:26:38,551 --> 00:26:40,253 WE NEED TO KNOW WHAT THE TARGET 719 00:26:40,253 --> 00:26:42,655 POPULATIONS FOR US TO STUDY 720 00:26:42,655 --> 00:26:43,590 SUSCEPTIBILITY VERSUS RESILIENCE 721 00:26:43,590 --> 00:26:46,059 ON ARE AND TO THINK REALLY ABOUT 722 00:26:46,059 --> 00:26:48,027 HEALTH PROMOTION INTERVENTIONS 723 00:26:48,027 --> 00:26:48,595 THAT FOSTER RESILIENCE. 724 00:26:48,595 --> 00:26:49,762 WE NEED TO UNDERSTAND WHY AND 725 00:26:49,762 --> 00:26:52,098 HOW THEY WORK AND WE NEED TO USE 726 00:26:52,098 --> 00:26:53,032 THE POWER OF DISCOVERY SCIENCE 727 00:26:53,032 --> 00:27:03,509 TO UNDERSTAND THOSE THINGS. 728 00:27:03,743 --> 00:27:04,744 WE NEED TO HAPPENED AND FIGURE 729 00:27:04,744 --> 00:27:06,512 OUT WHETHER WE CAN FIND TARGETS 730 00:27:06,512 --> 00:27:08,448 FOR INTERCEPTION THAT PROMOTE 731 00:27:08,448 --> 00:27:10,683 RESILIENCE AND HOW WE CAN USE 732 00:27:10,683 --> 00:27:11,951 DISCOVERIES REGARDING THESE 733 00:27:11,951 --> 00:27:15,455 CLINICAL ENDOTYPES TO INFORM OUR 734 00:27:15,455 --> 00:27:16,656 DISCOVERY SCIENCE. 735 00:27:16,656 --> 00:27:18,458 WE NEED TO UNDERSTAND WHICH 736 00:27:18,458 --> 00:27:19,225 TRANSLATIONAL RESEARCH PLATFOR 737 00:27:19,225 --> 00:27:20,960 THE PURPOSES ARE REQUIRED FOR US 738 00:27:20,960 --> 00:27:24,397 TO APPLY FUNDAMENTAL DISCOVERIES 739 00:27:24,397 --> 00:27:25,365 REGARDING PROGENITOR RESILIENCE 740 00:27:25,365 --> 00:27:27,166 TO HUMAN POPULATIONS AND THEN I 741 00:27:27,166 --> 00:27:29,335 WANT TO THINK ABOUT WHETHER 742 00:27:29,335 --> 00:27:32,105 RESILIENCE IS INDEED THE INVERSE 743 00:27:32,105 --> 00:27:32,605 OF SUSCEPTIBILITY. 744 00:27:32,605 --> 00:27:36,743 AND IF IT'S NOT, HOW CAN WE USE 745 00:27:36,743 --> 00:27:40,713 OUR MODEL SYSTEM TO ACTUALLY 746 00:27:40,713 --> 00:27:43,116 UNDERSTAND RESPIRATOR HEALTH 747 00:27:43,116 --> 00:27:44,717 INSTEAD OF ALWAYS FOCUSING ON 748 00:27:44,717 --> 00:27:46,319 THE DEVELOPMENT OF DISEASE? 749 00:27:46,319 --> 00:27:47,954 I THINK I HAVE 1 MORE SLIDE JUST 750 00:27:47,954 --> 00:27:50,256 TO THANK A BUNCH OF PEOPLE, BUT 751 00:27:50,256 --> 00:27:56,529 I WILL LEAVE IT THERE. 752 00:27:56,529 --> 00:27:57,964 AND I AM HAPPY TO MOVE FORWARD 753 00:27:57,964 --> 00:27:58,431 WITH THE WORKSHOP. 754 00:27:58,431 --> 00:27:59,632 IF THERE ARE QUESTIONS, I THINK 755 00:27:59,632 --> 00:28:02,135 WE WITH PUT THEM IN THE CHAT AND 756 00:28:02,135 --> 00:28:03,169 WEAVE THEM THROUGH OUR 757 00:28:03,169 --> 00:28:07,840 DISCUSSION AS TIME IMZ -- GOES. 758 00:28:07,840 --> 00:28:09,475 THANKS SO MUCH FOR YOUR TIME AND 759 00:28:09,475 --> 00:28:11,344 ATTENTION, WE LOOK FORWARD TO A 760 00:28:11,344 --> 00:28:13,980 GREAT WORKSHOP, THANKS AGAIN TO 761 00:28:13,980 --> 00:28:15,815 NHLBI ORGANIZERS AND THANKS TO 762 00:28:15,815 --> 00:28:17,517 JOSE FOR GRACIOUSLY TOLERATING 763 00:28:17,517 --> 00:28:19,319 ME AS A CO-CHAIR. 764 00:28:19,319 --> 00:28:29,295 WE CAN MOVE FORWARD I THINK. 765 00:28:29,295 --> 00:28:35,034 >> OKAY, I THINK WE SHOULD START 766 00:28:35,034 --> 00:28:36,736 BY THANKING RAVI AND JOSE FOR 767 00:28:36,736 --> 00:28:37,337 THE STARTING SPEECH. 768 00:28:37,337 --> 00:28:42,775 NOW WE MOVE TO SESSION 1 769 00:28:42,775 --> 00:28:43,810 TOGETHER WITH [INDISCERNIBLE] 770 00:28:43,810 --> 00:28:45,878 HERE, WE CO WHICH HAVE CHAIRED 771 00:28:45,878 --> 00:28:47,513 THE FIRST SESSION, LONG STEM 772 00:28:47,513 --> 00:28:50,416 PROGENITOR CELL AND THE 773 00:28:50,416 --> 00:28:55,822 MECHANISM OF STRESS RESPONSE 774 00:28:55,822 --> 00:29:00,693 EMPLOY SO SOUR FIRST SPEAKER 775 00:29:00,693 --> 00:29:03,463 DR. SEUNG HYE HAN, ARE YOU HERE? 776 00:29:03,463 --> 00:29:05,264 >> YES, I AM HERE. 777 00:29:05,264 --> 00:29:06,466 >> OH, HERE. 778 00:29:06,466 --> 00:29:09,268 SHE'S ASSISTANT PROFESSOR FROM 779 00:29:09,268 --> 00:29:09,969 NORTHWESTERN UNIVERSITY AND 780 00:29:09,969 --> 00:29:13,106 SHE'S A PHYSICIAN SCIENTISTS. 781 00:29:13,106 --> 00:29:16,709 HER PRIMARY INTEREST IN THE LAB 782 00:29:16,709 --> 00:29:18,411 STUDYING THE MECHANISM 783 00:29:18,411 --> 00:29:21,080 EPITHELIAL REPAIR AND THE REPAIR 784 00:29:21,080 --> 00:29:25,618 OCCUR RESULLING IN FIBROSIS, SO 785 00:29:25,618 --> 00:29:28,688 WITHOUT FURTHER ADO, SEUNG 786 00:29:28,688 --> 00:29:32,792 HYE THE STAGE IS YOURS, THANK 787 00:29:32,792 --> 00:29:32,959 YOU. 788 00:29:32,959 --> 00:29:34,093 >> OKAY, THIS IS ME AND THEN WE 789 00:29:34,093 --> 00:29:38,664 CAN GO TO THE NEXT SLIDE I 790 00:29:38,664 --> 00:29:39,332 THINK. 791 00:29:39,332 --> 00:29:42,301 YES, SO HI, EVERYONE, WELCOME TO 792 00:29:42,301 --> 00:29:43,603 THE WORKSHOP AND WE'RE REALLY 793 00:29:43,603 --> 00:29:47,440 EXCITED TO HEAR MORE ABOUT ALL 794 00:29:47,440 --> 00:29:49,308 THE GREAT TALKS SCHEDULED FOR 795 00:29:49,308 --> 00:29:50,243 THIS WORKSHOP. 796 00:29:50,243 --> 00:29:52,678 YOU JUST HEARD FROM DR. KALHAN 797 00:29:52,678 --> 00:29:54,847 ABOUT THE LUNG HEALTH AND 798 00:29:54,847 --> 00:29:57,150 RESILIENCE FROM THE POPULATION 799 00:29:57,150 --> 00:29:57,717 STUDY PERSPECTIVE. 800 00:29:57,717 --> 00:30:00,953 NOW WE'RE GOING TO SHIFT GEARS A 801 00:30:00,953 --> 00:30:05,558 LITTLE BIT AND FOCUS ON THE MORE 802 00:30:05,558 --> 00:30:09,495 FUNDAMENTAL SCIENCE, MORE 803 00:30:09,495 --> 00:30:11,831 SMALLER VIEW, LUNG STEM AND 804 00:30:11,831 --> 00:30:15,735 PROGENITOR CELL RESILIENCE. 805 00:30:15,735 --> 00:30:16,969 NEXT SLIDE, PLEASE. 806 00:30:16,969 --> 00:30:19,071 SO THE LUNG EPITHELIUM AND 807 00:30:19,071 --> 00:30:21,908 SUSCEPTIBLE TO VIRAL BACTERIAL 808 00:30:21,908 --> 00:30:24,811 AND TOXIC INSULT ACCIDENT, BUT 809 00:30:24,811 --> 00:30:26,446 THIS SUSCEPTIBILITY IS OFFSET BY 810 00:30:26,446 --> 00:30:28,047 A REMARKABLE CAPACITY TO REPAIR 811 00:30:28,047 --> 00:30:30,683 AND GAIN FUNCTION AFTER INJURY 812 00:30:30,683 --> 00:30:34,120 BY STEM PROGENITOR CELLS. 813 00:30:34,120 --> 00:30:35,588 THIS REGENERATE CAPACITY WITH 814 00:30:35,588 --> 00:30:37,990 THE LUNG WAS SEEN RECENTLY IN 815 00:30:37,990 --> 00:30:41,394 MANY PATIENT RECOVERING FROM 816 00:30:41,394 --> 00:30:44,063 SARS-COV-2 IN THE 817 00:30:44,063 --> 00:30:46,332 [INDISCERNIBLE] ANATOMICALLY THE 818 00:30:46,332 --> 00:30:48,000 LONGEST DIVIDED FUNCTIONAL THESE 819 00:30:48,000 --> 00:30:49,268 THINGS BUT CONTINUOUSLY CONNECT 820 00:30:49,268 --> 00:30:50,369 THE REGION. 821 00:30:50,369 --> 00:30:54,440 SO I STOLE SOME PICTURES FROM 822 00:30:54,440 --> 00:30:55,074 DR. MARIA BASIL'S REVIEW PAPER 823 00:30:55,074 --> 00:30:59,445 AND AS YOU CAN SEE IT IS DIVIDED 824 00:30:59,445 --> 00:31:01,280 PROXIMALLY, IN THE BRONCH I AND 825 00:31:01,280 --> 00:31:06,052 THE SMALL AIR WAYS USUAL 826 00:31:06,052 --> 00:31:07,086 BRONCHIAL AREA IN THE 827 00:31:07,086 --> 00:31:12,158 RESPIRATORY AIR WAY AND THE 828 00:31:12,158 --> 00:31:14,794 ALVEOLAR, AND THOSE AREAS HAVE A 829 00:31:14,794 --> 00:31:18,364 DISTINCT EPITHELIAL CELL 830 00:31:18,364 --> 00:31:20,166 POPULATION AND SLIGHTLY 831 00:31:20,166 --> 00:31:21,334 DIFFERENT STEM PROGENITOR STEM 832 00:31:21,334 --> 00:31:22,001 CELL POPULATION. 833 00:31:22,001 --> 00:31:23,002 AND YOU SEE ON THE RIGHT SIDE, 834 00:31:23,002 --> 00:31:26,973 YOU SEE A BUNCH OF VERY MANY 835 00:31:26,973 --> 00:31:31,777 CELL POPULATIONS THAT IS 836 00:31:31,777 --> 00:31:32,378 DISTINCTLY DISTRIBUTED 837 00:31:32,378 --> 00:31:35,615 THROUGHOUT THE AIRWAY. 838 00:31:35,615 --> 00:31:38,317 LATER IN THIS SESSION YOU WILL 839 00:31:38,317 --> 00:31:42,555 HEAR FROM DR. BASIL AND 840 00:31:42,555 --> 00:31:43,189 DR. [INDISCERNIBLE], FOR THOSE, 841 00:31:43,189 --> 00:31:45,658 AND ON MY TALK I WILL FOCUS ON 842 00:31:45,658 --> 00:31:48,327 THE WORK IN OUR REGION AND THE 843 00:31:48,327 --> 00:31:50,363 FACTORS THAT CONTROL EPITHELIAL 844 00:31:50,363 --> 00:31:52,031 STEM CELL FATE WHICH MAY BE A 845 00:31:52,031 --> 00:31:56,469 TARGET TO PROMOTE REWRILIENCE. 846 00:31:56,469 --> 00:31:59,005 NEXT SLIDE. 847 00:31:59,005 --> 00:32:01,073 SO THE ALVEOLAR EPITHELIUM 848 00:32:01,073 --> 00:32:03,376 CONSISTS OF TYPE 1 AND TYPE 2 849 00:32:03,376 --> 00:32:03,609 CELLS. 850 00:32:03,609 --> 00:32:05,578 MANY, MANY STUDY VS SHOWN THAT 851 00:32:05,578 --> 00:32:08,080 TYPE 2 CELLS ARE PARTIA WILY 852 00:32:08,080 --> 00:32:09,615 COMMITTED STEM CELLS THAT CAN 853 00:32:09,615 --> 00:32:11,684 SELF-RENEW AND THEN GIVE RISE TO 854 00:32:11,684 --> 00:32:14,053 TYPE 1 CELLS WHICH IS 855 00:32:14,053 --> 00:32:16,556 RESPONSIBLE FOR THE GAS 856 00:32:16,556 --> 00:32:17,356 EXCHANGE. 857 00:32:17,356 --> 00:32:22,295 SEVERAL SIGNALING PATHWAYS SUCH 858 00:32:22,295 --> 00:32:27,633 AS WNT, AND BETA KACCT TIENIN, 859 00:32:27,633 --> 00:32:33,005 CDC 42, BMP, NOTCH, YAP/TAZ, 860 00:32:33,005 --> 00:32:34,907 HAVE BEEN SUGGESTED TO CONTROL 861 00:32:34,907 --> 00:32:37,343 THIS ATP STEM CELL BEHAVIOR. 862 00:32:37,343 --> 00:32:37,677 NEXT SLIDE. 863 00:32:37,677 --> 00:32:41,147 THANKS TO THE RECENT ADVANCES IN 864 00:32:41,147 --> 00:32:43,115 SINGLE CELL SEQUENCING AND 865 00:32:43,115 --> 00:32:44,283 TECHNOLOGIES, MANY GROUPS 866 00:32:44,283 --> 00:32:46,652 INCLUDING OURS HAVE IDENTIFIED 867 00:32:46,652 --> 00:32:55,428 AND CONFIRMED THE EXISTENCE OF 868 00:32:55,428 --> 00:32:56,262 INTERMEDIATE TRANSITIONAL CELLS 869 00:32:56,262 --> 00:32:59,932 BETWEEN [INDISCERNIBLE] AND 870 00:32:59,932 --> 00:33:01,334 [INDISCERNIBLE] CELL 871 00:33:01,334 --> 00:33:01,734 CHARACTERIZATION. 872 00:33:01,734 --> 00:33:09,742 KERATIN 8 IN MICE, AND CDKN1A 873 00:33:09,742 --> 00:33:10,676 WHICH IS GROWING. 874 00:33:10,676 --> 00:33:13,746 IN THE PATIENT LUNGS WITH IDIO 875 00:33:13,746 --> 00:33:17,083 PATHIC PULMONARY FIBROSIS AND 876 00:33:17,083 --> 00:33:19,619 COVID-19 PNEUMONIA. 877 00:33:19,619 --> 00:33:21,120 NEXT SLIDE PLEASE. 878 00:33:21,120 --> 00:33:22,054 SO PROFESSOR LIDDELOWIOUS 879 00:33:22,054 --> 00:33:24,790 STUDIES HAVE SHOWN THAT SEVERAL 880 00:33:24,790 --> 00:33:27,393 PATHWAYS ARE EMBRACING THE 881 00:33:27,393 --> 00:33:29,228 TRADITIONAL CELL STATUS EMPLOY A 882 00:33:29,228 --> 00:33:31,030 STUDY FROM DR. SHIEWLER'S GROUP 883 00:33:31,030 --> 00:33:35,701 FOUND THAT MANY PATHWAYS RELATED 884 00:33:35,701 --> 00:33:39,038 TO MICROMETABOLISM SUMP 885 00:33:39,038 --> 00:33:41,407 ASOXIDATIVE PHOSPHORYLATION, 886 00:33:41,407 --> 00:33:43,109 EIF2 TARGETS TRANSLATION, TARGET 887 00:33:43,109 --> 00:33:46,846 AND UNFOLDED PROTEIN RESPONSES 888 00:33:46,846 --> 00:33:48,414 ARE UPREGULATED IN TRANSITIONAL 889 00:33:48,414 --> 00:33:51,651 CELL STATE AND IN THE AT1 890 00:33:51,651 --> 00:33:55,021 DIFFERENTIATION. 891 00:33:55,021 --> 00:33:59,258 NEXT SLIDE, PLEASE. 892 00:33:59,258 --> 00:34:04,997 IN ADDITION OUR HUMAN CORE STUDY 893 00:34:04,997 --> 00:34:05,965 SUGGESTS THAT MITOCHONDRIA 894 00:34:05,965 --> 00:34:09,035 COMPLEX 1 MAY BE IN THE 895 00:34:09,035 --> 00:34:11,537 DEVELOPMENT OF PULMONARY 896 00:34:11,537 --> 00:34:12,204 FIBROSIS. 897 00:34:12,204 --> 00:34:12,805 DR. [INDISCERNIBLE] REPORTED 898 00:34:12,805 --> 00:34:14,807 LAST YEAR THAT THE 1 ASSEMBLY 899 00:34:14,807 --> 00:34:17,410 PATHWAY IS ENRICHED IN PATIENT 900 00:34:17,410 --> 00:34:21,814 WITH FAMILIAL PULL MONITOR AREY 901 00:34:21,814 --> 00:34:25,317 FIBROSIS. 902 00:34:25,317 --> 00:34:27,319 NEXT, PLEASE. 903 00:34:27,319 --> 00:34:32,658 SO WE ASKED THE QUESTION DOES 904 00:34:32,658 --> 00:34:34,593 MITOCHONDRIAL METABOLISM CONTROL 905 00:34:34,593 --> 00:34:35,961 LUNG EPITHELIAL STEM PROGENITOR 906 00:34:35,961 --> 00:34:36,662 CELL FATE? 907 00:34:36,662 --> 00:34:37,229 NEXT. 908 00:34:37,229 --> 00:34:41,634 SO WE STARTED WITH A QUESTION, 909 00:34:41,634 --> 00:34:46,172 THAT IS MITOCHONDRIA COMPLEX 1 910 00:34:46,172 --> 00:34:49,008 OR 2, SENTIAL FOR LUNG 911 00:34:49,008 --> 00:34:50,009 DEVELOPMENT. 912 00:34:50,009 --> 00:34:55,114 WE USE SFTPC SYSTEM THAT CRE 913 00:34:55,114 --> 00:34:56,515 COMBINES EMBRYONIC WITH DAY 5 914 00:34:56,515 --> 00:35:00,920 AND WITH [INDISCERNIBLE] AND 915 00:35:00,920 --> 00:35:02,455 SDHD FLOCKS MICE TO COMPLETE 916 00:35:02,455 --> 00:35:04,590 COMPLEX 1 FUNCTION AND COMPLEX 2 917 00:35:04,590 --> 00:35:06,125 FUNCTION RESPECTIVELY EMPLOY SO 918 00:35:06,125 --> 00:35:07,026 THESE MICE, THIS KNOCKOUT MICE 919 00:35:07,026 --> 00:35:11,197 WILL NOT HAVE ANY COMPLEX 1 920 00:35:11,197 --> 00:35:12,565 FUNCTION OR COMPLEX 2 FUNCTION 921 00:35:12,565 --> 00:35:16,802 IN THE DIGITAL LUNG EPITHELIUM 922 00:35:16,802 --> 00:35:20,106 AFTER EMBRYONIC DAY 10.5. 923 00:35:20,106 --> 00:35:20,773 NEXT SLIDE. 924 00:35:20,773 --> 00:35:23,142 SO THE LOSS OF MITOCHONDRIA 925 00:35:23,142 --> 00:35:26,312 COMPLEX 1 FUNCTION BUT NOT 926 00:35:26,312 --> 00:35:30,716 COMPLEX 2 IN THE LUNG EPITHELIUM 927 00:35:30,716 --> 00:35:31,851 RESULT IN POSTNATAL LETHALITY. 928 00:35:31,851 --> 00:35:35,421 SO WHEN WE LOOK AT THIS LUNG 929 00:35:35,421 --> 00:35:36,989 HISTOLOGY ABOUT THIS 930 00:35:36,989 --> 00:35:37,690 [INDISCERNIBLE] KNOCKOUT MICE 931 00:35:37,690 --> 00:35:39,959 WHICH DOESN'T HAVE ANY COMPLEX 932 00:35:39,959 --> 00:35:42,161 LUNG FUNCTION IN THE LUNG 933 00:35:42,161 --> 00:35:44,797 EPITHELIUM, THEY DIDN'T HAVE ANY 934 00:35:44,797 --> 00:35:45,965 INCREASED CELL DEATH OR IMMUNE 935 00:35:45,965 --> 00:35:49,802 CELL FILTRATION BUT RATHER THE 936 00:35:49,802 --> 00:35:53,038 LUNG EPITHELIUM SHOWS VERY 937 00:35:53,038 --> 00:35:55,775 HYPOTROAPIC CELLS. 938 00:35:55,775 --> 00:35:57,910 ESSENTIALLY THEY'RE LONG 939 00:35:57,910 --> 00:35:58,577 EPITHELIAL CELL [INDISCERNIBLE] 940 00:35:58,577 --> 00:35:58,944 WOULD CHANGE. 941 00:35:58,944 --> 00:36:02,748 SO WE WANTED TO KNOW, WHICH PART 942 00:36:02,748 --> 00:36:05,584 OF THE COMPLEX LUNG FUNCTION IS 943 00:36:05,584 --> 00:36:12,057 RESPONSIBLE FOR THIS PHENOTYPE? 944 00:36:12,057 --> 00:36:12,658 NEXT SLIDE. 945 00:36:12,658 --> 00:36:15,628 SO AS YOU SEE IN THE CARTOON AT 946 00:36:15,628 --> 00:36:17,730 THE BOTTOM, COMPLEX LUNG DOES 947 00:36:17,730 --> 00:36:20,266 HAVE ROUGHLY 3 FUNCTION. 948 00:36:20,266 --> 00:36:22,168 IT DOES PUMP UP [INDISCERNIBLE] 949 00:36:22,168 --> 00:36:24,637 THAT EVENTUALLY CONTRIBUTE TO 950 00:36:24,637 --> 00:36:27,072 THE ATP SYNTHESIS, AND 951 00:36:27,072 --> 00:36:29,008 REGENERATE THE REACTIVE OXIDANT 952 00:36:29,008 --> 00:36:30,976 SPECIES AND REGENERATE THE NAD, 953 00:36:30,976 --> 00:36:34,413 SO WE USE THIS NDI 1 PROTEIN, 954 00:36:34,413 --> 00:36:36,215 THIS IS EAST PROTEIN, ESSENTIA 955 00:36:36,215 --> 00:36:37,917 WILY THE EAST VERSION OF COMPLEX 956 00:36:37,917 --> 00:36:40,419 1. 957 00:36:40,419 --> 00:36:44,490 IT DOES THE COMPLEX 1 FUNCTION, 958 00:36:44,490 --> 00:36:46,759 COMPLEX 1, MAMMALIAN COMPLEX 1 959 00:36:46,759 --> 00:36:48,494 FUNCTION WITH ADG REGENERATION 960 00:36:48,494 --> 00:36:50,663 BUT IT DOES NOT PUMP UP THE 961 00:36:50,663 --> 00:36:51,931 PROTON PUMP THEREFORE IT DOESN'T 962 00:36:51,931 --> 00:36:53,332 REALLY ACTUALLY CONTRIBUTE TO 963 00:36:53,332 --> 00:36:56,936 THE ATP SYNTHESIS OR IT DOESN'T 964 00:36:56,936 --> 00:37:02,041 GENERATE THE REACTIVE OXIDANT 965 00:37:02,041 --> 00:37:04,610 SPECIES, SO WE EXPRESS IN THESE 966 00:37:04,610 --> 00:37:06,946 KNOCKOUT MICE TO SEE IF WHICH 967 00:37:06,946 --> 00:37:08,714 FUNCTION OF THE MAMMALIAN 968 00:37:08,714 --> 00:37:11,417 COMPLEX 1 IS CAUSING THIS 969 00:37:11,417 --> 00:37:16,055 PHENOTYPE, IF WE CAN RESCUE THE 970 00:37:16,055 --> 00:37:19,391 LETHALITY OF THIS NDUFS 2 971 00:37:19,391 --> 00:37:21,594 KNOCKOUT MICE BY EXPRESSING NDUF 972 00:37:21,594 --> 00:37:25,464 1, THAT MEANS THAT THE LACK OF 973 00:37:25,464 --> 00:37:28,067 REGENERATION CAUSED THE 974 00:37:28,067 --> 00:37:31,270 PHENOTYPE. 975 00:37:31,270 --> 00:37:31,937 NEXT SLIDE. 976 00:37:31,937 --> 00:37:37,610 SO THE EAST PROTEIN NDI 1 977 00:37:37,610 --> 00:37:40,379 PREVENTS TOTALITY OF NDUFs 2 978 00:37:40,379 --> 00:37:41,447 MICE IN THE PATHOLOGY INDICATING 979 00:37:41,447 --> 00:37:46,952 THAT THE LACK OF OF NAD 980 00:37:46,952 --> 00:37:48,020 REGENERATION, NOT THE SYNTHESIS 981 00:37:48,020 --> 00:37:50,155 OR CHANGES IN REACTIVE OXYGEN 982 00:37:50,155 --> 00:37:53,359 SPECIES CAUSE THE PHENOTYPE OF 983 00:37:53,359 --> 00:37:58,163 THIS COMPLEX 1 KNOCKOUT MICE. 984 00:37:58,163 --> 00:37:59,198 NEXT, PLEASE. 985 00:37:59,198 --> 00:38:02,468 IN ORDER TO UNDERSTAND MORE OF 986 00:38:02,468 --> 00:38:07,039 THE MOLECULAR PHENOTYPE OF THE 987 00:38:07,039 --> 00:38:08,107 ABNORMAL EPITHELIAL CELLS IN 988 00:38:08,107 --> 00:38:11,310 KNOCKOUT MICE, WE PERFORMED AN 989 00:38:11,310 --> 00:38:13,212 RNA SEQ AT POSTNATAL WAY 21 AND 990 00:38:13,212 --> 00:38:16,916 OBSERVED THE TRANSITIONAL CELLS 991 00:38:16,916 --> 00:38:20,586 ARE EXPANDED IN THIS NDUFS2 992 00:38:20,586 --> 00:38:21,053 KNOCKOUT MICE. 993 00:38:21,053 --> 00:38:23,789 THESE CELLS HAVE A SIMILAR 994 00:38:23,789 --> 00:38:26,158 TRANSCRIPTION PROFILE TO THOSE 995 00:38:26,158 --> 00:38:28,460 RECORDED IN MOUSE LUNG INJURY 996 00:38:28,460 --> 00:38:30,396 MODELS EXPRESSING BOTH AT2 ASK 997 00:38:30,396 --> 00:38:33,365 AT1 MARK FIRST AS WELL AS 998 00:38:33,365 --> 00:38:40,773 KERATIN 8 AND CDK N1 A. 999 00:38:40,773 --> 00:38:41,440 NEXT SLIDES. 1000 00:38:41,440 --> 00:38:44,443 SO WE GOT THE LIST OF THE 1001 00:38:44,443 --> 00:38:47,279 INTEGRATED STRESS RESPONSE, IES 1002 00:38:47,279 --> 00:38:49,248 OUR TARGET GENES FROM 1003 00:38:49,248 --> 00:38:50,382 DR. [INDISCERNIBLE] AT 1004 00:38:50,382 --> 00:38:50,749 [INDISCERNIBLE]. 1005 00:38:50,749 --> 00:38:52,685 AND CALCULATED THE ISR 1006 00:38:52,685 --> 00:38:54,320 ENRICHMENT SCORE WHERE THE 1007 00:38:54,320 --> 00:38:56,989 HIGHER SCORE INDICATES A MORE 1008 00:38:56,989 --> 00:39:00,159 ENRICHED ISR GEN SIGNAL TOUR, 1009 00:39:00,159 --> 00:39:01,193 TRANSITIONAL CELLS IN THIS 1010 00:39:01,193 --> 00:39:05,364 KNOCKOUT MICE HAVE VERY HIGH ISR 1011 00:39:05,364 --> 00:39:10,736 ENRICHMENT SCORE. 1012 00:39:10,736 --> 00:39:12,004 NEXT SLIDE. 1013 00:39:12,004 --> 00:39:14,206 SO INTEGRATED STRESS RESPONSE IS 1014 00:39:14,206 --> 00:39:15,941 USUALLY AN ADAPTIVE PROCESS THAT 1015 00:39:15,941 --> 00:39:19,244 IS ACTIVATED BY STRESS, IT HELPS 1016 00:39:19,244 --> 00:39:21,447 THE CELLS ENDURE STRESSFUL 1017 00:39:21,447 --> 00:39:24,817 CONDITIONS AND THEN SOMETIMES IT 1018 00:39:24,817 --> 00:39:31,190 INDUCE APOPTOSIS. 1019 00:39:31,190 --> 00:39:31,890 NEXT. 1020 00:39:31,890 --> 00:39:33,892 HOWEVER THE ISR CAN BE 1021 00:39:33,892 --> 00:39:35,961 PATHOGENIC IF IT IS HYPER 1022 00:39:35,961 --> 00:39:37,196 ACTIVATED OR PERSISTENT. 1023 00:39:37,196 --> 00:39:43,068 SO THE SMALL MOLECULE ISR 1024 00:39:43,068 --> 00:39:44,570 INHIBITOR ISRI, CAN BRING IT 1025 00:39:44,570 --> 00:39:46,405 DOWN TO OPTIMAL LEVELS SO THE 1026 00:39:46,405 --> 00:39:50,709 CELLS CAN BECOME A MORE -- 1027 00:39:50,709 --> 00:39:52,411 THEY'RE THE BEST CONDITION TO GO 1028 00:39:52,411 --> 00:39:54,880 THROUGH THE STRESSFUL SITUATION. 1029 00:39:54,880 --> 00:39:57,282 YOU WILL HEAR MORE ABOUT THE ISR 1030 00:39:57,282 --> 00:39:59,651 INHIBITORS AND THE NEURODISEASE 1031 00:39:59,651 --> 00:40:03,522 FROM DR. HELEN MIRANDA TOMORROW. 1032 00:40:03,522 --> 00:40:04,957 SO STAY TUNED. 1033 00:40:04,957 --> 00:40:06,025 NEXT PLEASE. 1034 00:40:06,025 --> 00:40:09,795 SO, WE WANTED TO KNOW IF THOSE 1035 00:40:09,795 --> 00:40:12,097 HIGHER ISR THAT WE OBSERVED IN 1036 00:40:12,097 --> 00:40:15,034 TRANSITIONAL CELL IS ACTUALLY 1037 00:40:15,034 --> 00:40:17,770 THE CAUSAL PATHWAY TO INDUCE 1038 00:40:17,770 --> 00:40:20,105 THIS PHENOTYPE SO WE 1039 00:40:20,105 --> 00:40:25,844 ADMINISTERED THE ISR INHIBITOR 1040 00:40:25,844 --> 00:40:30,482 TO THIS NDUFS2 MICE, AND ABLE TO 1041 00:40:30,482 --> 00:40:32,851 MODERATE LETHALITY BY 70%. 1042 00:40:32,851 --> 00:40:34,720 THE OUR PATH INDICATE THAT THE 1043 00:40:34,720 --> 00:40:38,390 LACK OF NAD REGENERATION CAUSES 1044 00:40:38,390 --> 00:40:42,161 A POSTNATAL LETHALITY. 1045 00:40:42,161 --> 00:40:43,562 NEXT PLEASE. 1046 00:40:43,562 --> 00:40:47,099 SO WE PROPOSED THIS CONCEPTUAL 1047 00:40:47,099 --> 00:40:48,400 MODEL OF ATP 2 DIFFERENTIATION, 1048 00:40:48,400 --> 00:40:52,438 WE THINK THAT WHEN AT2 CELLS 1049 00:40:52,438 --> 00:40:54,406 BECOME TRANSITIONAL CELLS, THE 1050 00:40:54,406 --> 00:40:57,142 ADAPTIVE ISR, THE ADAPTIVE ISR 1051 00:40:57,142 --> 00:40:59,678 IS ACTIVATED BUT IT IS THE 1052 00:40:59,678 --> 00:41:01,413 ACTIVATED WHEN TRANSITIONAL 1053 00:41:01,413 --> 00:41:05,384 CELLS DIFFERENTIATE INTO AT1 1054 00:41:05,384 --> 00:41:12,591 CELLS. 1055 00:41:12,591 --> 00:41:13,759 NEXT. 1056 00:41:13,759 --> 00:41:17,596 HOWEVER, WITH THE MITOCHONDRIAL 1057 00:41:17,596 --> 00:41:19,098 DYSFUNCTION, SPECIFICALLY 1058 00:41:19,098 --> 00:41:20,866 ELEVATED NAD RATIO, THE 1059 00:41:20,866 --> 00:41:24,470 PATHOLOGIC ISR IS ACTIVATED AND 1060 00:41:24,470 --> 00:41:26,538 THE REMAINS HIGH AND PREVENTING 1061 00:41:26,538 --> 00:41:28,273 TRANSITIONAL CELLS FROM BECOMING 1062 00:41:28,273 --> 00:41:30,309 AT1 CELLS, WE HAVE A PREVIOUSLY 1063 00:41:30,309 --> 00:41:34,413 SHOWN THAT A SMALL MOLECULE 1064 00:41:34,413 --> 00:41:39,151 INHIBITOR OF ISR PROMOTES 82-81 1065 00:41:39,151 --> 00:41:41,286 DIFFERENTIATION AND IMPROVES 1066 00:41:41,286 --> 00:41:44,456 FIBROSIS IN BOTH MICE AND 1067 00:41:44,456 --> 00:41:46,625 ASBESTOS-INDUCED FIBROSIS 1068 00:41:46,625 --> 00:41:47,426 MODELS. 1069 00:41:47,426 --> 00:41:48,861 WE CURRENTLY DON'T KNOW THE 1070 00:41:48,861 --> 00:41:51,196 EXACT UPSTREAM AND THE DOWN 1071 00:41:51,196 --> 00:41:53,165 STREAM PATHWAYS OF THE PATHOLOGY 1072 00:41:53,165 --> 00:41:54,766 OF ISR THAT EFFECTS THE CELL 1073 00:41:54,766 --> 00:41:57,102 FATE AND THAT WE ARE USING 1074 00:41:57,102 --> 00:41:59,404 GENERATEDITTIC MOUSE MODELS TO 1075 00:41:59,404 --> 00:42:05,777 INVESTIGATE THEM. 1076 00:42:05,777 --> 00:42:06,445 NEXT SLIDE. 1077 00:42:06,445 --> 00:42:08,514 SO THE FUTURE DIRECTION WILL BE 1078 00:42:08,514 --> 00:42:12,117 TRYING TO ANSWER THE QUESTION 1079 00:42:12,117 --> 00:42:15,587 HOW DID THE INCREASED RESPONSE 1080 00:42:15,587 --> 00:42:16,388 CONTROL CELLULAR 1081 00:42:16,388 --> 00:42:17,356 DIFFERENTIATION. 1082 00:42:17,356 --> 00:42:19,224 AS YOU SEEN AGAIN SEEING AGAIN 1083 00:42:19,224 --> 00:42:21,059 IN THIS CARTOON THAT THE ISR IS 1084 00:42:21,059 --> 00:42:25,297 ACTIVATED BY 1 OF THE 4 KINASES 1085 00:42:25,297 --> 00:42:28,167 UPON STRESS RESULTING IN 1086 00:42:28,167 --> 00:42:29,368 PHOSPHORYLATION OF EIF-ALPHA AN 1087 00:42:29,368 --> 00:42:32,004 ACTIVATION OF THE ISR, 1088 00:42:32,004 --> 00:42:33,972 EVENTUALLY LEADS TO ESSENTIALLY 1089 00:42:33,972 --> 00:42:38,977 2 PATHWAY, 1 IS THE REDUCTION IF 1090 00:42:38,977 --> 00:42:41,079 GLOBAL PROTEIN TRANSLATION BUT 1091 00:42:41,079 --> 00:42:41,980 SIMULTANEOUSLY INCREASE 1092 00:42:41,980 --> 00:42:45,150 TRANSLATION OF A CERTAIN 1093 00:42:45,150 --> 00:42:45,918 TRANSCRIPTION FACTORS INCLUDING 1094 00:42:45,918 --> 00:42:49,254 ATP 4 AND THEN INCREASED THE 1095 00:42:49,254 --> 00:42:52,424 TRANSCRIPTION OF HOST OF STRESS 1096 00:42:52,424 --> 00:42:55,661 RESPONSE [INDISCERNIBLE] BUT WE 1097 00:42:55,661 --> 00:42:57,963 DON'T KNOW -- HOW, WHAT IS THE 1098 00:42:57,963 --> 00:43:00,365 FIRST QUESTION IS THAT HOW -- 1099 00:43:00,365 --> 00:43:02,467 WHAT IS THE UPSTREAM SIGNALS, 1100 00:43:02,467 --> 00:43:08,006 HOW DOES THE INCREASE IN NAD 1101 00:43:08,006 --> 00:43:08,907 TRIGGER THE ISR. 1102 00:43:08,907 --> 00:43:10,809 THANKS TO THE NHLBI THE PROJECT 1103 00:43:10,809 --> 00:43:12,077 TO ANSWER THIS QUESTION HAS BEEN 1104 00:43:12,077 --> 00:43:13,845 FUNDED SO WE'RE TRYING TO ANSWER 1105 00:43:13,845 --> 00:43:16,114 THIS QUESTION WITH A GENETIC 1106 00:43:16,114 --> 00:43:18,650 MODELS BUT THE NEXT MORE 1107 00:43:18,650 --> 00:43:20,485 IMPORTANT, MORE INTRIGUING 1108 00:43:20,485 --> 00:43:25,857 QUESTION IS IS THE ISR NECESSAY 1109 00:43:25,857 --> 00:43:27,226 FOR CELL DEFERENTIATION, IN 1110 00:43:27,226 --> 00:43:29,528 OTHER WORDS IS IT NECESSARY FOR 1111 00:43:29,528 --> 00:43:31,196 CELL DIFFERENTIATION OR 1112 00:43:31,196 --> 00:43:33,765 ACTIVATION OF OF THE PATHOLOGIC 1113 00:43:33,765 --> 00:43:35,367 ISR IS SUFFICIENT TO CHANGE THE 1114 00:43:35,367 --> 00:43:37,202 CELL FATE. 1115 00:43:37,202 --> 00:43:39,171 WE HAVE LIKE WE USE SOME GENETIC 1116 00:43:39,171 --> 00:43:41,340 MOUSE MODEL TO SHOW THAT 1117 00:43:41,340 --> 00:43:44,309 INDICATE THAT THE PATHOLOGIC ISR 1118 00:43:44,309 --> 00:43:46,712 ACTIVATION MAY BE DIVISION TO 1119 00:43:46,712 --> 00:43:51,116 CHANGE THE CELLS SO HOPEFULLY WE 1120 00:43:51,116 --> 00:43:53,352 CAN REPORT THE RESULT AT SOME 1121 00:43:53,352 --> 00:43:54,353 POINT IN THE PUBLIC FORM SOON 1122 00:43:54,353 --> 00:43:57,756 AND THE NEXT QUESTION IS THIS 1123 00:43:57,756 --> 00:44:00,459 CHANGE IN ISR IN CELL FATE DOES 1124 00:44:00,459 --> 00:44:02,561 THAT LEAD TO THE LUNG PATHOLOGY? 1125 00:44:02,561 --> 00:44:04,296 AND IF SO, WHICH DISEASES DOES 1126 00:44:04,296 --> 00:44:09,901 IT CAUSE A FIEB ROSEIS OR AND 1127 00:44:09,901 --> 00:44:12,537 WHAT'S THE PATHWAY AND WHICH ARM 1128 00:44:12,537 --> 00:44:13,905 OF THE DOWN STREAM PATHWAY OF 1129 00:44:13,905 --> 00:44:17,776 THIS ISR IS RELATED TO OR CAUSE 1130 00:44:17,776 --> 00:44:19,311 THIS PATHOLOGY, AND ALSO THIS -- 1131 00:44:19,311 --> 00:44:23,915 BUT AS I MENTIONED IN THE 1132 00:44:23,915 --> 00:44:24,850 EARLIER SEVERAL PATHWAYS HAVE 1133 00:44:24,850 --> 00:44:27,619 BEEN SUGGESTED TO CONTROL THE 1134 00:44:27,619 --> 00:44:29,187 ATP 2 STEM CELL BEHAVIOR BUT HOW 1135 00:44:29,187 --> 00:44:31,657 IS IT RELATED TO THIS ISR TO 1136 00:44:31,657 --> 00:44:34,559 THOSE OTHER SIGNALING PATHWAYS 1137 00:44:34,559 --> 00:44:35,827 AND HOW DOES IT CROSS TALK TO 1138 00:44:35,827 --> 00:44:37,462 EACH OTHER AND THEN DO THEY ALSO 1139 00:44:37,462 --> 00:44:38,997 CROSS TALK WITH OTHER CELL 1140 00:44:38,997 --> 00:44:41,833 TYPES, 2, AND THEN EVENTUALLY AS 1141 00:44:41,833 --> 00:44:42,768 A PHYSICIAN SCIENTISTS, WE WANT 1142 00:44:42,768 --> 00:44:47,739 TO FIND THE TARGET TO IMPROVE 1143 00:44:47,739 --> 00:44:51,810 OUR HEALTH SO IS THIS 1 OF THE 1144 00:44:51,810 --> 00:44:53,345 CAN WE IDENTIFY THE TARGET IN 1145 00:44:53,345 --> 00:44:56,315 THIS PATHWAY TO IMPROVE THE STEM 1146 00:44:56,315 --> 00:44:57,949 AND THE PROGENITOR RESILIENCE SO 1147 00:44:57,949 --> 00:45:01,653 THAT WE CAN EVENTUALLY OVERALL 1148 00:45:01,653 --> 00:45:05,524 IMPROVE LUNG HEALTH AND THE 1149 00:45:05,524 --> 00:45:07,759 RESILIENCE. 1150 00:45:07,759 --> 00:45:09,928 SO THAT'S MY OVERALL TALK SO FAR 1151 00:45:09,928 --> 00:45:15,400 AND THE NEXT SLIDES IS TO 1152 00:45:15,400 --> 00:45:16,435 ACKNOWLEDGE THE PEOPLE WHO WORK 1153 00:45:16,435 --> 00:45:21,440 WITH ME AND HELP ME TO DO THE 1154 00:45:21,440 --> 00:45:23,608 WORK, SO, I THINK I WILL STOP IN 1155 00:45:23,608 --> 00:45:29,548 HERE AND THEN, WE CAN PROBABLY 1156 00:45:29,548 --> 00:45:31,183 TAKE THE QUESTIONS IN THE 1157 00:45:31,183 --> 00:45:32,818 COMMENTS AT THE END OF THE 1158 00:45:32,818 --> 00:45:35,987 SESSION, I BELIEVE. 1159 00:45:35,987 --> 00:45:39,091 >> ALL QUESTIONS WILL BE 1160 00:45:39,091 --> 00:45:40,692 DISCUSSED IN THE PANEL 1161 00:45:40,692 --> 00:45:46,998 DISCUSSION AFTER THE WHOLE 1162 00:45:46,998 --> 00:45:48,400 SESSION EMPLOY SO THEN I'M GOING 1163 00:45:48,400 --> 00:45:54,406 TO INTRODUCE OUR NEXT SPEAKER 1164 00:45:54,406 --> 00:45:55,941 DR. MARIA BASIL, GOOD FRIEND OF 1165 00:45:55,941 --> 00:45:59,277 MINE AND ASSISTANT PROFESSOR OF 1166 00:45:59,277 --> 00:46:00,645 MEDICINE AT THE UNIVERSITY OF 1167 00:46:00,645 --> 00:46:01,580 PENNSYLVANIA. 1168 00:46:01,580 --> 00:46:02,981 SHE'S A PHYSICIAN-SCIENTIST WHO 1169 00:46:02,981 --> 00:46:08,687 WORKS ON THE COPD I HOPE THAT 1170 00:46:08,687 --> 00:46:12,524 SHE'S HERE, YEAH, I'M HERE AND 1171 00:46:12,524 --> 00:46:15,160 SO SHE HAS BEEN WORKING ON THE 1172 00:46:15,160 --> 00:46:17,662 AIRWAY STEM CELLS ESPECIALLY IN 1173 00:46:17,662 --> 00:46:20,966 HUMAN LUNG DEC AND SHE HAS FOUND 1174 00:46:20,966 --> 00:46:22,768 REMARKABLE STUDIES TO IDENTIFY 1175 00:46:22,768 --> 00:46:24,336 THE NEW TYPES OF AIRWAY 1176 00:46:24,336 --> 00:46:26,705 PROGENITOR CELLS AND THE LINK 1177 00:46:26,705 --> 00:46:27,906 WITH THE HUMAN PATHOLOGY SO 1178 00:46:27,906 --> 00:46:32,811 WE'RE VERY EXCITED TO HEAR ABOUT 1179 00:46:32,811 --> 00:46:39,284 HER TALK TODAY AND THEN IT'S ALL 1180 00:46:39,284 --> 00:46:39,818 YOURS NOW. 1181 00:46:39,818 --> 00:46:41,553 ALL RIGHT, SO THANK YOU FOR THE 1182 00:46:41,553 --> 00:46:43,622 INVITATION TO THE SPEAKERS TODAY 1183 00:46:43,622 --> 00:46:44,723 AND ORGANIZING THE WORKSHOP, 1184 00:46:44,723 --> 00:46:46,892 IT'S A FUN AGENDA AND I'M 1185 00:46:46,892 --> 00:46:47,592 LOOKING FORWARD TO HEARING 1186 00:46:47,592 --> 00:46:48,560 EVERYONE ELSE SPEAK AND YOU CAN 1187 00:46:48,560 --> 00:46:50,962 GO TO THE NEXT SLIDE EMPLOY SO 1188 00:46:50,962 --> 00:46:52,464 BECAUSE I WILL JUMP RIGHT IN AND 1189 00:46:52,464 --> 00:46:53,999 TELL YOU ABOUT MY FAVORITE 1190 00:46:53,999 --> 00:46:56,034 CHRONIC LUNG DEC THEY THINK 1191 00:46:56,034 --> 00:46:57,002 COULD BENEFIT FROM RESILIENCE 1192 00:46:57,002 --> 00:46:58,603 AND I WANT TO FRAME THIS, 1193 00:46:58,603 --> 00:47:00,605 EVERYONE ON THIS TALK KNOWS WHAT 1194 00:47:00,605 --> 00:47:01,907 COPD IS, AND EVERYONE ON THIS 1195 00:47:01,907 --> 00:47:03,175 TALK KNOWS IT'S A BIG PROBLEM 1196 00:47:03,175 --> 00:47:04,709 AND I WANT TO KIND OF FRAME IT 1197 00:47:04,709 --> 00:47:05,911 FOR YOU, THE WAY THAT I THINK 1198 00:47:05,911 --> 00:47:07,979 ABOUT IT, WHICH IS THAT THIS IS 1199 00:47:07,979 --> 00:47:09,080 A REALLY MASSIVE PROBLEM THAT'S 1200 00:47:09,080 --> 00:47:11,049 GOING TO BE INCREASING OVER THE 1201 00:47:11,049 --> 00:47:11,683 NEXT 20 YEARS. 1202 00:47:11,683 --> 00:47:14,052 THIS IS DATA FROM THE CDC AND 1203 00:47:14,052 --> 00:47:16,755 THE W. H. O. SHOWING THAT COPD 1204 00:47:16,755 --> 00:47:17,722 IS INCREDIBLE LOAMACYY PREVALENT 1205 00:47:17,722 --> 00:47:20,992 IN PARTS OF OUR NATION, NOT AN 1206 00:47:20,992 --> 00:47:24,329 ELECTION MAP, JUST A MAP OF COPD 1207 00:47:24,329 --> 00:47:24,629 PREVALENCE. 1208 00:47:24,629 --> 00:47:27,432 PART OF OUR NATION, UP TO 10% OF 1209 00:47:27,432 --> 00:47:30,035 THE ALL ADULLS HAVE BEEN TOLD 1210 00:47:30,035 --> 00:47:32,604 THEY HAVE SOME FORM OF CHRONIC 1211 00:47:32,604 --> 00:47:34,372 PULMONARY DISEASE, AND IT'S THE 1212 00:47:34,372 --> 00:47:35,407 LEADING CAUSE OF DEATH WORLD 1213 00:47:35,407 --> 00:47:37,375 WIDE AND IT'S NOT JUST A 1214 00:47:37,375 --> 00:47:38,410 SMOKER'S DISEASE, WE'VE HEARD 1215 00:47:38,410 --> 00:47:41,913 THAT THAT THERE'S LOTS OF OTHER 1216 00:47:41,913 --> 00:47:44,549 IDEOLOGIES FOR LUNG DEC, LIKE 1217 00:47:44,549 --> 00:47:45,484 AIR POLLUTION, BIOMATTER AND SO 1218 00:47:45,484 --> 00:47:46,218 THIS NUMBER WILL GROW EMPLOY 1219 00:47:46,218 --> 00:47:47,252 NEXT SLIDE ISSUE PLEASE. 1220 00:47:47,252 --> 00:47:49,654 SO I WANT TO JUST WANT TO FRAME 1221 00:47:49,654 --> 00:47:50,822 IT FOR THIS AUDIENCE ABOUT WHY 1222 00:47:50,822 --> 00:47:53,024 WE DO THE WORK THAT WE DO THAT 1223 00:47:53,024 --> 00:47:54,893 THIS IS A BASIC SCIENTIST, I 1224 00:47:54,893 --> 00:47:56,294 THINK ABOUT CELLS AND 1225 00:47:56,294 --> 00:47:57,128 TRANSCRIPTION FACTORS AND CELL 1226 00:47:57,128 --> 00:47:58,730 DIVISION A LOT BUT THIS IS 1227 00:47:58,730 --> 00:47:59,664 REALLY A SOCIAL JUSTICE ISSUE 1228 00:47:59,664 --> 00:48:00,999 AND I THINK IT'S WORTH BRINGING 1229 00:48:00,999 --> 00:48:03,168 UP AS WE DO THE WORK THAT WE DO, 1230 00:48:03,168 --> 00:48:08,073 THAT THIS IS A DISEASE THAT HAD 1231 00:48:08,073 --> 00:48:08,673 DISPROPORTIONATELY AFFECTED 1232 00:48:08,673 --> 00:48:10,342 PATIENTS OF COLOR ACROSS THE 1233 00:48:10,342 --> 00:48:12,077 UNITED STATES AND HAS BEEN 1234 00:48:12,077 --> 00:48:13,245 UNDERDIAGNOSED IN THESE PATIENTS 1235 00:48:13,245 --> 00:48:16,314 AND AS MUCH AS I LIKE TO SEE 1236 00:48:16,314 --> 00:48:17,516 FEMALES CATCH UP TO MALES AND 1237 00:48:17,516 --> 00:48:21,486 ALL SORTS OF WALK ANDS METRICS 1238 00:48:21,486 --> 00:48:22,787 OF LIFE, THIS IS NOT REALLY THE 1239 00:48:22,787 --> 00:48:24,456 GRAPH I WANT TO DISPLAY WHICH IS 1240 00:48:24,456 --> 00:48:26,091 OVER THE LAST 40 YEARS, WOMEN 1241 00:48:26,091 --> 00:48:27,492 HAVE SUCCESSFULLY CAUGHT UP TO 1242 00:48:27,492 --> 00:48:29,928 MEN IN PREVALENCE OF MORTALITY 1243 00:48:29,928 --> 00:48:31,263 FROM COPD. 1244 00:48:31,263 --> 00:48:36,334 AND SO THIS IS LIKE I SAID AN 1245 00:48:36,334 --> 00:48:36,902 ACCELERATING PROBLEM. 1246 00:48:36,902 --> 00:48:39,905 SO WHY DO I THINK ABOUT COPD. 1247 00:48:39,905 --> 00:48:41,773 WELL IT'S REALLY A DEGENERATIVE 1248 00:48:41,773 --> 00:48:42,007 DISEASE. 1249 00:48:42,007 --> 00:48:43,608 YOU DON'T NEED TO BE A 1250 00:48:43,608 --> 00:48:44,676 PATHOLOGIST TO BE ABLE TO LOOK 1251 00:48:44,676 --> 00:48:47,112 AT THAT LUNG AND SAY IT DOESN'T 1252 00:48:47,112 --> 00:48:47,579 LOOK GOOD. 1253 00:48:47,579 --> 00:48:49,447 SO UPPER LOW PREDOMINANT TISSUE, 1254 00:48:49,447 --> 00:48:50,148 DESTRUCTION LEADING TO THESE 1255 00:48:50,148 --> 00:48:53,552 HOLES IN THE LUNG. 1256 00:48:53,552 --> 00:48:54,019 NEXT SLIDE. 1257 00:48:54,019 --> 00:48:56,321 AND THE WAY I THINK ABOUT COPD 1258 00:48:56,321 --> 00:48:58,990 AS A STEM CELL OR PROGENITOR 1259 00:48:58,990 --> 00:49:01,726 CELL BIOLOGIST AS SOMEONE WITH A 1260 00:49:01,726 --> 00:49:02,961 BACKGROUND THIS DEVELOPMENTAL 1261 00:49:02,961 --> 00:49:04,396 BIOLOGY IS HOW IT EXISTS IN 1262 00:49:04,396 --> 00:49:05,997 CONTRAST TO THE FORMS OF INJURY 1263 00:49:05,997 --> 00:49:08,533 FOR EXAMPLE WE JUST HEARD ABOUT 1264 00:49:08,533 --> 00:49:10,135 FROM DR. HAN, SO THIS IS A CAT 1265 00:49:10,135 --> 00:49:13,738 SCAN OF A PATIENT WITH COPD ON 1266 00:49:13,738 --> 00:49:15,473 THE TOP AND VIRAL PNEUMONIA ON 1267 00:49:15,473 --> 00:49:17,309 THE BOTTOM EMPLOY SO BOTH OF 1268 00:49:17,309 --> 00:49:19,177 THESE DISEASES ARE MARKED BY 1269 00:49:19,177 --> 00:49:20,879 PROFOUND DISRUPTION OF TISSUE, 1270 00:49:20,879 --> 00:49:22,714 DISRUPTION OF THE GAS EXCHANGE 1271 00:49:22,714 --> 00:49:25,317 FUNCTION OF THE LUNG AND IN BOTH 1272 00:49:25,317 --> 00:49:28,853 OF THESE THIS ALVEOLAR 1273 00:49:28,853 --> 00:49:30,488 DISRUPTION AND COMPLETELY 1274 00:49:30,488 --> 00:49:30,889 DESTROYED. 1275 00:49:30,889 --> 00:49:32,591 BUT WHAT'S STRIKING TO ME AS A 1276 00:49:32,591 --> 00:49:33,425 STEM CELL DEVELOPMENTAL 1277 00:49:33,425 --> 00:49:35,427 BIOLOGIST IS THAT PATIENTS WITH 1278 00:49:35,427 --> 00:49:38,763 VIRAL PNEUMONIA, THEY END UP 1279 00:49:38,763 --> 00:49:40,131 INTUBATED IN OUR INTENSIVE CARE 1280 00:49:40,131 --> 00:49:42,200 UNIT AND 6 WEEKS LATER THEY WERE 1281 00:49:42,200 --> 00:49:43,468 CRITICALLY ILL IN THE UNIT, A 1282 00:49:43,468 --> 00:49:45,770 MONTH OR SO LATER THEY WALK IN 1283 00:49:45,770 --> 00:49:48,073 THE CLINIC AND THEY GET A CAT 1284 00:49:48,073 --> 00:49:49,774 SCAN ON THE BOTTOM, THEIR LUNG 1285 00:49:49,774 --> 00:49:52,277 HAS BEEN A WAY TO BE RESILIENT 1286 00:49:52,277 --> 00:49:53,445 TO GET THROUGH THIS INJURY AND 1287 00:49:53,445 --> 00:49:54,646 HEAL ITSELF ON THE OTHER SIDE 1288 00:49:54,646 --> 00:49:57,682 AND NOW MAYBE THEY'RE NOT 1289 00:49:57,682 --> 00:49:59,317 WEARING OXYGEN AND THEY'RE 1290 00:49:59,317 --> 00:50:01,353 RECOVERING FROM THIS RETINAL 1291 00:50:01,353 --> 00:50:02,287 LOCATIONRIMENTAL INJURY. 1292 00:50:02,287 --> 00:50:03,822 COPD DOES NOT WORK THAT WAY. 1293 00:50:03,822 --> 00:50:06,925 NO 1 HAS SEEN A PATIENT WITH 1294 00:50:06,925 --> 00:50:09,227 COPD WHO'S ALVEOLAR TISSUE HAS 1295 00:50:09,227 --> 00:50:12,364 GOTTEN BETTER. 1296 00:50:12,364 --> 00:50:12,897 NEXT SLIDE PLEASE. 1297 00:50:12,897 --> 00:50:14,633 AND SO WHEN I REALLY WANTED TO 1298 00:50:14,633 --> 00:50:16,368 THINK ABOUT HOW I WOULD APPROACH 1299 00:50:16,368 --> 00:50:17,302 THIS PROBLEM, I BECAME VERY 1300 00:50:17,302 --> 00:50:19,070 INTERESTED IN LIGHT OF THAT IN 1301 00:50:19,070 --> 00:50:21,339 THE DISTAL HUMAN AIR WAYS AND 1302 00:50:21,339 --> 00:50:22,874 THAT'S BECAUSE THERE'S BEEN A 1303 00:50:22,874 --> 00:50:26,044 PLETHORA OF DATA CULMINATING 1304 00:50:26,044 --> 00:50:28,446 REALLY IN THIS 2018 GROUP FROM 1305 00:50:28,446 --> 00:50:29,748 BRITISH COLUMBIA AND THE DATA 1306 00:50:29,748 --> 00:50:31,149 WENT ALL THE WAY BACK TO THE 1307 00:50:31,149 --> 00:50:38,023 PRESSURE VALIUM STUDIES IN THE 1308 00:50:38,023 --> 00:50:39,224 1960S, SUGGESTING THAT COPD WAS 1309 00:50:39,224 --> 00:50:42,560 A DISEASE THAT STARTED FIRST IN 1310 00:50:42,560 --> 00:50:43,595 THE DISTAL RESPIRATORY AIR WAYS 1311 00:50:43,595 --> 00:50:45,230 OF THE HUMAN LUNG BUT THIS 1312 00:50:45,230 --> 00:50:51,603 INJURY MAY PROCEED THAT SORT OF 1313 00:50:51,603 --> 00:50:54,105 SIN QUANON OF STIGMA, THAT THING 1314 00:50:54,105 --> 00:50:56,174 WE THINK OF OF EMPHYSEMA AND THE 1315 00:50:56,174 --> 00:50:57,208 DISTAL LUNGS. 1316 00:50:57,208 --> 00:50:58,643 BUT MICE LACK THIS REGION OF THE 1317 00:50:58,643 --> 00:51:00,245 LUNG, THEY DON'T HAVE THIS 1318 00:51:00,245 --> 00:51:01,179 TERTIARY STRUCTURE AND I'M SURE 1319 00:51:01,179 --> 00:51:03,248 MOST PEOPLE ON THIS CALL KIND OF 1320 00:51:03,248 --> 00:51:06,418 KNOW THAT DISTAL AIRWAY 1321 00:51:06,418 --> 00:51:06,751 STRUCTURE. 1322 00:51:06,751 --> 00:51:07,252 NEXT SLIDE. 1323 00:51:07,252 --> 00:51:08,319 SO IN THINKING ABOUT HOW I WAS 1324 00:51:08,319 --> 00:51:10,822 GOING TO START THINKING ABOUT 1325 00:51:10,822 --> 00:51:14,325 THIS, WE AND OTHERS AS WELL, 1326 00:51:14,325 --> 00:51:16,528 INCLUDING GOOD FRIEND OF MY 1327 00:51:16,528 --> 00:51:17,662 [INDISCERNIBLE] MURPHY WHO WAS 1328 00:51:17,662 --> 00:51:19,064 ON THE CALL, WITH 1329 00:51:19,064 --> 00:51:20,231 [INDISCERNIBLE] HO I KNOW IS IN 1330 00:51:20,231 --> 00:51:21,833 THE CALL BECAUSE HE'S IN THIS 1331 00:51:21,833 --> 00:51:24,269 SECTION, SO BEFORE WE KNEW EACH 1332 00:51:24,269 --> 00:51:26,071 OTHER WE WERE WORKING ON A 1333 00:51:26,071 --> 00:51:26,905 SIMILAR QUESTION HAND IN HAND 1334 00:51:26,905 --> 00:51:28,339 AND WE CAME TO VERY SIMILAR 1335 00:51:28,339 --> 00:51:30,608 CONCLUSIONS WHICH IS THAT 1336 00:51:30,608 --> 00:51:35,346 THERE'S A POPULATION OF 1337 00:51:35,346 --> 00:51:36,648 SECRETATTORY CELLS THAT LINE THE 1338 00:51:36,648 --> 00:51:39,651 HUMAN LUNG, THEY CALL THEM 1339 00:51:39,651 --> 00:51:41,619 TRBSCS, WHICH YOU CAN SEE I 1340 00:51:41,619 --> 00:51:42,554 MISSPELLED AT THE BOTTOM OF THE 1341 00:51:42,554 --> 00:51:45,223 SLIDE HERE WE CALL THIS 1342 00:51:45,223 --> 00:51:46,858 RESPIRATORY SECRET CELLS AND 1343 00:51:46,858 --> 00:51:48,927 THESE ARE SITTING IN THIS 1344 00:51:48,927 --> 00:51:50,095 RESPIRATORY AIR WAY OR THIS PART 1345 00:51:50,095 --> 00:51:53,965 OF THE LUNG THAT A COMPLEX 1346 00:51:53,965 --> 00:51:55,266 TERTIARY STRUCTURE DISTINCT TO 1347 00:51:55,266 --> 00:51:56,768 MAMMALS AND WE IDENTIFIED THIS 1348 00:51:56,768 --> 00:51:58,737 RARE POPULATION OF CELLS THAT 1349 00:51:58,737 --> 00:52:01,840 ARE AT2 LIKE BUT EXPRESS AIRWAY 1350 00:52:01,840 --> 00:52:03,675 MARKERS WHICH CALLED AT0S AND WE 1351 00:52:03,675 --> 00:52:05,844 REFER TO AS DOUBLE POSITIVE AT2 1352 00:52:05,844 --> 00:52:06,044 CELLS. 1353 00:52:06,044 --> 00:52:06,344 NEXT SLIDE. 1354 00:52:06,344 --> 00:52:08,446 AND I THINK IMPORTANTLY AS WE 1355 00:52:08,446 --> 00:52:09,981 THINK ABOUT HOW WE'RE GOING TO 1356 00:52:09,981 --> 00:52:10,715 APPROACH THESE QUESTIONS GOING 1357 00:52:10,715 --> 00:52:12,350 FORWARD, HOW WE WANT TO MODEL 1358 00:52:12,350 --> 00:52:13,718 THIS, BOTH OF US TOOK DIFFERENT 1359 00:52:13,718 --> 00:52:15,887 APPROACHES TO LOOK AT THIS 1360 00:52:15,887 --> 00:52:19,657 ACROSS SPECIES, SO I'M SHOWING 1361 00:52:19,657 --> 00:52:24,696 YOU HERE SINGLE CELLS 1362 00:52:24,696 --> 00:52:28,133 [INDISCERNIBLE] WORK ON MACAQUES 1363 00:52:28,133 --> 00:52:31,503 AND WE WORKED TO IDENTIFY THE 1364 00:52:31,503 --> 00:52:33,271 RESPIRATORY BRONCHIAL STRUCTURES 1365 00:52:33,271 --> 00:52:34,205 IN FERRETS AND IDENTIFYING AND 1366 00:52:34,205 --> 00:52:36,875 SHOWING THEY HAVE THE SAME CELL 1367 00:52:36,875 --> 00:52:38,009 POPULATIONS. 1368 00:52:38,009 --> 00:52:39,310 NEXT SLIDE, PLEASE. 1369 00:52:39,310 --> 00:52:40,879 SUBSEQUENT TO THIS, WHAT WE 1370 00:52:40,879 --> 00:52:42,547 REALLY WANTED TO DO WAS LOOK AT 1371 00:52:42,547 --> 00:52:44,149 THESE CELLS, AND ASK WHAT WAS 1372 00:52:44,149 --> 00:52:46,451 THEIR FUNCTION IN THE DISTAL 1373 00:52:46,451 --> 00:52:46,918 HUMAN LUNG. 1374 00:52:46,918 --> 00:52:49,988 AND FOR THIS, I TURN TO 1375 00:52:49,988 --> 00:52:51,489 COLLABORATE WITH DARYL COTTON 1376 00:52:51,489 --> 00:52:53,558 AND ANDREW HOPKINS AND ANDREW 1377 00:52:53,558 --> 00:52:54,826 WILSON AND THEIR WHOLE TEAM UP 1378 00:52:54,826 --> 00:52:57,562 THERE TO ASK THE QUESTION, TO 1379 00:52:57,562 --> 00:53:00,865 TEST THE HYPOTHESIS RATHER THAT 1380 00:53:00,865 --> 00:53:03,268 RAS CELLS COULD ACT AS A CELL 1381 00:53:03,268 --> 00:53:03,968 PROGENITOR. 1382 00:53:03,968 --> 00:53:04,803 THERE ARE SEVERAL REASONS WE 1383 00:53:04,803 --> 00:53:06,104 THOUGHT THIS MIGHT BE TRUE AND 1384 00:53:06,104 --> 00:53:07,972 SO WHAT I'M SHOWING IS A 1385 00:53:07,972 --> 00:53:09,107 PLETHORA OF INFORMATION 1386 00:53:09,107 --> 00:53:09,741 CONDENSED INTO 1 IMAGE WHICH IS 1387 00:53:09,741 --> 00:53:13,411 THAT WE WERE ABLE TO GROW THESE 1388 00:53:13,411 --> 00:53:14,913 RAS-LIKE CELLS DERIVE FRIDAY ES 1389 00:53:14,913 --> 00:53:17,382 CELLS AND AN ESL CULTURE SYSTEM 1390 00:53:17,382 --> 00:53:18,983 AND AIRWAY MEDIA AND THEN IF WE 1391 00:53:18,983 --> 00:53:21,286 ASKED COULD THESE CELLS 1392 00:53:21,286 --> 00:53:23,588 TRANSITION TO ALVEOLAR LIKE 1393 00:53:23,588 --> 00:53:24,756 CELLS USING ALVEOLAR CONDITIONS 1394 00:53:24,756 --> 00:53:26,591 THAT HAD BEEN DEFINED BY 1395 00:53:26,591 --> 00:53:27,792 DERILLEGALS AND ANG LEAN JACOBS 1396 00:53:27,792 --> 00:53:30,228 WE WERE ABLE TO SHOW THESE CELLS 1397 00:53:30,228 --> 00:53:32,297 WITHIN 48-72 HOURS COULD RAPIDLY 1398 00:53:32,297 --> 00:53:34,766 TURN UP THEIR SECRETATTORY CELL 1399 00:53:34,766 --> 00:53:37,001 FATE AND TURN ON THIS ALVEOLAR 1400 00:53:37,001 --> 00:53:38,503 LIKE PROGRAM AND THEY WERE ABLE 1401 00:53:38,503 --> 00:53:42,073 TO EXPRESS THE FACT IN PROTEIN C 1402 00:53:42,073 --> 00:53:45,176 AND ALSO PROCESS SURFACTIN 1403 00:53:45,176 --> 00:53:47,212 PROTEIN C THAT MADE IT LOOK LIKE 1404 00:53:47,212 --> 00:53:50,448 THEY WERE ACTING LIKE AT2 CELLS. 1405 00:53:50,448 --> 00:53:51,950 SO OF COURSE WE WANT TO LOOK AT 1406 00:53:51,950 --> 00:53:53,284 THIS IN LUNG DEC AND SO WHAT ARE 1407 00:53:53,284 --> 00:53:54,819 THE DISEASES THAT WOULD BE THE 1408 00:53:54,819 --> 00:53:56,187 MOST INTERESTED IN FOCUSING ON? 1409 00:53:56,187 --> 00:53:57,622 WELL OF COURSE I TOLD YOU 1410 00:53:57,622 --> 00:54:00,325 EARLIER THAT I'M REALLY 1411 00:54:00,325 --> 00:54:02,427 INTERESTED IN COPD OR CHRONIC 1412 00:54:02,427 --> 00:54:03,027 OBLIGATIONS JUCTIVE PULMONARY 1413 00:54:03,027 --> 00:54:04,095 DISEASE EMPLOY THERE ARE A LOT 1414 00:54:04,095 --> 00:54:06,164 OF OTHER DISEASES THAT OCCUR IN 1415 00:54:06,164 --> 00:54:13,071 THIS REGION OF LUNG THAT WORTH 1416 00:54:13,071 --> 00:54:14,472 CONSIDERING, BRONCHITEIS OBLIT 1417 00:54:14,472 --> 00:54:17,775 RANS SYNDROME, WHICH I WILL COME 1418 00:54:17,775 --> 00:54:19,277 BACK TO, AND LUNG TRANSPLANT, IF 1419 00:54:19,277 --> 00:54:21,045 YOU CAN MAKE IT TO A YEAR WITH 1420 00:54:21,045 --> 00:54:27,886 THE LUNG TRANSPLANT, THE MOST 1421 00:54:27,886 --> 00:54:30,655 LIKELY CAUSE OF BOS, AND THERE 1422 00:54:30,655 --> 00:54:32,857 ARE FORMS OF INTERSTITIAL LUNG 1423 00:54:32,857 --> 00:54:34,692 DISEASE, SOME DATA SUGGIEST 1424 00:54:34,692 --> 00:54:35,760 MAYBE EVEN IPF ORIGINATES IN 1425 00:54:35,760 --> 00:54:40,398 THIS REGION AND WORK FROM JIM 1426 00:54:40,398 --> 00:54:40,899 [INDISCERNIBLE]'S GROUP 1427 00:54:40,899 --> 00:54:42,000 SUGGESTED IT'S A DISEASE THAT WE 1428 00:54:42,000 --> 00:54:44,469 WILL ALL COME TO ENDURE SOME OF 1429 00:54:44,469 --> 00:54:46,104 US EARLIER THAN OTHERS IN AGING 1430 00:54:46,104 --> 00:54:47,538 AND IT ALSO AFFECTS THIS REGION 1431 00:54:47,538 --> 00:54:49,140 OF THE LUNG. 1432 00:54:49,140 --> 00:54:51,643 NEXT SLIDE, PLEASE. 1433 00:54:51,643 --> 00:54:53,711 SO WE STARTED BY LOOKING AT 1434 00:54:53,711 --> 00:54:54,913 CHRONIC OBLIGATIONS JUCT UF 1435 00:54:54,913 --> 00:54:57,282 PULMONARY DEC SO I WILL START 1436 00:54:57,282 --> 00:54:58,683 WITH END STAGE DISEASE, SO WEEZ 1437 00:54:58,683 --> 00:55:01,686 ARE GOING ON FOR TRANSPLANTATION 1438 00:55:01,686 --> 00:55:03,688 FURTHER FOR COPD, AND PATIENTS 1439 00:55:03,688 --> 00:55:05,957 WITH COPD, AND THE SEVERITY TO 1440 00:55:05,957 --> 00:55:07,325 WHICH THEY REQUIRE LUNG 1441 00:55:07,325 --> 00:55:09,560 TRANSPLANT, YOU CAN SEE WE SAW 1442 00:55:09,560 --> 00:55:11,696 AN INCREASE IN THE 3A 2 POSITIVE 1443 00:55:11,696 --> 00:55:15,333 CELLS AND ALSO I CALLED AT0 1444 00:55:15,333 --> 00:55:18,102 CELLS, AND CAN SEE THESE CELLS 1445 00:55:18,102 --> 00:55:20,171 ARE IDENTIFIED BY SUPPRESSION OF 1446 00:55:20,171 --> 00:55:23,241 SURFACTIN PROTEIN C, THEY LOOK A 1447 00:55:23,241 --> 00:55:25,410 LOT LIE AIRCRAFT T2 CELLS BUT 1448 00:55:25,410 --> 00:55:28,246 THEY KRE TINS CRETE 1449 00:55:28,246 --> 00:55:30,315 IMMUNOGLOBULIN 2, WHICH MAKES US 1450 00:55:30,315 --> 00:55:31,883 THINK THEY HAVIZE CHEESE 1451 00:55:31,883 --> 00:55:32,550 CHARACTERISTICS. 1452 00:55:32,550 --> 00:55:33,151 NEXT SLIDE. 1453 00:55:33,151 --> 00:55:34,886 SO IT'S IDENTIFYING SINGLE CELL 1454 00:55:34,886 --> 00:55:36,087 SEQUENCING CAN WE IDENTIFY THEM 1455 00:55:36,087 --> 00:55:37,355 IN SECTIONS FROM DIFFERENT 1456 00:55:37,355 --> 00:55:39,324 PATIENTS, SO AGAIN, IN PATIENTS 1457 00:55:39,324 --> 00:55:41,759 WITH END STAGE COPD WHO ARE AT 1458 00:55:41,759 --> 00:55:43,161 THE POINT OF TRANSPLANTATION, 1459 00:55:43,161 --> 00:55:44,996 COMPARED TO HEALTHY AGED MATCH 1460 00:55:44,996 --> 00:55:46,998 CONTROLS WHO WERE NEVER SMOKERS 1461 00:55:46,998 --> 00:55:50,201 WE SEE THESE DOUBLE POSITIVE OR 1462 00:55:50,201 --> 00:55:54,172 OT0 LIKE CELLS ARE INCREASED IN 1463 00:55:54,172 --> 00:55:54,906 THIS PATIENT POPULATION. 1464 00:55:54,906 --> 00:55:56,507 AND WHAT WE REALLY WANT TO GET 1465 00:55:56,507 --> 00:55:58,710 AT OF COURSE IS THIS SOMETHING 1466 00:55:58,710 --> 00:56:00,211 THAT'S EVOLVING OVER INJURY, IS 1467 00:56:00,211 --> 00:56:01,479 THIS PART OF DEVELOPMENT OF 1468 00:56:01,479 --> 00:56:02,914 DISEASE, SO NEXT SLIDE, PLEASE. 1469 00:56:02,914 --> 00:56:07,485 WE TOOK AN APPROACH WHEREY WE 1470 00:56:07,485 --> 00:56:09,153 USED NORMALLY LUNG DONORS AND 1471 00:56:09,153 --> 00:56:12,790 ASSAY, USED BASED ON REPORTED 1472 00:56:12,790 --> 00:56:13,658 SELF-REPORTED CIGARETTE SMOKE 1473 00:56:13,658 --> 00:56:14,692 EXPOSURE IN PACK YEARS SO 1474 00:56:14,692 --> 00:56:17,462 THERE'S A LOT OF CONFOUNDERS 1475 00:56:17,462 --> 00:56:21,132 HERE, I UNDERSTAND, BUT BASED ON 1476 00:56:21,132 --> 00:56:23,768 REPORTED, SELF-REPORTED P A C 1477 00:56:23,768 --> 00:56:24,902 REPORTERS IN DIFFERENT REGION OF 1478 00:56:24,902 --> 00:56:26,337 THE LUNG, WE ASKED WHAT WAS THE 1479 00:56:26,337 --> 00:56:27,872 PREVALENCE OF THESE CELLS ACROSS 1480 00:56:27,872 --> 00:56:28,639 THE LUNG. 1481 00:56:28,639 --> 00:56:30,942 AND AS WE -- WE OBSERVED WAS 1482 00:56:30,942 --> 00:56:35,813 THAT AS PATIENTS HAD AN 1483 00:56:35,813 --> 00:56:37,415 INCREASED AMOUNT OF SIGNATURE, 1484 00:56:37,415 --> 00:56:40,084 THEY ACCUMULATE MORE OF THESE 1485 00:56:40,084 --> 00:56:40,885 DOUBLE POSITIVE CELLS. 1486 00:56:40,885 --> 00:56:42,387 NEXT SLIDE, AS I MENTIONED THAT 1487 00:56:42,387 --> 00:56:44,255 ASSAY AND THAT EXPERIMENT IS 1488 00:56:44,255 --> 00:56:45,223 INCREDIBLE LOAMACY CONFOUNDED BY 1489 00:56:45,223 --> 00:56:46,357 ALL THE LIMITATIONS THAT COME 1490 00:56:46,357 --> 00:56:48,292 WITH HUMAN SUBJEKSENTIOUS 1491 00:56:48,292 --> 00:56:49,060 SPECIALLY DONATED LUNG RESEARCH 1492 00:56:49,060 --> 00:56:53,031 AND SO WE TURN THEN TO A 1493 00:56:53,031 --> 00:56:54,866 COLLABORATION WITH 1494 00:56:54,866 --> 00:56:55,299 [INDISCERNIBLE], AND 1495 00:56:55,299 --> 00:56:56,034 [INDISCERNIBLE] DOWN AT THE 1496 00:56:56,034 --> 00:57:00,571 UNIVERSITY OF ALABAMA WHERE WE 1497 00:57:00,571 --> 00:57:02,573 LOOKED AT THE FERRET MODEL THAT 1498 00:57:02,573 --> 00:57:03,307 [INDISCERNIBLE] HA PUBLISHED 1499 00:57:03,307 --> 00:57:05,176 MANY YEARS AGO, IF YOU GIVE A 1500 00:57:05,176 --> 00:57:06,577 CIGARETTE OR MANY SIGNATURESIETS 1501 00:57:06,577 --> 00:57:09,113 THEY GEP A LOT OF PATIENTS THAT 1502 00:57:09,113 --> 00:57:11,382 LOOK LOOK THE PATIENTS I TAKE 1503 00:57:11,382 --> 00:57:19,390 CARE OF, WEIGHT LOSS, AIRWAY 1504 00:57:19,390 --> 00:57:20,124 OBSTRUCT, IMMUNE INFILTRATE, AND 1505 00:57:20,124 --> 00:57:25,396 WE FOUND THERE WAS A INCREASE OF 1506 00:57:25,396 --> 00:57:26,898 DOUBLE POSITIVE CELLS IN THIS 1507 00:57:26,898 --> 00:57:27,131 DISEASE. 1508 00:57:27,131 --> 00:57:28,533 SO THIS SUGGIESTED TO US THIS 1509 00:57:28,533 --> 00:57:30,868 MODEL SYSTEM MAY BE 1510 00:57:30,868 --> 00:57:31,536 RECAPITULATING EPITHELIAL 1511 00:57:31,536 --> 00:57:32,637 RESPONSES THAT ARE ANALOGOUS TO 1512 00:57:32,637 --> 00:57:35,907 OUR PATIENTS AS WELL. 1513 00:57:35,907 --> 00:57:36,407 NEXT SLIDE. 1514 00:57:36,407 --> 00:57:39,243 SO I'LL TURN TO ANOTHER CHRONIC 1515 00:57:39,243 --> 00:57:40,178 DISEASE, JUST TO POINT OUT SOME 1516 00:57:40,178 --> 00:57:41,279 OF THE OTHER STUFF THAT WE'VE 1517 00:57:41,279 --> 00:57:44,315 BEEN WORKING ON IN THIS ARENA OF 1518 00:57:44,315 --> 00:57:46,217 THE DISTAL LUNG AND LOOKING AT 1519 00:57:46,217 --> 00:57:47,785 THE RESPONSE OF THE DISTAL LUNG 1520 00:57:47,785 --> 00:57:49,987 IN CHRONIC DISEASE EMPLOY SO 1521 00:57:49,987 --> 00:57:55,960 THIS IS DATA FROM 1522 00:57:55,960 --> 00:57:56,661 BRONCHIALALATED RELATED 1523 00:57:56,661 --> 00:57:58,196 SYNDROME, AND HAS 2 MAIN CAUSES 1524 00:57:58,196 --> 00:58:00,731 AND A FEW OTHER MORE RARE CAUSES 1525 00:58:00,731 --> 00:58:03,701 INCLUDING POST LUNG TRANSPLANT 1526 00:58:03,701 --> 00:58:04,535 AND POST HEMATOPOIETIC 1527 00:58:04,535 --> 00:58:05,036 TRANSPLANT. 1528 00:58:05,036 --> 00:58:07,505 AND YOU SEE WE COMBINED PATIENTS 1529 00:58:07,505 --> 00:58:09,006 FROM BOTH SYNDROMES ALONG WITH A 1530 00:58:09,006 --> 00:58:11,776 SERIES OF AGE AND GENDER MATCHED 1531 00:58:11,776 --> 00:58:12,043 CONTROLS. 1532 00:58:12,043 --> 00:58:14,011 AND WE CAN SEPARATE THESE BY 1533 00:58:14,011 --> 00:58:19,317 THEIR IMMUNE COMPONENT AND THEIR 1534 00:58:19,317 --> 00:58:20,485 NONIMMUNE COMPONENT ASSAY 1535 00:58:20,485 --> 00:58:20,785 SEPARATELY. 1536 00:58:20,785 --> 00:58:21,085 NEXT SLIDE. 1537 00:58:21,085 --> 00:58:24,622 SO WHAT WE WERE REALLY -- WE 1538 00:58:24,622 --> 00:58:25,823 LOOKED AT A BUNCH OF DIFFERENT 1539 00:58:25,823 --> 00:58:27,758 THINGS AND 1 OF THE THINGS WE 1540 00:58:27,758 --> 00:58:29,727 WERE REALLY STRUCK BY IS THAT IN 1541 00:58:29,727 --> 00:58:31,696 THE DISTAL AIRWAY EPITHELIUM AND 1542 00:58:31,696 --> 00:58:33,297 IN PARTICULAR IN THE AIR WAY 1543 00:58:33,297 --> 00:58:35,032 OPERATING GLOBALLIULATION AND IN 1544 00:58:35,032 --> 00:58:36,701 THE ALVEOLAR TYPE 2 POPULATION 1545 00:58:36,701 --> 00:58:38,369 WE SEE DRAMATIC INCREASE IN 1546 00:58:38,369 --> 00:58:41,539 SEVERAL FACTORS 1 OF WHICH IS 1547 00:58:41,539 --> 00:58:43,040 CXCLA OR INTERLEUKIN 8, I WILL 1548 00:58:43,040 --> 00:58:45,243 NOT PLAY THE ROLE OF AN 1549 00:58:45,243 --> 00:58:46,177 IMMUNOLOGIST TODAY BUT 1 OF THE 1550 00:58:46,177 --> 00:58:47,678 THINGS THAT THIS HAS BEEN SHOWN 1551 00:58:47,678 --> 00:58:50,948 TO DO IS RECRUIT SUBSETS OF 1552 00:58:50,948 --> 00:58:52,550 IMMUNE CELLS INCLUDING 1553 00:58:52,550 --> 00:58:53,618 NUTRIFILLS AND T-LYMPHOCYTES AND 1554 00:58:53,618 --> 00:58:55,553 THERE'S BEEN A LOT OF WORK ON 1555 00:58:55,553 --> 00:58:58,656 THE ROLE OF IMMUNE POPULATIONS 1556 00:58:58,656 --> 00:59:00,158 AND OBLIT RANS, AND NEXT SLIDE, 1557 00:59:00,158 --> 00:59:01,893 SO WE WANTED TO LOOK AT WHAT 1558 00:59:01,893 --> 00:59:04,328 WERE THE CELL AND LYMPHOCYTE 1559 00:59:04,328 --> 00:59:06,430 SUBSETS IN PARTICULAR, THAT WERE 1560 00:59:06,430 --> 00:59:07,865 RECRUITED INTO THE DISTAL LOG 1561 00:59:07,865 --> 00:59:11,502 AND THERE HAD BEEN A LOT OF WORK 1562 00:59:11,502 --> 00:59:13,404 BEFORE IN BALL STUDIES FROM MARK 1563 00:59:13,404 --> 00:59:14,906 SNYDER AND OTHERS LOOKING AT 1564 00:59:14,906 --> 00:59:15,873 SIMILAR QUESTIONS AND WHAT WE 1565 00:59:15,873 --> 00:59:18,509 SEE IS THAT IN THE DISTAL AIRWAY 1566 00:59:18,509 --> 00:59:20,378 IMMUNE CELLS, IN OUR PATIENTS 1567 00:59:20,378 --> 00:59:21,913 WITH END STAGE BRONCHIALITEIS, 1568 00:59:21,913 --> 00:59:25,983 SO THESE ARE PATIENTS WHO HAVE 1569 00:59:25,983 --> 00:59:27,418 BRONCHIALITEIS WE SEE 1570 00:59:27,418 --> 00:59:29,654 UPREGULATION IN MANY DIFFERENT 1571 00:59:29,654 --> 00:59:31,088 MARKERS INCLUDING EXHAUSTION 1572 00:59:31,088 --> 00:59:32,990 EFFECTOR AND THESE MARKERS IN 1573 00:59:32,990 --> 00:59:35,526 BLUE CALLED TRM MARKERS OR 1574 00:59:35,526 --> 00:59:37,328 TISSUE RESIDENT MEMORY MARKERS. 1575 00:59:37,328 --> 00:59:39,163 NEXT SLIDE. 1576 00:59:39,163 --> 00:59:46,437 SO WE USE MULTIPLEX 1577 00:59:46,437 --> 00:59:46,971 IMMUNOHISTOCHEMISTRY, I'M 1578 00:59:46,971 --> 00:59:47,705 SHOWING 4 IN THE LUNG, WE CAN 1579 00:59:47,705 --> 00:59:52,243 SEE THIS IS A SEGMENT OF A 1580 00:59:52,243 --> 00:59:53,077 PATIENT FROM BRONCHIAL OBLIT 1581 00:59:53,077 --> 00:59:55,379 RANS, WHERE YOU SEE THE 1582 00:59:55,379 --> 00:59:56,547 INFILTRATES IN THE PARTS OF THE 1583 00:59:56,547 --> 00:59:59,150 LUNG AND YOU CAN SEE THE TRM 1584 00:59:59,150 --> 01:00:00,651 MARKERS OF INHIBITORY AND 1585 01:00:00,651 --> 01:00:01,686 EFFECTED MARKERS AND THIS CO 1586 01:00:01,686 --> 01:00:04,155 EXPRESSION IS SORT OF 1 OF THE 1587 01:00:04,155 --> 01:00:05,690 CLASSICAL DEFINING FEATURES OF 1588 01:00:05,690 --> 01:00:10,194 THESE TRM SUBSETS. 1589 01:00:10,194 --> 01:00:12,763 NEXT SLIDE. 1590 01:00:12,763 --> 01:00:13,598 SO 1 THING WE'VE BEEN DOING IS 1591 01:00:13,598 --> 01:00:17,668 NOT JUST COLLECTING FROM 1592 01:00:17,668 --> 01:00:18,469 PATIENTS WITH BRONCHIALITEIS, 1593 01:00:18,469 --> 01:00:21,239 BUT ALL SORTS OF LUNG ISSUES, SO 1594 01:00:21,239 --> 01:00:23,107 I'M SHOWING TISSUE RESIDENT 1595 01:00:23,107 --> 01:00:25,376 MEMORY SIGNATURE THAT WE DERIVE 1596 01:00:25,376 --> 01:00:28,946 FRIDAY OUR PATIENT SASMEMS AND 1597 01:00:28,946 --> 01:00:30,915 COMPARED IT ACROSS A LARGE 1598 01:00:30,915 --> 01:00:31,949 SMATTERING OF DISEASES ACROSS 1599 01:00:31,949 --> 01:00:33,384 OUR COHORT HERE AND ASKING HOW 1600 01:00:33,384 --> 01:00:35,119 DOES THIS TISSUE MEMORY COMPARE 1601 01:00:35,119 --> 01:00:37,188 IN CD8S AND C, DID 4S ACROSS 1602 01:00:37,188 --> 01:00:38,022 MANY DIFFERENT LUNG DISEASES AND 1603 01:00:38,022 --> 01:00:40,024 WHAT I HOPE YOU CAN SEE IS THAT 1604 01:00:40,024 --> 01:00:41,325 WHILE TRM CELLS HAVE BEEN 1605 01:00:41,325 --> 01:00:43,094 IMPLICATE INDEED A LOT OF 1606 01:00:43,094 --> 01:00:43,794 DISEASES, THAT DISEASE SIGNATURE 1607 01:00:43,794 --> 01:00:46,931 IS VERY HIGH IN OUR PATIENTS 1608 01:00:46,931 --> 01:00:48,499 WITH BRONCHIALITEIS OBLIT RANZ 1609 01:00:48,499 --> 01:00:50,234 AND WE FIND THIS INTERESTING 1610 01:00:50,234 --> 01:00:51,502 THAT'S WORTH FOLLOWING UP ON. 1611 01:00:51,502 --> 01:00:53,104 AND SO NEXT SLIDE. 1612 01:00:53,104 --> 01:00:54,972 WITH THAT, I WILL JUST TAKE A 1613 01:00:54,972 --> 01:00:57,308 SECOND TO SAY THAT COPD AND 1614 01:00:57,308 --> 01:00:59,777 OTHER DISEASES OF THE RESPIRATOR 1615 01:00:59,777 --> 01:01:01,779 AIRWAYS ARE A MAJOR IMPACT AND 1616 01:01:01,779 --> 01:01:03,347 COPD IN PARTICULAR DEFINED BY 1617 01:01:03,347 --> 01:01:05,883 FAILURE OF REGENERATION IN THE 1618 01:01:05,883 --> 01:01:07,051 RESPIRATORY AIRWAY ANDS THERE 1619 01:01:07,051 --> 01:01:08,786 ARE UNIQUE POPULATIONS HERE AND 1620 01:01:08,786 --> 01:01:10,788 LARGE ANIMAL MODEL SYSTEMS MAY 1621 01:01:10,788 --> 01:01:12,290 BE REALLY BENEFICIAL FOR 1622 01:01:12,290 --> 01:01:15,860 ADVANCING OUR KNOWLEDGE IN THIS 1623 01:01:15,860 --> 01:01:16,727 AREA OF PULMONARY 1624 01:01:16,727 --> 01:01:17,194 PATHOPHYSIOLOGY. 1625 01:01:17,194 --> 01:01:17,495 NEXT SLIDE. 1626 01:01:17,495 --> 01:01:18,729 THAT'S WHO DID THE WORK 1627 01:01:18,729 --> 01:01:23,367 INCLUDING THE PICTURE DOWN THERE 1628 01:01:23,367 --> 01:01:24,769 OF PATRICK MELLORS, HE IS A 1629 01:01:24,769 --> 01:01:31,008 FELLOW HERE AT PENN, AND THE 1630 01:01:31,008 --> 01:01:33,044 FUNDING AND A PICTURE OF GROUP 1631 01:01:33,044 --> 01:01:34,679 AT A SURPRISE BIRTHDAY PARTY. 1632 01:01:34,679 --> 01:01:37,415 WITH THAT I AM HAPPY TO TAKE 1633 01:01:37,415 --> 01:01:38,582 QUESTIONS IN THE DISCUSSION 1634 01:01:38,582 --> 01:01:38,816 SESSION. 1635 01:01:38,816 --> 01:01:49,160 THANK YOU VERY MUCH. 1636 01:01:51,729 --> 01:01:52,330 >> THANKS SO MUCH. 1637 01:01:52,330 --> 01:01:58,135 NOW MOVING ON TO OUR NEXT 1638 01:01:58,135 --> 01:02:02,707 SPEAKER DR. JAYARAJ RAYAGOP A L, 1639 01:02:02,707 --> 01:02:04,075 PROFESSOR HARVARD MEDICAL 1640 01:02:04,075 --> 01:02:04,308 SCHOOL. 1641 01:02:04,308 --> 01:02:08,279 YAY IS A PRINCIPAL VRGS AT MGH 1642 01:02:08,279 --> 01:02:09,947 AND HE'S ALSO A PRINCIPLE 1643 01:02:09,947 --> 01:02:13,984 INVESTIGATOR AT THE HARVARD STEM 1644 01:02:13,984 --> 01:02:15,553 CELL INSTITUTE. 1645 01:02:15,553 --> 01:02:22,793 HE'S ALSO AFFILIATE MEMBER FOR 1646 01:02:22,793 --> 01:02:24,929 BROAD IT'S CONSTITUTE AND A 1647 01:02:24,929 --> 01:02:25,830 SCHOLAR. 1648 01:02:25,830 --> 01:02:27,665 JAY MAY A SIGNIFICANT IN THE 1649 01:02:27,665 --> 01:02:29,166 AREA OF STEM CELL AND TODAY HIS 1650 01:02:29,166 --> 01:02:33,304 TALK IS NEW AREA CELL TYPES, 1651 01:02:33,304 --> 01:02:35,639 HELOC CELL, FOR RESISTANT 1652 01:02:35,639 --> 01:02:39,210 RESERVOIR OF UNIQUE PLASTIC STEM 1653 01:02:39,210 --> 01:02:40,444 CELL. 1654 01:02:40,444 --> 01:02:44,982 THANKS A LOT, JAY. 1655 01:02:44,982 --> 01:02:49,420 >> THANKS SO MUCH I ENJOYED THE 1656 01:02:49,420 --> 01:02:50,488 TALKS A LOT AND UNDERSTAND WHAT 1657 01:02:50,488 --> 01:02:55,059 THE CONFERENCE IS ABOUT, THE 1658 01:02:55,059 --> 01:02:57,928 JUXTO POSITION OF THE KEY NEAT 1659 01:02:57,928 --> 01:02:59,230 SPEAKERS FRAMED WHAT IT IS. 1660 01:02:59,230 --> 01:03:01,866 I WILL TALK TO 1 SMALL ASPECT OF 1661 01:03:01,866 --> 01:03:03,234 IT. 1662 01:03:03,234 --> 01:03:05,102 IF YOU COULD FLIP TO THE NEXT 1663 01:03:05,102 --> 01:03:05,469 SLIDE. 1664 01:03:05,469 --> 01:03:08,105 A WHILE BACK, A GROUP AND MINE 1665 01:03:08,105 --> 01:03:09,140 REDEFINED THE AIRWAY EPITHELIUM 1666 01:03:09,140 --> 01:03:10,574 FROM SOMETHING THAT LOOKED 1667 01:03:10,574 --> 01:03:11,208 RELATIVELY SIMPLE TO SOMETHING 1668 01:03:11,208 --> 01:03:13,744 THAT WAS A LOT MORE RICH AND 1669 01:03:13,744 --> 01:03:17,047 COLORFUL EMPLOY IF YOU GO TO THE 1670 01:03:17,047 --> 01:03:19,116 NEXT SLIDE, YOU WILL SEE WE WERE 1671 01:03:19,116 --> 01:03:22,086 ABLE TO RESOLVE THE LINEAGE 1672 01:03:22,086 --> 01:03:23,721 HIERARCHY OF THE MOUSE TRACHEAL 1673 01:03:23,721 --> 01:03:25,189 EPITHELIUM AND THE HUMAN IS 1674 01:03:25,189 --> 01:03:26,457 STILL NOT QUITE DONE AS IT'S 1675 01:03:26,457 --> 01:03:27,992 MORE DIFFICULT BUT YOU CAN SEE A 1676 01:03:27,992 --> 01:03:29,693 LOT OF THE EMPHASIS IN THE 1677 01:03:29,693 --> 01:03:30,694 ORIGINAL PAPER WAS ON THE 1678 01:03:30,694 --> 01:03:33,998 DESCRIPTION OF THESE NEW AIRWAY 1679 01:03:33,998 --> 01:03:35,299 CELL TYPES, THE IONOSIGHT 1680 01:03:35,299 --> 01:03:37,334 CAPTURING MOST OF THE ATTENTION. 1681 01:03:37,334 --> 01:03:38,135 I THINK [INDISCERNIBLE] WILL 1682 01:03:38,135 --> 01:03:39,737 TALK ABOUT THAT LATER BUT THE 1683 01:03:39,737 --> 01:03:43,541 CELL THAT MOST INTRIGUED ME WAS 1684 01:03:43,541 --> 01:03:45,476 THE KRT13 POSITIVE CELL THAT 1685 01:03:45,476 --> 01:03:48,512 SEEMED TO BE INTERMEDIATE 1686 01:03:48,512 --> 01:03:51,081 BETWEEN BASAL CELLS AND 1687 01:03:51,081 --> 01:03:51,749 SECRETATTORY STEM CELLS. 1688 01:03:51,749 --> 01:03:53,017 NEXT SLIDE, PLEASE EMPLOY I WILL 1689 01:03:53,017 --> 01:03:54,885 STEP BACK AND TAKE YOU BACK TO 1690 01:03:54,885 --> 01:03:57,087 THE TEXTBOOK BECAUSE THE AIRWAY 1691 01:03:57,087 --> 01:04:02,359 EPITHELIUM IS AS MANY OF YOU 1692 01:04:02,359 --> 01:04:06,897 WILL REMEMBER, IS THE SEEN O 1693 01:04:06,897 --> 01:04:09,166 QUANON PSEUDOSTRATIFIED ELTHEL 1694 01:04:09,166 --> 01:04:11,802 NUM AND THE 2 LAYERS NUCLEI DID 1695 01:04:11,802 --> 01:04:14,505 NOT MEAN THAT EVERY CELL DIDN'T 1696 01:04:14,505 --> 01:04:15,706 TOUCH THE CELL BASEMENT 1697 01:04:15,706 --> 01:04:16,040 MEMBRANE. 1698 01:04:16,040 --> 01:04:20,344 SO IT'S A VERY PARTICULAR KIND 1699 01:04:20,344 --> 01:04:20,978 OF EPITHELIUM. 1700 01:04:20,978 --> 01:04:23,581 ONE OF THE CLASSIC OF THEM 1701 01:04:23,581 --> 01:04:24,615 INCLUDING SQUAMOUS AND 1702 01:04:24,615 --> 01:04:25,015 [INDISCERNIBLE]. 1703 01:04:25,015 --> 01:04:26,484 IF YOU GO TO THE NEXT SLIDE, THE 1704 01:04:26,484 --> 01:04:27,751 OTHER INTERESTING THING I WOULD 1705 01:04:27,751 --> 01:04:33,157 OBSERVE IS THE AIRWAY HAS VERY 1706 01:04:33,157 --> 01:04:35,659 FEW REACTION MECHANISMS AND WILL 1707 01:04:35,659 --> 01:04:37,528 2 BIGGEST 1S WHEN YOU LOOK AT 1708 01:04:37,528 --> 01:04:41,799 THE TISSUE, ARE THE GOBLET IN 1709 01:04:41,799 --> 01:04:43,467 THE MITSD AND SQUAMOUS PRODICTED 1710 01:04:43,467 --> 01:04:46,470 ON THE RIGHT. 1711 01:04:46,470 --> 01:04:48,372 AND RAVI, IF HE TOLD YOU ABOUT 1712 01:04:48,372 --> 01:04:50,474 COPD, HE WOULD SAY THAT BOTH OF 1713 01:04:50,474 --> 01:04:52,543 THESE PATHOLOGIES OCCUR IN 1 1714 01:04:52,543 --> 01:04:53,711 DISEASE AND THAT'S ACTUALLY TRUE 1715 01:04:53,711 --> 01:04:57,147 OF ASTHMA AND MOST INFLAMMATORY 1716 01:04:57,147 --> 01:05:00,451 AIRWAYS DISEASES BUT THERE HAS 1717 01:05:00,451 --> 01:05:01,285 BEEN ANY RESOLUTION TO WHY THAT 1718 01:05:01,285 --> 01:05:01,552 WOULD BE. 1719 01:05:01,552 --> 01:05:03,420 SO IF YOU GO TO THE NEXT SLIDE. 1720 01:05:03,420 --> 01:05:06,924 THE REASON I LIKED THOSE 1721 01:05:06,924 --> 01:05:07,992 CYTOKERATIN 13 CELLS EVEN MORE 1722 01:05:07,992 --> 01:05:09,293 THAN [INDISCERNIBLE] AT THE TIME 1723 01:05:09,293 --> 01:05:10,628 WAS BECAUSE THEY ACTUALLY 1724 01:05:10,628 --> 01:05:11,328 OCCURRED IN STRUCTURES. 1725 01:05:11,328 --> 01:05:17,468 AND WE CALL THOSE STRUCTURES 1726 01:05:17,468 --> 01:05:18,636 HILLOCKS, ON THE TOP AND ON THE 1727 01:05:18,636 --> 01:05:20,671 BOTTOM YOU WILL SEE A 1728 01:05:20,671 --> 01:05:21,605 [INDISCERNIBLE] WHERE THERE ARE 1729 01:05:21,605 --> 01:05:23,307 THESE CELLS THAT ARE DISTRIBUTED 1730 01:05:23,307 --> 01:05:24,742 AMONGST THE GREEN CILIATED CELLS 1731 01:05:24,742 --> 01:05:27,711 AND ON THE RIGHT LOWER PANEL YOU 1732 01:05:27,711 --> 01:05:30,347 WILL SEE THEY'RE CONNECTED BY 1733 01:05:30,347 --> 01:05:32,883 DESMODEL CITIZENSOMES ON EM. 1734 01:05:32,883 --> 01:05:35,519 NEXT SLIDE. 1735 01:05:35,519 --> 01:05:37,054 AND THESE HILLOCKS ARE FURTHER 1736 01:05:37,054 --> 01:05:38,789 MORE DESSERS FOR ALL THOSE RARE 1737 01:05:38,789 --> 01:05:43,360 CELL POPULATIONS WE DESCRIBED. 1738 01:05:43,360 --> 01:05:44,528 NEXT SLIDE. 1739 01:05:44,528 --> 01:05:46,130 SO WHEY WANT TO LEAVE YOU WITH 1740 01:05:46,130 --> 01:05:49,900 FOR THE TIME BEING IS THAT THE 1741 01:05:49,900 --> 01:05:51,569 PSEUDOSTRATIFIED EPITHELIUM IS 1742 01:05:51,569 --> 01:05:52,937 INDEED VERY COLORFUL WITH ALL 1743 01:05:52,937 --> 01:05:54,905 THESE NEW RARE CELLS WHOSE 1744 01:05:54,905 --> 01:05:56,173 DEFINITION AND FUNCTIONS REALLY 1745 01:05:56,173 --> 01:05:57,675 ARE ONLY BEGINNING TO BE 1746 01:05:57,675 --> 01:06:00,010 UNDERSTOOD BUT WITHIN THAT, THE 1747 01:06:00,010 --> 01:06:02,046 HILLOCK IS A DISCREET EPITHELIUM 1748 01:06:02,046 --> 01:06:03,247 STRUCTURE THAT REALLY SEEMS TO 1749 01:06:03,247 --> 01:06:08,719 HAVE ITS OWN PROPERTIES. 1750 01:06:08,719 --> 01:06:09,486 NEXT SLIDE. 1751 01:06:09,486 --> 01:06:12,122 SO WE WERE VERY CONCERNED 1752 01:06:12,122 --> 01:06:13,490 BECAUSE THE HILLOCK APPEARED TO 1753 01:06:13,490 --> 01:06:15,793 HAVE THAT KIND OF SQUAMOUS 1754 01:06:15,793 --> 01:06:19,630 MORPHOLOGY ON THE SURFACE CELLS 1755 01:06:19,630 --> 01:06:24,134 THAN I SHOWED YOU IN THAT ONPH 1756 01:06:24,134 --> 01:06:25,536 OS IMAGE. 1757 01:06:25,536 --> 01:06:27,371 BUT THE AIRWAY EPITHELIUM IS NOT 1758 01:06:27,371 --> 01:06:29,673 SUPPOSED TO HAVE THOSE CELLS 1759 01:06:29,673 --> 01:06:30,708 UNLESS THERE'S A METAPLASTIC 1760 01:06:30,708 --> 01:06:33,177 RESPONSE AND AS I SAID THE 1761 01:06:33,177 --> 01:06:40,784 TEXTBOOKS HAVE DEFINED THIS ASA 1762 01:06:40,784 --> 01:06:43,120 AGHT WAY, BUT THE HILLOCKS WORK 1763 01:06:43,120 --> 01:06:45,789 ON THIS SO IF YOU HIT CLOCK ON 1764 01:06:45,789 --> 01:06:53,464 THIS, YOU WILL SEE WE LABELED 1765 01:06:53,464 --> 01:06:54,932 INDIVIDUAL HHILLOCKS, BUT IT 1766 01:06:54,932 --> 01:06:57,234 LOOKS LIKE THE EPITHELIUM HAS 1767 01:06:57,234 --> 01:06:59,069 THE [INDISCERNIBLE] CELLS, SO 1768 01:06:59,069 --> 01:07:00,871 THE HILLOCKS ARE STRATIFIED 1769 01:07:00,871 --> 01:07:02,339 SQUAMOUS CELLS EXISTING IN THE 1770 01:07:02,339 --> 01:07:06,977 NORMAL AIR WAY OF THE MOUSE. 1771 01:07:06,977 --> 01:07:10,114 NEXT SLIDE. 1772 01:07:10,114 --> 01:07:11,882 AND WHAT I WANT TO POINT OUT IN 1773 01:07:11,882 --> 01:07:14,118 THIS CARTOON, IF YOU LOOK AT THE 1774 01:07:14,118 --> 01:07:16,086 MARKER OF THE CYTOKERATIN 13, 1775 01:07:16,086 --> 01:07:18,389 THERE'S A GRADIENT BUT EVEN THE 1776 01:07:18,389 --> 01:07:23,727 BASIL STEM CELLS WITHIN THE 1777 01:07:23,727 --> 01:07:24,962 HILLOCK EXPRESS KRT13, SO THOSE 1778 01:07:24,962 --> 01:07:26,563 SEEM TO BE DIFFERENT THAN THE 1779 01:07:26,563 --> 01:07:30,267 STEM CELLS OF THE STRATIFIED 1780 01:07:30,267 --> 01:07:30,567 EPITHELIUM. 1781 01:07:30,567 --> 01:07:32,736 NEXT SLIDE. 1782 01:07:32,736 --> 01:07:33,871 THE OTHER INTRIGUING PROPERTY 1783 01:07:33,871 --> 01:07:36,874 WHICH WE HAVE STILL NOT RESOLVED 1784 01:07:36,874 --> 01:07:38,375 IS THAT HILLOCKS DON'T SEEM TO 1785 01:07:38,375 --> 01:07:40,344 BEHAVE LIKE OTHER DEVELOPMENTAL 1786 01:07:40,344 --> 01:07:40,678 STRUCTURES. 1787 01:07:40,678 --> 01:07:41,779 FOR EXAMPLE WHAT I MEAN BY THAT 1788 01:07:41,779 --> 01:07:44,615 IS THEY ARE NOT BILATERALLY 1789 01:07:44,615 --> 01:07:45,082 SYMMETRIC. 1790 01:07:45,082 --> 01:07:46,316 IN DIFFERENT ANIMALS YOU WILL 1791 01:07:46,316 --> 01:07:47,951 SEE DIFFERENT PATTERNS OF THESE 1792 01:07:47,951 --> 01:07:49,019 HILLOCKS, AND ON THE RIGHT YOU 1793 01:07:49,019 --> 01:07:52,189 WILL SEE A CARTOON, WHERE THEY 1794 01:07:52,189 --> 01:07:54,058 SEEM TO OCCUR IN 3 1795 01:07:54,058 --> 01:07:56,293 CHARACTERISTIC REGIONS BUT THEY 1796 01:07:56,293 --> 01:07:57,027 ARE NOT STEREOTYPED. 1797 01:07:57,027 --> 01:07:58,696 IT'S STILL A PUSLE, WE DON'T 1798 01:07:58,696 --> 01:08:01,565 HAVE A RESOLUTION TO, BUT MAY 1799 01:08:01,565 --> 01:08:02,499 CARRY IMPLICATIONS AND DISEASE 1800 01:08:02,499 --> 01:08:10,474 AND WE CAN SPECULATE ABOUT THAT 1801 01:08:10,474 --> 01:08:11,141 LATER. 1802 01:08:11,141 --> 01:08:11,442 NEXT SLIDE. 1803 01:08:11,442 --> 01:08:12,643 BUT WHAT'S THE FUNCTION? 1804 01:08:12,643 --> 01:08:15,512 BECAUSE THEY WERE SQUAMOUS AND 1805 01:08:15,512 --> 01:08:17,114 STRATIFIED THEY REMIND US OF 1806 01:08:17,114 --> 01:08:18,982 SKIN AND THEY HAVE PLENTY OF 1807 01:08:18,982 --> 01:08:19,750 [INDISCERNIBLE], SO WE WONDERED 1808 01:08:19,750 --> 01:08:21,952 IF THEY HAVE A BARRIER FUNCTION. 1809 01:08:21,952 --> 01:08:27,691 SO HERE'S A ANIMAL TREATED WITH 1810 01:08:27,691 --> 01:08:29,093 NAPH ALENE, AND YOU WILL SEE 1811 01:08:29,093 --> 01:08:34,098 THERE'S VERY FEW LEFT AFTER 1812 01:08:34,098 --> 01:08:34,932 NAPTHALENE, BUT THERE'S SOME UP 1813 01:08:34,932 --> 01:08:36,233 THERE IN THE GLANCE WHERE THERE 1814 01:08:36,233 --> 01:08:38,635 IS SUPPOSED TO BE A STEM CELL 1815 01:08:38,635 --> 01:08:39,470 RESERVE POPULATION BUT 1816 01:08:39,470 --> 01:08:41,438 NONETHELESS, YOU SEE THE 1817 01:08:41,438 --> 01:08:43,006 HILLOCKS ARE ALMOST THE ONLY 1818 01:08:43,006 --> 01:08:44,241 REMAINING STRUCTURES ON THIS AIR 1819 01:08:44,241 --> 01:08:50,314 WAY EPITHELIUM. 1820 01:08:50,314 --> 01:08:51,648 NEXT SLIDE. 1821 01:08:51,648 --> 01:08:52,750 EVEN MORE REMARKABLY, THEY 1822 01:08:52,750 --> 01:08:54,785 SURVIVE IN A FREEZER OVER 1823 01:08:54,785 --> 01:08:56,386 MULTIPLE TIMES ACTUALLY AND 1824 01:08:56,386 --> 01:08:59,623 ABSENCE OF ANY KIND OF DMSO, SO 1825 01:08:59,623 --> 01:09:01,191 THESE STRUCTURES ALSO PHYSICALLY 1826 01:09:01,191 --> 01:09:09,333 RESIST AMAZING FORMS OF INJURY. 1827 01:09:09,333 --> 01:09:10,434 NEXT SLIDE. 1828 01:09:10,434 --> 01:09:12,402 AND HERE THEY RESIST FLU 1829 01:09:12,402 --> 01:09:15,005 INFECTION, THEY WON'T BE SEEN BY 1830 01:09:15,005 --> 01:09:18,842 THE MTB IN FLU, SO THEY ARE 1831 01:09:18,842 --> 01:09:19,276 RESILIENT. 1832 01:09:19,276 --> 01:09:19,576 NEXT SLIDE. 1833 01:09:19,576 --> 01:09:24,414 IN FACT, THEY ARE RESILIENT TO 1834 01:09:24,414 --> 01:09:27,684 EVERYTHING WE CAN THROW AT THEM, 1835 01:09:27,684 --> 01:09:30,821 I'VE ALREADY SHOWN YOU FLU, 1836 01:09:30,821 --> 01:09:36,293 FREEZE THAT YOU, AND NAPH 1837 01:09:36,293 --> 01:09:38,562 THALENE, BUT WITH WE THROUGH 1838 01:09:38,562 --> 01:09:40,297 MORE AT IT, THE STRUCTURES 1839 01:09:40,297 --> 01:09:41,698 RESISTED TO SOME DEGREE. 1840 01:09:41,698 --> 01:09:44,234 I WOULD POINT OUT THEY ALSO 1841 01:09:44,234 --> 01:09:45,068 RESIST PROTEASE DIGESTION, THIS 1842 01:09:45,068 --> 01:09:46,003 IS IMPORTANT NOT BECAUSE IT'S 1843 01:09:46,003 --> 01:09:48,405 SOMETHING THAT YOU OFTEN 1844 01:09:48,405 --> 01:09:52,042 ENCOUNTER, ALTHOUGH MANY 1845 01:09:52,042 --> 01:09:53,777 ALLERGIENS DO HAVE PROTEASES BUT 1846 01:09:53,777 --> 01:09:55,512 I PUT IT HERE BECAUSE MANY OF 1847 01:09:55,512 --> 01:09:58,215 OUR SINGLE CELL DATA SETS MAY 1848 01:09:58,215 --> 01:10:00,818 NOT CONTAIN HILLOCKS BECAUSE 1849 01:10:00,818 --> 01:10:02,052 AFTER SINGLE CELL DISASSOCIATION 1850 01:10:02,052 --> 01:10:05,589 THEY'RE LIKELY TO BE 1851 01:10:05,589 --> 01:10:05,989 UNDERREPRESENTED. 1852 01:10:05,989 --> 01:10:06,290 NEXT SLIDE. 1853 01:10:06,290 --> 01:10:07,991 SO WHAT DO THEY DO? 1854 01:10:07,991 --> 01:10:09,059 HERE IS WHAT THEY DO. 1855 01:10:09,059 --> 01:10:11,028 IF YOU TAKE 1 OF THOSE HILLOCKS 1856 01:10:11,028 --> 01:10:13,664 AND IF YOU TAKE 1 OF THOSE, 1857 01:10:13,664 --> 01:10:16,166 DAMAGE THEM AND PUT THE TRACHEAL 1858 01:10:16,166 --> 01:10:17,000 EXPLANT INTO TISSUE CULTURE, CAN 1859 01:10:17,000 --> 01:10:19,069 YOU SEE WHAT THEY DO. 1860 01:10:19,069 --> 01:10:22,706 THEY RESURFACE THE AIRWAY 1861 01:10:22,706 --> 01:10:27,678 EPITHELIUM. 1862 01:10:27,678 --> 01:10:28,478 NEXT SLIDE. 1863 01:10:28,478 --> 01:10:29,780 WE PERFORMED A LINEAGE TRACE, 1864 01:10:29,780 --> 01:10:32,282 WHERE YOU SEE THE TRACE 1865 01:10:32,282 --> 01:10:33,584 INDICATED BY TOMATO AND YOU 1866 01:10:33,584 --> 01:10:35,886 WEIGH THE COURSE OVER 1867 01:10:35,886 --> 01:10:37,955 REGENERATION, YOU SEE THAT THE 1868 01:10:37,955 --> 01:10:41,491 TD TOMATO OVERTAKES THE AIRWAY 1869 01:10:41,491 --> 01:10:42,826 EPITHELIUM. 1870 01:10:42,826 --> 01:10:43,126 NEXT SLIDE. 1871 01:10:43,126 --> 01:10:45,729 AND INDEED, NOT ONLY DOES THE 1872 01:10:45,729 --> 01:10:50,100 HILLOCK REMAKE THE ENTIRE 1873 01:10:50,100 --> 01:10:53,904 PSEUDOSTRATIFIED EPITHELIUM SO 1874 01:10:53,904 --> 01:10:56,573 THE NONLOCK MAKES THE 1875 01:10:56,573 --> 01:10:58,876 EPITHELIUM, IT EVEN MAKES THIS 1876 01:10:58,876 --> 01:11:00,110 PANOPLY OF THESE CELLS. 1877 01:11:00,110 --> 01:11:01,245 NEXT SLIDE. 1878 01:11:01,245 --> 01:11:02,546 WHAT'S MORE REMARKABLE IS IF YOU 1879 01:11:02,546 --> 01:11:05,449 DO A CLONAL LINEAGE TRACING OR 1880 01:11:05,449 --> 01:11:07,451 RAINBOW LINEAGE TRACING, I WOULD 1881 01:11:07,451 --> 01:11:09,052 SAY, THE HILLOCKS THROW OFF 1882 01:11:09,052 --> 01:11:11,021 THESE VERY, VERY LARGE CLONES OF 1883 01:11:11,021 --> 01:11:13,090 CELLS THAT BECOME 1884 01:11:13,090 --> 01:11:13,724 PSEUDOSTRATIFIED AIRWAY 1885 01:11:13,724 --> 01:11:16,059 EPITHELIUM AND I SHOWED YOU THAT 1886 01:11:16,059 --> 01:11:19,329 BOX BECAUSE IT'S APPROXIMATELY 1887 01:11:19,329 --> 01:11:21,465 THE SIZE OF THE [INDISCERNIBLE]. 1888 01:11:21,465 --> 01:11:24,034 SO THERE ARE CELLS THAT CAN 1889 01:11:24,034 --> 01:11:24,902 UNDERGO MASSIVE EXPANSION EMPLOY 1890 01:11:24,902 --> 01:11:26,436 NEXT SLIDE. 1891 01:11:26,436 --> 01:11:29,206 SO, THE OTHER THING I POINT OUT 1892 01:11:29,206 --> 01:11:31,875 IS HILLOCKS LOOK A LOT LIKE 1893 01:11:31,875 --> 01:11:32,910 SQUAMOUS METAPLASIA THAT'S BEEN 1894 01:11:32,910 --> 01:11:34,444 NOTICED FOR A LONG TIME. 1895 01:11:34,444 --> 01:11:38,515 THE BEST DEFINED MOLECULARLY 1896 01:11:38,515 --> 01:11:43,587 FORM OF SCWAIPOUS METAPLACIA IS 1897 01:11:43,587 --> 01:11:44,021 VITAMINA DEFICIENCY. 1898 01:11:44,021 --> 01:11:45,622 NEXT SLIDE. 1899 01:11:45,622 --> 01:11:47,157 I WILL SKIP THE FINDING THAT I 1900 01:11:47,157 --> 01:11:48,325 DIDN'T -- I DIDN'T HAVE TIME TO 1901 01:11:48,325 --> 01:11:50,994 SHOW YOU THE ACTUAL DATA BUT IN 1902 01:11:50,994 --> 01:11:52,729 THE SETTING OF VITAMIN A 1903 01:11:52,729 --> 01:11:54,865 DEFICIENCY IN A MOUSE, HILLOCKS 1904 01:11:54,865 --> 01:11:55,866 GET BIGGER. 1905 01:11:55,866 --> 01:11:59,202 SO THE SOURCE OF VITAMIN A 1906 01:11:59,202 --> 01:12:00,771 DEFICIENCY ASSOCIATED SQUAMOUS 1907 01:12:00,771 --> 01:12:01,605 METAPLACIA IS HILLOCKS. 1908 01:12:01,605 --> 01:12:04,074 NOW I CAN'T MAKE THAT STATEMENT 1909 01:12:04,074 --> 01:12:06,843 ABOUT OTHER INJURIES, I CAN'T 1910 01:12:06,843 --> 01:12:08,478 MAKE THAT STATEMENT ABOUT 1911 01:12:08,478 --> 01:12:10,247 SMOKES, ASTHMA OR COPD BUT IT 1912 01:12:10,247 --> 01:12:11,515 REMAINS TO BE DETERMINED WHAT 1913 01:12:11,515 --> 01:12:14,184 THE RULE OF THE HILLOCK IS IN 1914 01:12:14,184 --> 01:12:15,686 THOSE DISEASES, BUT WHAT IS 1915 01:12:15,686 --> 01:12:18,121 INTERESTING IS WHEN YOU COMPARE 1916 01:12:18,121 --> 01:12:23,927 HILLOCK BASAL CELLS TO NORMAL 1917 01:12:23,927 --> 01:12:29,333 BASIL CELLS, HILLOCK BASIL CELLS 1918 01:12:29,333 --> 01:12:30,467 SHOW DEMONSTRATION BUT THEY 1919 01:12:30,467 --> 01:12:36,073 METRICS TAB O LIES RETINOIC ASIT 1920 01:12:36,073 --> 01:12:43,480 DIFFERENTLY. 1921 01:12:43,480 --> 01:12:45,148 NEXT SLIDE. 1922 01:12:45,148 --> 01:12:47,617 AND IF YOU SUBSIDIARY CONSTITUTE 1923 01:12:47,617 --> 01:12:54,658 BASAL STEM CELL, BUT THE CELLS 1924 01:12:54,658 --> 01:12:58,061 ON THE LEFT RESIST THIS. 1925 01:12:58,061 --> 01:12:59,396 NEXT SLIDE. 1926 01:12:59,396 --> 01:13:01,798 AND HERE HUMAN HILLOCKS EXIST. 1927 01:13:01,798 --> 01:13:03,333 WHAT'S INTERESTING INTEREST 1928 01:13:03,333 --> 01:13:04,634 THESE HUMAN HILLOCKS IS ACTUALLY 1929 01:13:04,634 --> 01:13:07,371 THEY WOULD BE ENTIRELY MISSED BY 1930 01:13:07,371 --> 01:13:09,006 PATHOLOGISTS, THEY WOULD NOT 1931 01:13:09,006 --> 01:13:10,807 RECOGNIZE THIS STRUCTURE AS 1932 01:13:10,807 --> 01:13:13,577 PATHOLOGIC BECAUSE IT DOESN'T 1933 01:13:13,577 --> 01:13:16,680 QUITE QUALIFY FOR THE DEFINITION 1934 01:13:16,680 --> 01:13:17,814 OF SQUAMOUS METAPLACIA. 1935 01:13:17,814 --> 01:13:18,882 SO PATHOLOGISTS SEE THESE THINGS 1936 01:13:18,882 --> 01:13:20,183 BUT THEY DON'T KNOW WHAT TO MAKE 1937 01:13:20,183 --> 01:13:22,786 OF THEM. 1938 01:13:22,786 --> 01:13:25,188 NOW ALONGSIDE SARRA LYNN'S LUNG 1939 01:13:25,188 --> 01:13:27,491 MAP INITIATIVE, WE WILL BE ABLE 1940 01:13:27,491 --> 01:13:30,260 TO MARK THESE HILLOCKS AND USING 1941 01:13:30,260 --> 01:13:30,894 TRANSCRIPT ORDER OF MICRONSICS 1942 01:13:30,894 --> 01:13:33,563 DEFINE WHAT THEY ARE. 1943 01:13:33,563 --> 01:13:34,231 NEXT SLIDE. 1944 01:13:34,231 --> 01:13:36,333 SO WHY CONTINUE TO STUDY THE 1945 01:13:36,333 --> 01:13:38,201 HILLOCK, I THINK THERE'S A 1946 01:13:38,201 --> 01:13:41,071 COUPLE OF REASONS, THE REASON I 1947 01:13:41,071 --> 01:13:42,672 DON'T HAVE A SLIDE FOR IS 1948 01:13:42,672 --> 01:13:44,641 EXACTLY WHAT YOU HAVE DEDICATED 1949 01:13:44,641 --> 01:13:48,412 THIS CONFERENCE TOWARDS WHICH IS 1950 01:13:48,412 --> 01:13:49,613 RESILIENCE. 1951 01:13:49,613 --> 01:13:51,314 THE HILLOCKS SEEM TO RESIST 1952 01:13:51,314 --> 01:13:52,382 EVERY INJURY WE CAN THROW AT 1953 01:13:52,382 --> 01:13:55,018 THEM AND THEN THEY EXPAND. 1954 01:13:55,018 --> 01:13:57,220 AND INDEED, RECENTLY WE WERE 1955 01:13:57,220 --> 01:13:59,656 TALKING TO SAM JAMES FROM UCL 1956 01:13:59,656 --> 01:14:01,858 AND PETER CAMPBELL FROM THE 1957 01:14:01,858 --> 01:14:03,093 SANGER AND THEY'VE IDENTIFY 1958 01:14:03,093 --> 01:14:04,628 THESE CELLS THAT EXPANDED THAT 1959 01:14:04,628 --> 01:14:07,998 CAN BE SEEN AFTER THE CESSATION 1960 01:14:07,998 --> 01:14:08,298 OF SMOKING. 1961 01:14:08,298 --> 01:14:10,600 SO THE QUESTION IS, ARE THOSE 1962 01:14:10,600 --> 01:14:11,735 HILLOCK CELLS OR ARE THEY 1963 01:14:11,735 --> 01:14:12,402 SOMETHING ELSE. 1964 01:14:12,402 --> 01:14:14,871 BUT THE OTHER REASON TO STUDY 1965 01:14:14,871 --> 01:14:16,873 HILLOCKS IS THAT, YOU KNOW THERE 1966 01:14:16,873 --> 01:14:18,708 IS THIS CLASSIC METAPLASTIC 1967 01:14:18,708 --> 01:14:20,677 SEQUENCE, SO MAYBE THE HILLOCKS 1968 01:14:20,677 --> 01:14:22,446 HELP IN TERMS OF RESILIENCE, BUT 1969 01:14:22,446 --> 01:14:25,215 AT THE SAME TIME, MAYBE HILLOCKS 1970 01:14:25,215 --> 01:14:29,019 ARE ACTUALLY THE ORIGIN FOR THE 1971 01:14:29,019 --> 01:14:30,620 SQUAMOUS METAPLACIA, DYSPLASIA 1972 01:14:30,620 --> 01:14:33,023 AND CARCINOMA INSITU THAT 1 1973 01:14:33,023 --> 01:14:34,391 FINDS IN SQUAMOUS CELL CANCER OR 1974 01:14:34,391 --> 01:14:35,225 MAYBE NOT. 1975 01:14:35,225 --> 01:14:37,327 THEY COULD EITHER BE A SOURCE OF 1976 01:14:37,327 --> 01:14:38,929 RESILIENCE OR A SOURCE OF CANCER 1977 01:14:38,929 --> 01:14:41,765 OR THEY COULD INDEED BE BOTH, WE 1978 01:14:41,765 --> 01:14:47,170 SIMPLY JUST DON'T KNOW YET. 1979 01:14:47,170 --> 01:14:47,471 NEXT SLIDE. 1980 01:14:47,471 --> 01:14:49,372 SO I'LL END EARLY, I THINK I 1981 01:14:49,372 --> 01:14:52,909 SAID WHAT I HAD TO SAY BRIEFLY, 1982 01:14:52,909 --> 01:14:53,944 SO THE QUESTIONS REALLY NOW ARE 1983 01:14:53,944 --> 01:14:58,048 WHAT IS THE IMPORTANCE OF THE 1984 01:14:58,048 --> 01:14:59,483 HILLOCK, WE DON'T KNOW IF THE 1985 01:14:59,483 --> 01:15:01,318 MOUSE, WE CERTAINLY DON'T KNOW 1986 01:15:01,318 --> 01:15:01,885 IN THE HUMAN. 1987 01:15:01,885 --> 01:15:05,021 THE FIRST THING WE NEED TO DO IS 1988 01:15:05,021 --> 01:15:06,957 FIND THEM, AND THE LUNG MAP WILL 1989 01:15:06,957 --> 01:15:10,227 HELP US DO THAT AND THEN WE CAN 1990 01:15:10,227 --> 01:15:11,862 ASK OURSELVES ARE THERE 1991 01:15:11,862 --> 01:15:13,730 DIFFERENT FLAVORS OF SQUAMOUS 1992 01:15:13,730 --> 01:15:14,064 METAPLACIA. 1993 01:15:14,064 --> 01:15:15,765 IT'S A TERM WE THROW AROUND 1994 01:15:15,765 --> 01:15:16,299 WITHOUT DEFINING IT. 1995 01:15:16,299 --> 01:15:18,668 AND I WOULD ARGUE NOW THAT THE 1996 01:15:18,668 --> 01:15:22,572 HILLOCK IS BETTER DEFINED THAN 1997 01:15:22,572 --> 01:15:23,240 THE SQUAMOUS METAPLACIAS, MAYBE 1998 01:15:23,240 --> 01:15:26,643 THERE ARE A VARIETY OF SQUAMOUS 1999 01:15:26,643 --> 01:15:28,011 METAPLACIAS THAT CARE DIFFERENT 2000 01:15:28,011 --> 01:15:28,345 IMPLICATIONS. 2001 01:15:28,345 --> 01:15:30,747 AND THEN OF COURSE THE MOLECULAR 2002 01:15:30,747 --> 01:15:32,983 QUESTIONS, LIKE WHAT IS THE 2003 01:15:32,983 --> 01:15:35,018 EPIGENETIC BASIS OF HILLOCK 2004 01:15:35,018 --> 01:15:37,087 PLASTICITY AND IT WON'T TAKE YOU 2005 01:15:37,087 --> 01:15:39,055 LONG TO REALIZE THAT COULD HAVE 2006 01:15:39,055 --> 01:15:40,590 IMP LAYICATIONS FOR 2007 01:15:40,590 --> 01:15:41,758 REGENERATION, FOR COPD AND 2008 01:15:41,758 --> 01:15:43,727 ASTHMA AND LUNG CANCER AND THEN 2009 01:15:43,727 --> 01:15:47,964 THERE'S THIS CURIOSITY OF WHY DO 2010 01:15:47,964 --> 01:15:49,933 THE HILLOCK'S NOT HAVE A 2011 01:15:49,933 --> 01:15:51,501 STEREOTYPED PATTERN AND THAT OF 2012 01:15:51,501 --> 01:15:52,169 COURSE HAS IMPLICATIONS FOR 2013 01:15:52,169 --> 01:15:54,037 DISEASE AND I WILL JUST END WITH 2014 01:15:54,037 --> 01:15:56,540 THAT AIAN LITTLE BIT EARLY. 2015 01:15:56,540 --> 01:15:57,941 BUT WE'VE GOT OURSELVES BACK ON 2016 01:15:57,941 --> 01:15:59,075 TIME. 2017 01:15:59,075 --> 01:16:01,111 AND IT'S MY PLEASURE TO THEN 2018 01:16:01,111 --> 01:16:03,513 INTRODUCE OUR NEXT SPEAKER WHO I 2019 01:16:03,513 --> 01:16:05,448 HAD THE WONDERFUL PLEASURE OF 2020 01:16:05,448 --> 01:16:06,983 HAVING PASSED THROUGH OUR OWN 2021 01:16:06,983 --> 01:16:11,621 LABORATORY QUITE A LONG TIME AGO 2022 01:16:11,621 --> 01:16:13,990 BUT NOW TATA IS A PROFESSOR, OR 2023 01:16:13,990 --> 01:16:16,826 NO, NO, HE HAS TENURE AT DUKE 2024 01:16:16,826 --> 01:16:19,062 AND HAS DONE REMARKABLE WORK IN 2025 01:16:19,062 --> 01:16:21,231 THE ALVEOLAR REGION AND INDEED 2026 01:16:21,231 --> 01:16:22,832 GLANDS BUT I DON'T THINK WE WILL 2027 01:16:22,832 --> 01:16:25,802 TELL YOU ABOUT GLANDS TODAY. 2028 01:16:25,802 --> 01:16:26,102 >> GREAT. 2029 01:16:26,102 --> 01:16:27,771 THANK YOU, THANKS FOR THE KIND 2030 01:16:27,771 --> 01:16:28,104 INTRODUCTION. 2031 01:16:28,104 --> 01:16:30,440 AND THANKS TO THE ORGANIZER FOR 2032 01:16:30,440 --> 01:16:32,776 HAVING ME HERE, AND ORGANIZING 2033 01:16:32,776 --> 01:16:33,643 THIS EXCITING WORKSHOP. 2034 01:16:33,643 --> 01:16:34,544 I'M REALLY LOOKING FORWARD TO 2035 01:16:34,544 --> 01:16:35,979 LISTEN TO THE REST OF THE TALKS 2036 01:16:35,979 --> 01:16:38,315 AS WELL AS THE DISCUSSIONS IN 2037 01:16:38,315 --> 01:16:48,592 THE NEXT 2 DAYS. 2038 01:16:48,792 --> 01:16:49,492 NEXT PLEASE. 2039 01:16:49,492 --> 01:16:51,528 I AM A CELLULAR BIOLOGIST BY 2040 01:16:51,528 --> 01:16:54,698 TRAINING BUT THINKING ABOUT THE 2041 01:16:54,698 --> 01:16:55,432 LUNG, YOU KNOW 1 IMPORTANT 2042 01:16:55,432 --> 01:16:57,367 ASPECT OF THE LUNG THAT WE HAVE 2043 01:16:57,367 --> 01:16:59,369 BEEN INTERESTED IN IS THE 2044 01:16:59,369 --> 01:17:00,170 ORGANIZATION OF THE LUNG. 2045 01:17:00,170 --> 01:17:06,009 YOU KNOW HOW DOES THE LUNG 2046 01:17:06,009 --> 01:17:07,310 ACTUALLY ORGANIZE IT'S 2047 01:17:07,310 --> 01:17:08,578 SELF-DURING DEVELOPMENT BUT HOW 2048 01:17:08,578 --> 01:17:11,181 IT MAINTAINS THE LIFE AS WELL AS 2049 01:17:11,181 --> 01:17:12,849 WHEN THERE IS INJURY, CAN IT 2050 01:17:12,849 --> 01:17:14,251 REBUILD IT BACK, SO THE REASON 2051 01:17:14,251 --> 01:17:17,087 WE GOT INTO THIS IS WE ARE NOW 2052 01:17:17,087 --> 01:17:21,024 TALKING ABOUT MANY OF THE 2053 01:17:21,024 --> 01:17:21,625 RESPIRATORY DISEASES, 1 KEY 2054 01:17:21,625 --> 01:17:23,193 IMPORTANT THING THAT AM CANS UP 2055 01:17:23,193 --> 01:17:25,395 IS PHYSIOLOGY. 2056 01:17:25,395 --> 01:17:26,997 SO, HERE, WE'RE TALKING ABOUT 2057 01:17:26,997 --> 01:17:28,632 FUNCTION, LUNG FUNCTION, AND 2058 01:17:28,632 --> 01:17:30,467 THAT'S TIGHTLY ALIGNED WITH THE 2059 01:17:30,467 --> 01:17:32,435 STRUCTURES, SO IT'S THE 2060 01:17:32,435 --> 01:17:34,604 STRUCTURE FUNCTION RELATIONSHIP 2061 01:17:34,604 --> 01:17:36,506 THAT REALLY DEFINES AND IT'S 2062 01:17:36,506 --> 01:17:37,774 FUNCTION THROUGHOUT THE LIFE AS 2063 01:17:37,774 --> 01:17:40,677 WELL AS YOU KNOW WHEN THERE IS 2064 01:17:40,677 --> 01:17:42,279 DAMAGE, OR DIFFERENT DISEASES SO 2065 01:17:42,279 --> 01:17:44,514 THAT'S AN ASPECT WE ARE REALLY 2066 01:17:44,514 --> 01:17:53,790 EXCITED ABOUT. 2067 01:17:53,790 --> 01:17:55,625 NEXT PLEASE EMPLOY AND IN THAT 2068 01:17:55,625 --> 01:17:57,394 ASPECT 1 THING WE ARE REALLY 2069 01:17:57,394 --> 01:17:59,129 INTERESTED IN IS, WHAT ARE THE 2070 01:17:59,129 --> 01:18:00,297 DIFFERENT CELL TYPES AND 2071 01:18:00,297 --> 01:18:01,564 DIFFERENT PARTS OF THE LUNG, AND 2072 01:18:01,564 --> 01:18:04,301 WHAT ARE THE CELLS THAT HAVE THE 2073 01:18:04,301 --> 01:18:06,703 ABILITY TO REPAIR WHEN THERE IS 2074 01:18:06,703 --> 01:18:09,439 DAMAGE THAT CAN SUSTAIN TOWARD 2075 01:18:09,439 --> 01:18:10,440 THE LIFE. 2076 01:18:10,440 --> 01:18:12,409 AND IN THAT PART, I'M MAINLY 2077 01:18:12,409 --> 01:18:14,444 GOING TO FOCUS ON THIS DISTAL 2078 01:18:14,444 --> 01:18:16,713 PART OF THE LUNG WHICH IS THE 2079 01:18:16,713 --> 01:18:18,615 ALVERMEN INFECTED O LIE, SO AS 2080 01:18:18,615 --> 01:18:22,118 YOU KNOW, ALVEOLAR TISSUES ARE 2081 01:18:22,118 --> 01:18:24,554 TIGHTLY PACKED WITHIN THIS THIN 2082 01:18:24,554 --> 01:18:26,389 MEMBRANE WALL, THE ALVEOLAR 2083 01:18:26,389 --> 01:18:29,125 RECEPTOR WITH 2 EPITHELIAL 2084 01:18:29,125 --> 01:18:30,527 LININGS, AS YOU CAN SEE HERE IN 2085 01:18:30,527 --> 01:18:33,396 GREEN, SO WHAT YOU SEE IN GREEN 2086 01:18:33,396 --> 01:18:35,398 HERE IS THE ALVEOLAR TYPE 1 2087 01:18:35,398 --> 01:18:36,433 CELLULAR MARKER THAT YOU SEE, 2088 01:18:36,433 --> 01:18:39,436 THERE ARE 2 LININGS AND BOTH 2089 01:18:39,436 --> 01:18:41,771 SITES, SO THERE IS -- THERE ARE 2090 01:18:41,771 --> 01:18:43,707 3 DIFFERENT ALVEOLAR SACKS HERE 2091 01:18:43,707 --> 01:18:44,574 SEPARATED BY THESE THIN MEMBRANE 2092 01:18:44,574 --> 01:18:47,344 AS WELL AND IN THE MITSD WE HAVE 2093 01:18:47,344 --> 01:18:48,445 THIS INTERSTITIAL SPACE. 2094 01:18:48,445 --> 01:18:51,181 SO HOW ARE THESE CELLS ABLE TO 2095 01:18:51,181 --> 01:18:54,017 ORGANIZE THEMSELVES AND MAINTAIN 2096 01:18:54,017 --> 01:18:54,751 THROUGHOUT THE LUNG AND WHEN 2097 01:18:54,751 --> 01:18:56,019 IT'S TISSUE CULTURE MEDIAD CAN 2098 01:18:56,019 --> 01:18:57,854 THEY REBUILD IT BACK? 2099 01:18:57,854 --> 01:18:58,922 THESE ARE SOME OF THE QUESTIONS 2100 01:18:58,922 --> 01:19:02,525 WE HAVE BEEN ASKING AND I THINK 2101 01:19:02,525 --> 01:19:04,728 IT'S A -- FROMAGE ENGINEERING 2102 01:19:04,728 --> 01:19:07,330 POINT, IT'S AN ENGINEERING MODEL 2103 01:19:07,330 --> 01:19:10,734 AND THE DISEASE BUILT INTO SUCH 2104 01:19:10,734 --> 01:19:12,969 THIN, EXTREMELY THIN ALVEOLAR 2105 01:19:12,969 --> 01:19:14,471 LINING AND WE KNOW FROM MANY 2106 01:19:14,471 --> 01:19:16,873 STUDIES FROM MANY GROUPS THAT 2107 01:19:16,873 --> 01:19:18,742 THERE ARE THESE EPIHELIAL CELLS, 2108 01:19:18,742 --> 01:19:20,310 THE TYPE 2 CELLS AND THE TYPE 1 2109 01:19:20,310 --> 01:19:23,913 CELLS, TYPE 2 CELLS SERVE AS THE 2110 01:19:23,913 --> 01:19:25,415 STEM CELLS OF THE ALVERMEN 2111 01:19:25,415 --> 01:19:27,951 INFECTED O LIAISON AND THE 2112 01:19:27,951 --> 01:19:29,486 INTERSTITIAL FIBROBLASTS AND THE 2113 01:19:29,486 --> 01:19:31,087 CAPILLARY IMMUNE SETS AND THE 2114 01:19:31,087 --> 01:19:32,255 EXTRA CELLULAR MATRIX BUT MY 2115 01:19:32,255 --> 01:19:33,690 TALK IS MAINLY GOING TO TALK 2116 01:19:33,690 --> 01:19:35,425 ABOUT THE EPITHELIAL CELLS AND 2117 01:19:35,425 --> 01:19:38,428 THE FIBROBLASTS AND WE HAVE BEEN 2118 01:19:38,428 --> 01:19:41,798 INTERESTED IN LOOKING AT HOW DO 2119 01:19:41,798 --> 01:19:43,266 THESE CELLS RESPOND WHEN THERE 2120 01:19:43,266 --> 01:19:47,137 IS DAMAGE, AND HOW DO THEY 2121 01:19:47,137 --> 01:19:49,372 INTERACT TWEEZE THEEN 2 2122 01:19:49,372 --> 01:19:51,341 DIFFERENT COMPARTMENTS. 2123 01:19:51,341 --> 01:19:52,175 NEXT PLEASE. 2124 01:19:52,175 --> 01:19:54,377 SO THE REASON WE ASK THAD IS IN 2125 01:19:54,377 --> 01:20:01,050 MANY DISEASES, THESE CELLS THE 2126 01:20:01,050 --> 01:20:03,820 ALVEOLAR TISSUES ARE UNDERGOING 2127 01:20:03,820 --> 01:20:04,754 DISORGANIZATION. 2128 01:20:04,754 --> 01:20:05,088 NEXT, PLEASE. 2129 01:20:05,088 --> 01:20:07,590 FOR EXAMPLE, IN FIBROSIS IF YOU 2130 01:20:07,590 --> 01:20:10,593 LOOK AT IT IN THIS, ALVEOLAR 2131 01:20:10,593 --> 01:20:11,761 TISSUES ARE COMPLETELY OCCUPIED 2132 01:20:11,761 --> 01:20:14,831 BY THESE MATE RICK PRODUCING MY 2133 01:20:14,831 --> 01:20:16,900 O FIBROBLASTS AND MANY OTHER 2134 01:20:16,900 --> 01:20:19,335 CELLS INCLUDING IMMUNE CELL ANDS 2135 01:20:19,335 --> 01:20:22,172 EPITHELIEL CELLS ARE LOST 2136 01:20:22,172 --> 01:20:23,740 EVENTUALLY. 2137 01:20:23,740 --> 01:20:25,642 NEXT PLEASE, WHEREAS IN 2138 01:20:25,642 --> 01:20:26,709 EMPHYSEMA, THIS IS DEMONSTRATING 2139 01:20:26,709 --> 01:20:28,745 LUNG DEC WHERE WE SEE THE LOSS 2140 01:20:28,745 --> 01:20:31,581 OF TISSUE, IN OTHER WORDS THERE 2141 01:20:31,581 --> 01:20:32,515 IS ALVEOLAR SIMPLIFICATION, SO 2142 01:20:32,515 --> 01:20:34,984 WE ARE SIMPLY LOOKING AT THESE 2 2143 01:20:34,984 --> 01:20:36,119 OPPOSING PHENOTYPES WHERE THERE 2144 01:20:36,119 --> 01:20:37,754 IS A COMPLEX -- INCREASE THE 2145 01:20:37,754 --> 01:20:39,956 COMPLEXITY OF THE TISSUE AS SEEN 2146 01:20:39,956 --> 01:20:41,491 IN FIBROSIS, THERE ARE 2147 01:20:41,491 --> 01:20:43,726 SIMPLIFICATION OF THE TISSUE 2148 01:20:43,726 --> 01:20:45,061 LIKE IN EMPHYSEMA AND NOT TO 2149 01:20:45,061 --> 01:20:47,030 FORGET, WE ALSO SEE LUNG 2150 01:20:47,030 --> 01:20:47,864 CANCERS, ALSO, ALTHOUGH I'M NOT 2151 01:20:47,864 --> 01:20:50,600 GOING TO TALK MUCH ABOUT THIS, 2152 01:20:50,600 --> 01:20:54,437 BUT WE DO SEE THESE CELLS AT 2153 01:20:54,437 --> 01:20:55,505 QUITE DIFFERENT STATES AND 2154 01:20:55,505 --> 01:20:57,774 EXPANSION OF THE CELL 2155 01:20:57,774 --> 01:21:01,110 POPULATIONS AND THAT'S WHAT THE 2156 01:21:01,110 --> 01:21:03,179 CODE OF THE LAB WE'VE BEEN 2157 01:21:03,179 --> 01:21:05,515 INTERESTED IN. 2158 01:21:05,515 --> 01:21:12,322 NEXT PLEASE. 2159 01:21:12,322 --> 01:21:13,790 NEXT PLEASE. 2160 01:21:13,790 --> 01:21:14,757 SO TO CONTINUE, WE'VE BEEN 2161 01:21:14,757 --> 01:21:16,226 ASKING THESE QUESTIONS, HOW ARE 2162 01:21:16,226 --> 01:21:19,429 THEY ABLE TO GENERATE THESE LARN 2163 01:21:19,429 --> 01:21:21,164 TIN TYPE 1 CELLS, WE KNOW THEY 2164 01:21:21,164 --> 01:21:23,566 GENERATE BUT HOW DO THEY 2165 01:21:23,566 --> 01:21:24,534 GENERATE SUCH A LARGE STRUCTURE 2166 01:21:24,534 --> 01:21:27,437 THAT WE SEE IN TYPE 1 CELLS. 2167 01:21:27,437 --> 01:21:27,871 NEXT, PLEASE. 2168 01:21:27,871 --> 01:21:30,173 TO ADDRESS THIS QUESTION, THERE 2169 01:21:30,173 --> 01:21:32,342 ARE SOME TECHNICAL CAVEATS FOR 2170 01:21:32,342 --> 01:21:35,078 EXAMPLE, WE CANNOT GET ENOUGH 2171 01:21:35,078 --> 01:21:36,446 CELLS FROM NATIVE LUNGS BECAUSE 2172 01:21:36,446 --> 01:21:37,814 OF THEIR EXTREME THIN STRUCTURE 2173 01:21:37,814 --> 01:21:40,683 OF THESE TYPE 1 CELLS, AND 2174 01:21:40,683 --> 01:21:43,086 THAT'S WHERE OUR LAB, AS WELL AS 2175 01:21:43,086 --> 01:21:45,889 MANY OTHER LABS HAVE DEVELOPED 2176 01:21:45,889 --> 01:21:46,523 ORGANOID MODELS. 2177 01:21:46,523 --> 01:21:48,758 IN OUR CASE WE DEVELOPED THESE 2178 01:21:48,758 --> 01:21:49,559 CHEMICALLY DEFINED CONDITIONS 2179 01:21:49,559 --> 01:21:51,528 WHERE WE TAKE A SINGLE TYPE 2 2180 01:21:51,528 --> 01:21:52,829 CELL AND EXPAND THEM INTO 10S 2181 01:21:52,829 --> 01:21:56,165 AND THOUSANDS OF CELLS IF NOT 2182 01:21:56,165 --> 01:21:57,967 MILLIONS AND ALSO ABLE TO 2183 01:21:57,967 --> 01:22:01,738 GENERATE TYPE 1 CELLS USING 2184 01:22:01,738 --> 01:22:04,107 THESE ALVEOLAR SPHERE MODEL 2185 01:22:04,107 --> 01:22:05,141 SYSTEMS. 2186 01:22:05,141 --> 01:22:06,543 TO FORMAL LAB MEMBERS THEY HAVE 2187 01:22:06,543 --> 01:22:08,745 TAKEN ON THIS PROJECT AND USED 2188 01:22:08,745 --> 01:22:10,413 THESE MODELS TO UNDERSTAND THE 2189 01:22:10,413 --> 01:22:12,348 MECHANISMS INVOLVED IN TYPE 2 2190 01:22:12,348 --> 01:22:14,918 AND TYPE 1 CONVERSION, NEXT 2191 01:22:14,918 --> 01:22:15,184 PLEASE. 2192 01:22:15,184 --> 01:22:17,520 AND HERE IS THE SIMPLE -- 2193 01:22:17,520 --> 01:22:18,555 SIMPLIFIED VIEW OF HOW THE 2194 01:22:18,555 --> 01:22:21,691 SYSTEM WORKS SO WE CAN TAKE A 2195 01:22:21,691 --> 01:22:23,393 SINGLE TYPE 2 CELL AND 2196 01:22:23,393 --> 01:22:24,327 DIFYEPTIATE THEM INTO THE LARGE 2197 01:22:24,327 --> 01:22:26,496 TYPE 1 CELL SO THIS IS EXACTLY 2198 01:22:26,496 --> 01:22:28,231 THE SAME CELL, IT'S A TIME LAPSE 2199 01:22:28,231 --> 01:22:30,533 IMAGE WHERE THE SINGLE CELL 2200 01:22:30,533 --> 01:22:32,335 GENERATED THESE LARGE FLAT CELL 2201 01:22:32,335 --> 01:22:35,538 OUTSIDE THE BODIES AND USING 2202 01:22:35,538 --> 01:22:36,339 MOLECULAR PROFILING AND 2203 01:22:36,339 --> 01:22:38,341 DIFFERENT WAYS OF CHARACTERIZING 2204 01:22:38,341 --> 01:22:41,077 THESE CULTURES, WE NOW KNOW THEY 2205 01:22:41,077 --> 01:22:43,613 ACTUALLY FOLLOW SIMILAR 2206 01:22:43,613 --> 01:22:45,949 PATTERNS, MOLECULAR PATTERNS AS 2207 01:22:45,949 --> 01:22:46,816 WELL AS MORPHOLOGICAL PATTERNS 2208 01:22:46,816 --> 01:22:48,451 WE SEE IN THE HUMAN LUNGS SO 2209 01:22:48,451 --> 01:22:50,286 USING THE SYSTEM, NOW WE CAN 2210 01:22:50,286 --> 01:22:53,256 LOOK AT MORE REFINELY THE 2211 01:22:53,256 --> 01:22:55,858 MOLECULAR PATTERNS. 2212 01:22:55,858 --> 01:22:56,893 NEXT PLEASE. 2213 01:22:56,893 --> 01:22:59,862 AND WE PERFORM SINGLE CELL 2214 01:22:59,862 --> 01:23:00,463 TRANSCRIPTOMIC ANALYSIS AND 2215 01:23:00,463 --> 01:23:02,899 FOUND THERE ARE TYPE 2 CELLS, 2216 01:23:02,899 --> 01:23:04,100 THERE ARE REPLICATING TYPE 2 2217 01:23:04,100 --> 01:23:06,269 CELLS, TYPE 1 CELLS AND THEN WE 2218 01:23:06,269 --> 01:23:07,570 CAME ACROSS THIS POPULATION THAT 2219 01:23:07,570 --> 01:23:11,975 WE DIDN'T KNOW MUCH ABOUT, NEXT 2220 01:23:11,975 --> 01:23:12,208 PLEASE. 2221 01:23:12,208 --> 01:23:12,809 AND NEXT. 2222 01:23:12,809 --> 01:23:14,310 AND WE FOUND THERE ARE UNIQUE 2223 01:23:14,310 --> 01:23:17,814 MARKERS THAT ARE ASSOCIATED WITH 2224 01:23:17,814 --> 01:23:19,315 THESE CELL CLUSTERS THAT WE 2225 01:23:19,315 --> 01:23:23,386 DIDN'T KNOW BEFORE AND SOME OF 2226 01:23:23,386 --> 01:23:24,187 THEM ARE CTGF AND 2227 01:23:24,187 --> 01:23:26,155 [INDISCERNIBLE] AND MANY OTHER 2228 01:23:26,155 --> 01:23:27,690 MARKERS AND FINALLY WE SEE THIS 2229 01:23:27,690 --> 01:23:28,257 TYPE 1 CELL. 2230 01:23:28,257 --> 01:23:29,892 SO NOT ONLY WE HAVE THESE 2231 01:23:29,892 --> 01:23:31,060 DIFFERENT CELL CLUSTERS AND 2232 01:23:31,060 --> 01:23:33,696 MARKERS BUT NOW WE MAP THEM 2233 01:23:33,696 --> 01:23:35,999 CHRONOLOGICALLY SO WE KNOW THE 2234 01:23:35,999 --> 01:23:37,200 CHRONOLOGICAL EVENTS STARTING 2235 01:23:37,200 --> 01:23:39,535 FROM TYPE 2 ALL THE WAY INTO THE 2236 01:23:39,535 --> 01:23:42,905 TYPE 1, NEXT PLEASE. 2237 01:23:42,905 --> 01:23:47,577 AND NOT ONLY ORGANOIDS, IN 2238 01:23:47,577 --> 01:23:49,779 EXVIVO CULTURES BUT WE CLONE THE 2239 01:23:49,779 --> 01:23:51,080 SINGLE CELL STAGE IN VIVO UPON 2240 01:23:51,080 --> 01:23:51,314 INJURY. 2241 01:23:51,314 --> 01:23:53,483 FOR EXAMPLE, IF YOU LABEL 2242 01:23:53,483 --> 01:23:55,585 ALVEOLAR TYPE 2 CELLS HERE IN 2243 01:23:55,585 --> 01:23:59,122 RED AND FOLLOW UP WITH 2244 01:23:59,122 --> 01:24:00,323 BLEOMYCIN, WE SEE THESE UNIQUE 2245 01:24:00,323 --> 01:24:01,924 MARKERS THAT COME AS A TRANSIENT 2246 01:24:01,924 --> 01:24:02,125 STATE. 2247 01:24:02,125 --> 01:24:03,493 AS CAN YOU SEE HERE THEY'RE NOT 2248 01:24:03,493 --> 01:24:05,895 PRESENT IN THE STARTING 2249 01:24:05,895 --> 01:24:07,096 POPULATION, NEITHER IN THE END 2250 01:24:07,096 --> 01:24:10,066 TERMINAL TYPE 1 CELLS BUT THEY 2251 01:24:10,066 --> 01:24:12,568 TRANSIENTLY EMERGE DURING INJURY 2252 01:24:12,568 --> 01:24:12,802 REPAIR. 2253 01:24:12,802 --> 01:24:13,269 NEXT PLEASE. 2254 01:24:13,269 --> 01:24:15,238 THE SAME THING CAN BE VISUALIZED 2255 01:24:15,238 --> 01:24:18,941 IN THE SCHEMATIC THESE TYPE 2 2256 01:24:18,941 --> 01:24:20,109 CELLS GO THROUGH THESE CELL 2257 01:24:20,109 --> 01:24:22,879 STATE SO WE LIKE TO CALL THEM 2258 01:24:22,879 --> 01:24:24,681 TRANSITIONAL STATE BEFORE THEY 2259 01:24:24,681 --> 01:24:27,984 DIFFERENTIATE INTO TYPE 1 CELLS. 2260 01:24:27,984 --> 01:24:28,751 NEXT, PLEASE. 2261 01:24:28,751 --> 01:24:32,822 AND AN IMPORTANT ASPECT OF THIS 2262 01:24:32,822 --> 01:24:34,657 TRANSITIONAL STATUS THAT THE 2263 01:24:34,657 --> 01:24:35,725 ACTIVATE MANY SIGNALING PATHWAYS 2264 01:24:35,725 --> 01:24:38,127 AND SOME OF THEM ARE VERY 2265 01:24:38,127 --> 01:24:39,395 FAMILIAR FROM A DEC POINT OF 2266 01:24:39,395 --> 01:24:45,501 VIEW, AS YOU CAN SEE HERE 2267 01:24:45,501 --> 01:24:48,905 THERE'S TGFBETTA, P53 SIGNALING 2268 01:24:48,905 --> 01:24:51,641 WAGHT PATHWAY, CELLULAR 2269 01:24:51,641 --> 01:24:52,542 SENESCENCE, DNA DAMAGE CHECK 2270 01:24:52,542 --> 01:24:55,178 POINT, SO NOW WE SEE THERE IS AN 2271 01:24:55,178 --> 01:24:56,779 OVERLAP WITH CERTAIN DISEASES 2272 01:24:56,779 --> 01:24:59,482 BUT FOR EXAMPLE, IN EMPHYSEMA 2273 01:24:59,482 --> 01:25:04,487 AND FIBROSIS, NEXT PLEASE. 2274 01:25:04,487 --> 01:25:06,689 SO WE GROW SOME OF THESE IN 2275 01:25:06,689 --> 01:25:08,324 LUNGS TO SEE IF WE CAN SEE THE 2276 01:25:08,324 --> 01:25:09,726 SIMILAR STATES AND MARKERS. 2277 01:25:09,726 --> 01:25:11,461 INDEED WE SEE THEM. 2278 01:25:11,461 --> 01:25:13,029 FOR EXAMPLE, IN HEGHTY LUNGS WE 2279 01:25:13,029 --> 01:25:17,433 SEE TYPE 2 CELLS BUT IF YOU LOOK 2280 01:25:17,433 --> 01:25:20,136 AT THE NONFIBROTIC REGIONS AND 2281 01:25:20,136 --> 01:25:20,703 PULMONARY FIBROTIC LUPGS WE 2282 01:25:20,703 --> 01:25:22,438 SLEEP APNEA AND OBESITYY 2283 01:25:22,438 --> 01:25:25,374 ABUNDANCE OF THESE CELL 2284 01:25:25,374 --> 01:25:27,777 DIVISIONS SURROUNDING THE CELLS 2285 01:25:27,777 --> 01:25:31,481 THAT OFTEN CALL MY O FIBROBLAST. 2286 01:25:31,481 --> 01:25:32,982 SO INDEED THESE TRANSITIONAL 2287 01:25:32,982 --> 01:25:34,217 STATES NOT ONLY INJURY REPAIRED 2288 01:25:34,217 --> 01:25:35,952 BUT WE SAW AN ARK KIEWMULATION 2289 01:25:35,952 --> 01:25:38,588 OF PERSISTENT OF THESE 2290 01:25:38,588 --> 01:25:40,556 TRANSITIONAL STATES AND DISEASES 2291 01:25:40,556 --> 01:25:42,792 LIKE PULL MANORY FIBROSIS. 2292 01:25:42,792 --> 01:25:43,459 NEXT, PLEASE. 2293 01:25:43,459 --> 01:25:45,361 NOT ONLY MARKERS BUT ALSO SOME 2294 01:25:45,361 --> 01:25:47,864 OF THE SIGNALING ACTIVITIES, 2295 01:25:47,864 --> 01:25:50,500 LIKE CELLULAR SENESCENCE, DNA 2296 01:25:50,500 --> 01:25:52,101 DAMAGE REPAIR, NEXT PLEASE. 2297 01:25:52,101 --> 01:25:54,303 ALSO AS I MENTIONED CELLULAR 2298 01:25:54,303 --> 01:25:57,006 SENESCENCE SHOWN HERE WITH THE 2299 01:25:57,006 --> 01:25:59,542 STATUS ACTIVATED, WE SEE THESE 2300 01:25:59,542 --> 01:26:03,412 IN FIBROTIC LUNGS, BUT NOT IN 2301 01:26:03,412 --> 01:26:05,181 HEALTHY CONTROLS. 2302 01:26:05,181 --> 01:26:06,149 NEXT PLEASE. 2303 01:26:06,149 --> 01:26:08,818 SO HAVING SEEN P53 SIGNALING WE 2304 01:26:08,818 --> 01:26:12,688 SIMPLY DISRUPTED P53, USING 2305 01:26:12,688 --> 01:26:13,823 CLASSICAL [INDISCERNIBLE] MODELS 2306 01:26:13,823 --> 01:26:14,991 AND AND HERE WE FOUND IS A 2307 01:26:14,991 --> 01:26:16,559 CONTROL LUNG IN A 3D 2308 01:26:16,559 --> 01:26:18,628 VISUALIZATION WHERE YOU ARE 2309 01:26:18,628 --> 01:26:20,029 SEEING A SINGULAR ALVEOLAR CUP 2310 01:26:20,029 --> 01:26:21,264 FROM 1 VIEW. 2311 01:26:21,264 --> 01:26:23,733 THIS IS A CELL TYPE 2 THAT 2312 01:26:23,733 --> 01:26:26,435 DIFREBTIATED INTO TYPE 1, NEXT 2313 01:26:26,435 --> 01:26:26,903 PLEASE. 2314 01:26:26,903 --> 01:26:28,171 WHEREAS IN P53 KNOCK OUT WHAT WE 2315 01:26:28,171 --> 01:26:30,006 FOUND IS THESE LINEAGE LEVEL 2316 01:26:30,006 --> 01:26:32,608 CELLS DID NOT DIFFERENTIATE INTO 2317 01:26:32,608 --> 01:26:34,477 THIS LARGE FLAT TYPE 1 CELL, 2318 01:26:34,477 --> 01:26:38,214 INSTEAD THEY KIND OF BALOONED 2319 01:26:38,214 --> 01:26:40,483 OUT INDICATING THERE IS 2320 01:26:40,483 --> 01:26:41,918 [INDISCERNIBLE] DISREGULATION. 2321 01:26:41,918 --> 01:26:43,052 IN ANALOGY 1 COULD TAKE IN A 2322 01:26:43,052 --> 01:26:45,488 WAY, SO IN CONTROLS WE SEE THIS 2323 01:26:45,488 --> 01:26:47,223 THIN CRUST PIZZA LIKE TYPE 1 2324 01:26:47,223 --> 01:26:49,659 CELLS, DERIVED FROM THE TYPE 2. 2325 01:26:49,659 --> 01:26:52,128 WHEREAS IN P53 KNOCK OUT SEEEE 2326 01:26:52,128 --> 01:26:53,596 THE SOUR DOE LIKE STRUCTURE 2327 01:26:53,596 --> 01:26:59,702 INDICATING THAT THERE IS A 2328 01:26:59,702 --> 01:27:03,639 STRUCTURAL ORGANIZATION OF THESE 2329 01:27:03,639 --> 01:27:04,407 TYPE 2 [INDISCERNIBLE]. 2330 01:27:04,407 --> 01:27:05,408 NEXT PLEASE, SO JUST TO 2331 01:27:05,408 --> 01:27:07,677 SUMMARIZE WHAT I'VE SHOWN YOU SO 2332 01:27:07,677 --> 01:27:09,779 FAR UPON INJURY, THESE TYPE 2 2333 01:27:09,779 --> 01:27:12,081 CELLS GENERATED THESE UNIQUE 2334 01:27:12,081 --> 01:27:14,483 MOLECULARLY UNIQUE TRANSITIONAL 2335 01:27:14,483 --> 01:27:14,684 STATE. 2336 01:27:14,684 --> 01:27:16,185 NEXT PLEASE. 2337 01:27:16,185 --> 01:27:18,888 THAT ARE HIGHLY ENRICHED FOR P53 2338 01:27:18,888 --> 01:27:20,990 SIGNALING, DNA DAMAGE AND MANY 2339 01:27:20,990 --> 01:27:21,591 OTHER PATHWAYS. 2340 01:27:21,591 --> 01:27:25,061 NEXT PLEASE, AND NEXT. 2341 01:27:25,061 --> 01:27:26,362 AND NORMALLY, THESE TRANSITIONAL 2342 01:27:26,362 --> 01:27:29,765 STATES GO ON TO MAKE THESE LARGE 2343 01:27:29,765 --> 01:27:32,168 TYPE 1 CELLS, HOWEVER 2344 01:27:32,168 --> 01:27:32,668 UNDERNON[INDISCERNIBLE] 2345 01:27:32,668 --> 01:27:33,603 CONDITIONS THESE TYPE 2 CELLS 2346 01:27:33,603 --> 01:27:36,305 ARE UNABLE TO DIFFERENT YAILT, 2347 01:27:36,305 --> 01:27:39,742 THESE TRANSLATION STATES ARE 2348 01:27:39,742 --> 01:27:40,676 UNABLE TO DIFFERENT JAIT INTO 2349 01:27:40,676 --> 01:27:42,044 TYPE 1. 2350 01:27:42,044 --> 01:27:42,678 APPROXIMATE INSTEAD THEY SPEND 2351 01:27:42,678 --> 01:27:43,946 TIME IN THESE TISSUES AND THEY 2352 01:27:43,946 --> 01:27:48,351 ARE OFTEN ASSOCIATED WITH THESE 2353 01:27:48,351 --> 01:27:49,518 MY O FIEB ROW BLASTS. 2354 01:27:49,518 --> 01:27:52,955 SO IN THE AREA WE STUDIED AND 2355 01:27:52,955 --> 01:27:54,690 PUBLISHED A FEW YEARS AGO, AND 2356 01:27:54,690 --> 01:27:57,226 THERE WERE A FEW PAPERS, 2357 01:27:57,226 --> 01:27:58,261 IULOUSED THEM HERE, 1 FROM 2358 01:27:58,261 --> 01:27:58,794 [INDISCERNIBLE] GROUP AND 2359 01:27:58,794 --> 01:28:00,930 ANOTHER 1 FROM [INDISCERNIBLE] 2360 01:28:00,930 --> 01:28:03,132 GROUP IN UK, SIMILARLY 2361 01:28:03,132 --> 01:28:04,066 IDENTIFIED THIS TRANSITIONAL 2362 01:28:04,066 --> 01:28:04,267 STATE. 2363 01:28:04,267 --> 01:28:05,935 AT THAT TIME WE DIDN'T KNOW WHAT 2364 01:28:05,935 --> 01:28:08,170 THIS TRANSITIONAL STATE ARE 2365 01:28:08,170 --> 01:28:08,704 ACTUALLY DOING. 2366 01:28:08,704 --> 01:28:10,973 ALL WE FOUND WAS THERE IS 2367 01:28:10,973 --> 01:28:11,507 ASSOCIATION. 2368 01:28:11,507 --> 01:28:13,276 AND THAT OPENED UP MORE 2369 01:28:13,276 --> 01:28:16,579 QUESTIONS, 1 OF THE QUESTION IS, 2370 01:28:16,579 --> 01:28:17,780 ARE THESE TRANSLATIONAL STATES 2371 01:28:17,780 --> 01:28:21,050 INVOLVED IN DEVELOPMENT OF 2372 01:28:21,050 --> 01:28:24,620 FIBROSIS. 2373 01:28:24,620 --> 01:28:25,254 NEXT PLEASE. 2374 01:28:25,254 --> 01:28:28,224 @ SAME TIME WE SAW WHEN AND 2375 01:28:28,224 --> 01:28:28,925 WHERE THEY EMERGE. 2376 01:28:28,925 --> 01:28:30,192 DO WE SEE DIFFERENT INJURY 2377 01:28:30,192 --> 01:28:33,496 CONDITIONS THAT IT'S ONLY 1 TYPE 2378 01:28:33,496 --> 01:28:34,797 AND THAT TOO, WHAT ARE THE 2379 01:28:34,797 --> 01:28:35,898 SENSES IN THE TISSUE. 2380 01:28:35,898 --> 01:28:37,199 IN OTHER WORDS IS THERE A LOSS 2381 01:28:37,199 --> 01:28:39,168 OF A SINGLE CELL TYPE IN THE 2382 01:28:39,168 --> 01:28:41,537 LUNG THAT LEADS TO INDUCTION OF 2383 01:28:41,537 --> 01:28:42,538 THESE TRANSITIONAL STATES? 2384 01:28:42,538 --> 01:28:46,375 AND THAT'S WHERE WE PROBED 2385 01:28:46,375 --> 01:28:47,476 ELIMINATING THESE DIFFERENT CELL 2386 01:28:47,476 --> 01:28:47,677 TYPES. 2387 01:28:47,677 --> 01:28:51,314 WE TARTED WITH THE TYPE 2 CELLS, 2388 01:28:51,314 --> 01:28:52,682 FIBROBLAST ENDOTHELIAL CELLS, I 2389 01:28:52,682 --> 01:28:56,819 WILL NOT SHOW ALL THE DATA, NEXT 2390 01:28:56,819 --> 01:28:57,053 PLEASE. 2391 01:28:57,053 --> 01:29:00,056 TWO PHARMA LAB MEMBERS WHO 2392 01:29:00,056 --> 01:29:02,425 CONDUCTED THESE EXPERIMENTS, 2393 01:29:02,425 --> 01:29:06,862 NEXT PLEASE, SO WE ELIMINATED 2394 01:29:06,862 --> 01:29:08,664 FIBROBLASTS IN CELL TYPES. 2395 01:29:08,664 --> 01:29:11,801 IT TURNS OUT THAT ELIMINATION OF 2396 01:29:11,801 --> 01:29:13,836 ATP ALONE IS SUFFICIENT TO 2397 01:29:13,836 --> 01:29:15,237 INDUCE TRANSITIONAL STATE AND 2398 01:29:15,237 --> 01:29:16,605 NOT ONLY THIS EPITHELIAL 2399 01:29:16,605 --> 01:29:21,110 TRANSITIONAL STATE BUT WE SEE A 2400 01:29:21,110 --> 01:29:23,012 CASCADE OF EVENTS THAT LED TO 2401 01:29:23,012 --> 01:29:24,380 WHOLE INJURY REPAIR PROGRAM 2402 01:29:24,380 --> 01:29:25,915 THAT'S ACTIVATED IN DIFFERENT 2403 01:29:25,915 --> 01:29:27,616 CELL TYPES INCLUDING IN THE 2404 01:29:27,616 --> 01:29:29,118 IMMUNE CELLS, FIBROBLASTS AND AS 2405 01:29:29,118 --> 01:29:33,289 WELL AS ENDOTHELIAL CELLS. 2406 01:29:33,289 --> 01:29:35,758 NEXT PLEASE. 2407 01:29:35,758 --> 01:29:36,192 NEXT. 2408 01:29:36,192 --> 01:29:41,630 AS I MENTIONED LOSS OF TYPE 1 2409 01:29:41,630 --> 01:29:42,565 ALONE INDUCED THESE CASCADE 2410 01:29:42,565 --> 01:29:43,366 [INDISCERNIBLE] WHICH CAN BE 2411 01:29:43,366 --> 01:29:45,668 SEEN HERE IN THIS HISTOLOGICAL 2412 01:29:45,668 --> 01:29:49,772 IMAGE AND THE CONTROL IS SIMPLE 2413 01:29:49,772 --> 01:29:52,575 HND WHEREAS AFTER AT1 ABLATION, 2414 01:29:52,575 --> 01:29:58,614 WE SEE THESE DENSE FIBROTIC, 2415 01:29:58,614 --> 01:30:00,149 SEMIFIBROTIC REGIONS IN THE 2416 01:30:00,149 --> 01:30:04,120 GREAT PROCESS. 2417 01:30:04,120 --> 01:30:04,887 NEXT PLEASE. 2418 01:30:04,887 --> 01:30:09,325 AND WE WANTED TO UNDERSTAND WHAT 2419 01:30:09,325 --> 01:30:11,660 ARE THE MOLECULAR EVENTS GOING 2420 01:30:11,660 --> 01:30:14,363 ON DURING REPAIR. 2421 01:30:14,363 --> 01:30:16,065 SO WE PERFORMED SINGLE 2422 01:30:16,065 --> 01:30:17,233 TRANSCRIPT ORDER OF MICRONS 2423 01:30:17,233 --> 01:30:19,402 ANALYSIS, THE SINGLE CELL TYPE, 2424 01:30:19,402 --> 01:30:21,470 LED TO DEVELOPMENT OF GENERATION 2425 01:30:21,470 --> 01:30:23,372 OF THESE CASCADE OF EVENTS 2426 01:30:23,372 --> 01:30:25,074 INCLUDING GENERATION OF THE 2427 01:30:25,074 --> 01:30:25,708 TRANSITIONAL STAGE. 2428 01:30:25,708 --> 01:30:28,644 WE CAN SEE HERE IN A TIME CODE, 2429 01:30:28,644 --> 01:30:31,614 NEXT PLEASE, AND WE ALSO -- 2430 01:30:31,614 --> 01:30:34,717 NEXT, WE ALSO LOOKED AT AMAZING 2431 01:30:34,717 --> 01:30:36,786 CHIMAL CELLS, IN THIS CASE WE 2432 01:30:36,786 --> 01:30:38,187 INTEGRATE DIFFERENT DATA SETS 2433 01:30:38,187 --> 01:30:39,688 FROM OUR OWN MULTIPLE INJURY 2434 01:30:39,688 --> 01:30:44,393 MODELS AS WELL AS OTHER DATA 2435 01:30:44,393 --> 01:30:48,030 SETS INCLUDING THE INJURY MODEL 2436 01:30:48,030 --> 01:30:49,665 FROM THE [INDISCERNIBLE] GROUP. 2437 01:30:49,665 --> 01:30:51,000 NEXT PLEASE. 2438 01:30:51,000 --> 01:30:51,767 WE FOWBD ESSENTIALLY DIFFERENT 2439 01:30:51,767 --> 01:30:56,872 CELL TYPES THAT OTHERS HAVE 2440 01:30:56,872 --> 01:30:58,074 DESCRIBED AND SOME UNIQUE 2441 01:30:58,074 --> 01:31:01,243 TRANSITIONAL STATES SOME ARE 2442 01:31:01,243 --> 01:31:04,914 MARKED BY META1, AND SFRP1 CELLS 2443 01:31:04,914 --> 01:31:07,716 AND WE CALL THEM INFLAMMATORY 2444 01:31:07,716 --> 01:31:09,885 FIBROBLASTS BASED ON SIGNATURES, 2445 01:31:09,885 --> 01:31:14,323 NEXT, PLEASE, AND WE ALSO FOUND 2446 01:31:14,323 --> 01:31:19,261 THESE RUNX1 CELLS AND REMODELING 2447 01:31:19,261 --> 01:31:19,562 FIBROBLASTS. 2448 01:31:19,562 --> 01:31:19,962 NEXT PLEASE. 2449 01:31:19,962 --> 01:31:23,732 THE REASON WE CALL THEM -- NEXT 2450 01:31:23,732 --> 01:31:24,567 -- THE REMODELING IS BECAUSE IF 2451 01:31:24,567 --> 01:31:28,437 WE LOOK AT THE SIGNATURES OF 2452 01:31:28,437 --> 01:31:30,272 THESE CELL STATES THESE ARE 2453 01:31:30,272 --> 01:31:31,774 TRANSIENT BUT WE SEE THE 2454 01:31:31,774 --> 01:31:33,742 FIBROBLAST, WE SEE A LOT OF 2455 01:31:33,742 --> 01:31:36,045 THESE COUNTS ASSOCIATE WIDE THE 2456 01:31:36,045 --> 01:31:39,682 ECM ASSEM MYELIN, ECM COLLAGEN, 2457 01:31:39,682 --> 01:31:41,117 [INDISCERNIBLE] AND VARIOUS 2458 01:31:41,117 --> 01:31:43,085 PROTEASES, AS YOU CAN CAN SEE 2459 01:31:43,085 --> 01:31:46,755 HERE IN THIS PLOT, THIS 2460 01:31:46,755 --> 01:31:47,823 TRANSIENT REMODELING FIBROBLAST, 2461 01:31:47,823 --> 01:31:50,759 ACTIVATE A LOT OF THESE ECM 2462 01:31:50,759 --> 01:31:53,028 RELATED PROTEINS. 2463 01:31:53,028 --> 01:31:53,529 NEXT PLEASE. 2464 01:31:53,529 --> 01:31:54,897 AND MORE IMPORTANTLY, SOME OF 2465 01:31:54,897 --> 01:31:57,700 THEM HAVE BEEN DESCRIBED AS 2466 01:31:57,700 --> 01:32:00,970 ASSOCIATED WITH DIFFERENT 2467 01:32:00,970 --> 01:32:03,239 DISEASES THROUGH GWAS STUDIES 2468 01:32:03,239 --> 01:32:06,075 INCLUDING THE TGF BETA PROTEIN 2469 01:32:06,075 --> 01:32:08,043 AND [INDISCERNIBLE], AND VARIOUS 2470 01:32:08,043 --> 01:32:11,180 OTHER ECM RELATED PROTEINS. 2471 01:32:11,180 --> 01:32:11,480 NEXT PLEASE. 2472 01:32:11,480 --> 01:32:13,549 SO JUST TO SUMMARIZE WHAT WE'VE 2473 01:32:13,549 --> 01:32:14,984 SHOWN, I'M NOT GOING TO SHOW ALL 2474 01:32:14,984 --> 01:32:18,387 THE MAJORS AND FOLLOW UP DATA 2475 01:32:18,387 --> 01:32:21,157 BUT UPON DAMAGE, FIRST WE SEE 2476 01:32:21,157 --> 01:32:26,896 IMAGES OF THESE ALVEOLAR 2477 01:32:26,896 --> 01:32:30,199 FIBROBLASTS TURNING INTO THESE 2478 01:32:30,199 --> 01:32:34,003 SFRP1 +, THEN WE ALSO SEE THE 2479 01:32:34,003 --> 01:32:36,172 TRANSITIONAL STATE, POSITIVE 2480 01:32:36,172 --> 01:32:39,508 CELLS OR BATPs AND THEN WE SEE 2481 01:32:39,508 --> 01:32:41,644 THE RUNX1 SALES DURING THE 2482 01:32:41,644 --> 01:32:42,211 INJURY REPAIR PROCESS. 2483 01:32:42,211 --> 01:32:43,979 SO WHEN THERE IS A SIMPLE 2484 01:32:43,979 --> 01:32:45,915 INJURY, THESE CELLS ARE GOING 2485 01:32:45,915 --> 01:32:47,082 THROUGH THE DIFFERENT TRANSITION 2486 01:32:47,082 --> 01:32:49,451 STEPS IN THE EPITHELIUM AND THE 2487 01:32:49,451 --> 01:32:50,886 FIBROBLAST AND THEY FULLY AREY 2488 01:32:50,886 --> 01:32:51,954 PAY, THEY GO BACK TO 2489 01:32:51,954 --> 01:32:52,321 [INDISCERNIBLE]. 2490 01:32:52,321 --> 01:32:53,355 HOWEVER, WE ASKED THE QUESTION, 2491 01:32:53,355 --> 01:32:55,357 WHAT IS THE ROLE OF THIS 2492 01:32:55,357 --> 01:32:56,725 TRANSITION STATES, WHAT HAPPENS 2493 01:32:56,725 --> 01:32:59,261 IF WE DISRUPT THEM, CAN WE 2494 01:32:59,261 --> 01:33:01,363 ACTIVATE THEM, CAN WE DEPLETE 2495 01:33:01,363 --> 01:33:03,933 THEM THROUGH GENETIC APPROACHES, 2496 01:33:03,933 --> 01:33:04,567 OF CELEBRATION APPROACHES. 2497 01:33:04,567 --> 01:33:06,769 THAT'S WHAT WE DID. 2498 01:33:06,769 --> 01:33:07,336 NEXT PLEASE. 2499 01:33:07,336 --> 01:33:10,172 SO HERE IS JUST AN EXAMPLE OF 2500 01:33:10,172 --> 01:33:13,809 SCHEMATIC WHEN WE ELIMINATED THE 2501 01:33:13,809 --> 01:33:15,211 EPITHELIAL TRANSITION STATE, 2502 01:33:15,211 --> 01:33:19,448 THROUGH GENETIC AS WELL AS VIRAL 2503 01:33:19,448 --> 01:33:21,183 BASED ABLATION APPROACHES AS 2504 01:33:21,183 --> 01:33:25,020 WELL AS FIBROBLASTS, BY DELETING 2505 01:33:25,020 --> 01:33:27,122 RUNX1 AND FIBROBLASTS ARE 2506 01:33:27,122 --> 01:33:27,823 ELIMINATING THE FIBROBLAST, WHAT 2507 01:33:27,823 --> 01:33:29,925 WE FOUND WAS INSTEAD OF REPAIR 2508 01:33:29,925 --> 01:33:31,860 THANKSGIVING TISSUE, THIS 2509 01:33:31,860 --> 01:33:33,162 TISSUE, ACTUALLY UNDERWENT 2510 01:33:33,162 --> 01:33:34,196 SIMPLIFYICATION, MEANING IT'S A 2511 01:33:34,196 --> 01:33:38,367 KIND OF A COMPROMISED IN WHICH 2512 01:33:38,367 --> 01:33:40,769 NO CELL SET UNDERGOING IMP 2513 01:33:40,769 --> 01:33:41,604 LIAISONFICATION INSTEAD OF 2514 01:33:41,604 --> 01:33:42,571 REBUILDING THE WHOLE THING, SO 2515 01:33:42,571 --> 01:33:44,440 THE WAY WE SEE THIS IS THAT IN 2516 01:33:44,440 --> 01:33:46,075 THE ABSENCE OF THESE 2517 01:33:46,075 --> 01:33:48,277 TRANSITIONAL STATES, BOTH IN THE 2518 01:33:48,277 --> 01:33:49,778 EPITHELIUM AND FIBROBLASTS, THIS 2519 01:33:49,778 --> 01:33:51,180 TISSUE IS UNABLE TO REBUILD 2520 01:33:51,180 --> 01:33:54,950 BACK, BECAUSE OF LACK OF THESE 2521 01:33:54,950 --> 01:33:56,218 STRUCTURAL COMPETENCE INCLUDING 2522 01:33:56,218 --> 01:33:58,787 MANY ECM PROTEINS THEY SIMPLY 2523 01:33:58,787 --> 01:34:00,856 UNDERGO COMPROMISE, IN OTHER 2524 01:34:00,856 --> 01:34:02,625 WORS TISSUE SIMPLIFICATION AS 2525 01:34:02,625 --> 01:34:03,459 SEEN IN EMSEEMA. 2526 01:34:03,459 --> 01:34:03,926 NEXT PLEASE. 2527 01:34:03,926 --> 01:34:05,594 OT OTHER HAND IF WE ACTIVATE 2528 01:34:05,594 --> 01:34:11,900 SOME OF THESE CELL STATES, 2529 01:34:11,900 --> 01:34:15,271 PERSISTENT, KEEP THEM LONGER 2530 01:34:15,271 --> 01:34:17,139 THROUGH EPIGENETIC AND 2531 01:34:17,139 --> 01:34:17,840 PHARMAICOLOGGICCAL APPROACHES 2532 01:34:17,840 --> 01:34:20,376 NOW WE SEE INCREASE IN TISSUE 2533 01:34:20,376 --> 01:34:22,144 COMPLEXITY WHERE DENSE MY O 2534 01:34:22,144 --> 01:34:24,880 FIBROBLASTS AND ECM PRODUCED 2535 01:34:24,880 --> 01:34:27,750 THAT LOOKS LIKE [INDISCERNIBLE] 2536 01:34:27,750 --> 01:34:28,617 FIEBOSEIS, WE PERFORMED 2537 01:34:28,617 --> 01:34:31,553 PHYSIOLOGICAL ASSAYS ANDY WOO 2538 01:34:31,553 --> 01:34:33,989 SEE SIMILAR OBSTRUCTIVE ON OR 2539 01:34:33,989 --> 01:34:35,724 RESTRICTIVE PHYSIOLOGY,AY 2540 01:34:35,724 --> 01:34:39,361 REFLECTING THE TOP EMPHYSEMA 2541 01:34:39,361 --> 01:34:45,934 PROCESS. 2542 01:34:45,934 --> 01:34:46,702 NEXT PLEASE. 2543 01:34:46,702 --> 01:34:48,237 SO NOW WE NEED TO UNDERSTAND HOW 2544 01:34:48,237 --> 01:34:49,605 THEY CONTROL THESE STATES. 2545 01:34:49,605 --> 01:34:51,240 FOR EXAMPLE IN AGING WE SEE MANY 2546 01:34:51,240 --> 01:34:52,541 MORE OF THESE ARE IN THE 2547 01:34:52,541 --> 01:34:56,845 DISEASES WE SEE, SO WHAT'S 2548 01:34:56,845 --> 01:34:57,780 HAPPENING DURING THESE 2549 01:34:57,780 --> 01:34:59,281 TRANSITIONS WITHIN EPITHELIUM 2550 01:34:59,281 --> 01:34:59,748 AND FIBROBLASTS. 2551 01:34:59,748 --> 01:35:03,419 AND ALSO HOW ARE DIFFERENT 2552 01:35:03,419 --> 01:35:05,154 SIGNALING PATHWAYS, DNA AND AND 2553 01:35:05,154 --> 01:35:07,022 INCREASE IN P53 SIGNALING ARE 2554 01:35:07,022 --> 01:35:11,393 MUTATIONS IN P53 SIGNALING, 2555 01:35:11,393 --> 01:35:12,461 IMPACT THE TRAJECTORY OF THESE 2556 01:35:12,461 --> 01:35:16,398 CELLS AND HOW DO WE RECOVER THEM 2557 01:35:16,398 --> 01:35:18,567 WHEN THERE IS ACTIVATION OF 2558 01:35:18,567 --> 01:35:20,035 EVIDENT ACTIVATION OF THESE 2559 01:35:20,035 --> 01:35:20,736 DIFFERENT PATHWAYS. 2560 01:35:20,736 --> 01:35:23,505 THESE 2 DIFFERENT DISEASES 2561 01:35:23,505 --> 01:35:27,142 ALTHOUGH FROM A CLINICAL POINT 2562 01:35:27,142 --> 01:35:29,978 OF VIEW EMPHYSEMA AND FIBROSIS 2563 01:35:29,978 --> 01:35:34,283 AT 2 OPPOSING SITES WE THINK 2564 01:35:34,283 --> 01:35:36,352 THAT THESE EMANATE FROM THE 2565 01:35:36,352 --> 01:35:39,588 SIMILAR EVENT THAT'S WHY I PUT 2566 01:35:39,588 --> 01:35:41,690 MY TITLE EMPHYSEMA AND FIBROSIS 2567 01:35:41,690 --> 01:35:44,326 AND 2 WITH THE SAME COIN AND THE 2568 01:35:44,326 --> 01:35:45,394 COIN IS THE INJURY REPAIR 2569 01:35:45,394 --> 01:35:46,595 PROCESS AND THE PATHWAYS 2570 01:35:46,595 --> 01:35:47,996 ASSOCIATED WITH THIS PROCESS. 2571 01:35:47,996 --> 01:35:50,766 AND INDEED, IN HUMANS WE KNOW 2572 01:35:50,766 --> 01:35:52,868 THAT THESE COMBINED PULMONARY 2573 01:35:52,868 --> 01:35:54,937 FIBROSIS AND EMPHYSEMA WHERE WE 2574 01:35:54,937 --> 01:35:56,105 CAN ACTUALLY SEE BOTH EVENTS ARE 2575 01:35:56,105 --> 01:35:58,540 HAPPENING IN THE SAME LUNGS, IN 2576 01:35:58,540 --> 01:36:00,409 SOME CASES IN FACT IN 2577 01:36:00,409 --> 01:36:01,577 NEIGHBORING REGIONS IN THIS 2578 01:36:01,577 --> 01:36:04,880 CASE, IT SHOWS THERE IS A 2579 01:36:04,880 --> 01:36:07,483 SECONDARY NODULE IN 1 SIDE IT'S 2580 01:36:07,483 --> 01:36:08,784 EMPHYSEMA, THE OTHER SIDE 2581 01:36:08,784 --> 01:36:13,489 FIEBOSEIS, SO WITH THAT, NEXT 2582 01:36:13,489 --> 01:36:13,722 PLEASE. 2583 01:36:13,722 --> 01:36:15,124 I WOULD LIKE TO THANK ALL MY LAB 2584 01:36:15,124 --> 01:36:16,859 MEMBER WHO IS HAVE ACTUALLY DONE 2585 01:36:16,859 --> 01:36:19,395 SOME OF THE PRESENT AND PAST 2586 01:36:19,395 --> 01:36:19,928 MEMBERS INCLUDING 2587 01:36:19,928 --> 01:36:21,130 [INDISCERNIBLE] WHO IS ALSO ON 2588 01:36:21,130 --> 01:36:22,431 THIS CALL AND FOR YOUR 2589 01:36:22,431 --> 01:36:22,698 ATTENTION. 2590 01:36:22,698 --> 01:36:33,175 HAPPY TO TAKE ANY QUESTIONS. 2591 01:36:34,476 --> 01:36:35,444 >> THANK YOU TATA FOR A GREAT 2592 01:36:35,444 --> 01:36:35,778 TALK. 2593 01:36:35,778 --> 01:36:37,379 WE ARE IN THE DISCUSSION PART OF 2594 01:36:37,379 --> 01:36:37,913 THE SESSION. 2595 01:36:37,913 --> 01:36:39,448 WE CAN GO OVER SOME QUESTIONS IN 2596 01:36:39,448 --> 01:36:41,917 THE CHAT BECAUSE I KNOW THAT 2597 01:36:41,917 --> 01:36:46,989 THERE ARE SOME GREAT QUESTIONS 2598 01:36:46,989 --> 01:36:48,624 THAT MAYBE IT'S BETTER TO 2599 01:36:48,624 --> 01:36:51,326 DISCUSS THEM IN PERSON EMPLOY 2600 01:36:51,326 --> 01:36:55,831 SO, I KNOW THAT 2601 01:36:55,831 --> 01:36:56,498 DR. [INDISCERNIBLE] HAS RAISED 2602 01:36:56,498 --> 01:36:58,400 HAND FOR A LONG TIME SO MAYBE WE 2603 01:36:58,400 --> 01:37:08,777 CAN GO WITH HIM FIRST. 2604 01:37:14,950 --> 01:37:16,151 WE CAN'T HEAR YOU. 2605 01:37:16,151 --> 01:37:16,518 >> HEM O. 2606 01:37:16,518 --> 01:37:17,920 >> NOW WE HEAR YOU. 2607 01:37:17,920 --> 01:37:18,720 >> THANK YOU. 2608 01:37:18,720 --> 01:37:19,087 THANK YOU. 2609 01:37:19,087 --> 01:37:22,658 THANK YOU ALL FOR -- THIS WAS AN 2610 01:37:22,658 --> 01:37:29,131 ABSOLUTELY WONDERFUL SESSION AND 2611 01:37:29,131 --> 01:37:33,535 THANK YOU ALL FOR BRINGING SUCH 2612 01:37:33,535 --> 01:37:34,937 NEW AND INTERESTING INFORMATION 2613 01:37:34,937 --> 01:37:36,238 EMPLOY I HAVE ALREADY A LOT OF 2614 01:37:36,238 --> 01:37:39,074 THE ANSWERS ALREADY WITH THE 2615 01:37:39,074 --> 01:37:42,144 EXCEPTION OF LAST, TATA, SO I 2616 01:37:42,144 --> 01:37:44,413 MAY GET STARTED WITH THAT, WHAT 2617 01:37:44,413 --> 01:37:50,452 I HAVE IF I READ WHAT I HAVE 2618 01:37:50,452 --> 01:37:52,087 JUST WRITTEN IT IS REMARKABLE 2619 01:37:52,087 --> 01:37:53,489 HOW MUCH THESE DISEASEITATES 2620 01:37:53,489 --> 01:37:54,790 NEAR DEVELOPMENT AND IN FACT, 2621 01:37:54,790 --> 01:38:01,163 BOTH IN HUMAN AND MICE, IN FACT 2622 01:38:01,163 --> 01:38:04,333 THIS, IS A PUBLICATION THAT IT'S 2623 01:38:04,333 --> 01:38:05,934 SOON TO COME FROM OUR LAB IN 2624 01:38:05,934 --> 01:38:11,039 CELL AND WHAT I WOULD LIKE TO 2625 01:38:11,039 --> 01:38:14,510 LEARN TATA, IS PROBABLY A 2626 01:38:14,510 --> 01:38:15,911 QUESTION THAT WE HAVE AND IT 2627 01:38:15,911 --> 01:38:17,546 APPEARS WHETHER THIS IS -- IS 2628 01:38:17,546 --> 01:38:19,281 THERE A LINK BETWEEN A 2629 01:38:19,281 --> 01:38:20,249 CHRONOLOGICAL LINK BETWEEN THE 2630 01:38:20,249 --> 01:38:21,750 APPEARANCE OF THESE MARKERS, FOR 2631 01:38:21,750 --> 01:38:26,822 EXAMPLE IN WHAT YOU HAVE 2632 01:38:26,822 --> 01:38:29,324 DESCRIBED IN THE FIBROSIS AND 2633 01:38:29,324 --> 01:38:32,494 ALSO, IS THERE ANY EVIDENCE THAT 2634 01:38:32,494 --> 01:38:35,230 WE CAN THINK THAT ALL OF THESE 2635 01:38:35,230 --> 01:38:37,199 MARKERS ARE FUNCTIONAL IN SOME 2636 01:38:37,199 --> 01:38:41,570 WAYS AND THERE'S OF COURSE THE 2637 01:38:41,570 --> 01:38:42,971 WORK FROM RACHEL [INDISCERNIBLE] 2638 01:38:42,971 --> 01:38:45,908 WHO TALKS ABOUT THE KERATIN 8, 2639 01:38:45,908 --> 01:38:47,409 YOU HAVE VERY INTERESTING 2640 01:38:47,409 --> 01:38:50,579 OBSERVATION ABOUT THE P53, BUT 2641 01:38:50,579 --> 01:38:53,048 THERE'S SO MANY OF THESE MARKERS 2642 01:38:53,048 --> 01:38:56,685 AND SO CONSERVATIVE, PLEASE ANY 2643 01:38:56,685 --> 01:38:58,053 THOUGHTS ABOUT THAT? 2644 01:38:58,053 --> 01:38:58,854 >> YEAH, ABSOLUTELY. 2645 01:38:58,854 --> 01:39:02,357 SO THE TRANSITION STATES IN 2646 01:39:02,357 --> 01:39:03,525 DISEASE, SO [INDISCERNIBLE] MOST 2647 01:39:03,525 --> 01:39:04,826 OF THE PROFILINGS AND ANALYSIS 2648 01:39:04,826 --> 01:39:08,463 THAT HAS BEEN DONE IN THE FIELD, 2649 01:39:08,463 --> 01:39:09,831 INCLUDING OUR OWN FROM HUMAN 2650 01:39:09,831 --> 01:39:11,600 TISSUES POINT OF VIEW, CAN'T 2651 01:39:11,600 --> 01:39:13,669 COME FROM LATE STAINLS, EVEN 2652 01:39:13,669 --> 01:39:16,204 THEN WE CAN ACTUALLY SEE 2653 01:39:16,204 --> 01:39:16,805 GRADIENTS OF [INDISCERNIBLE]. 2654 01:39:16,805 --> 01:39:19,107 SO THERE IS A REGION THAT'S 2655 01:39:19,107 --> 01:39:22,044 PROGRESSING AND WELL IS ALREADY 2656 01:39:22,044 --> 01:39:24,680 A DENSE FIBROTIC REGION, 2657 01:39:24,680 --> 01:39:26,281 BRONCHIALIZED REGION FOR EXAMPLE 2658 01:39:26,281 --> 01:39:29,651 IN FIBROSIS SO WE SEE THESE 2659 01:39:29,651 --> 01:39:31,954 EVENTS, THE DIFFERENT TYPES OF 2660 01:39:31,954 --> 01:39:33,221 [INDISCERNIBLE] AND STATES 2661 01:39:33,221 --> 01:39:35,057 ASSOCIATED MARKERS WAS THE 2662 01:39:35,057 --> 01:39:36,191 EPITHELIUM AND THE MESSENTERIEN 2663 01:39:36,191 --> 01:39:37,426 KINE IN THESE PROGRESSIVE ZONES 2664 01:39:37,426 --> 01:39:40,562 SO IN A WAY THE PROGRESSIVE 2665 01:39:40,562 --> 01:39:43,632 ZONES ACTUALLY GIVING DOES -- 2666 01:39:43,632 --> 01:39:46,735 VIEW THAT, YOU KNOW HOW -- WHAT 2667 01:39:46,735 --> 01:39:47,336 ARE THE CHRONOLOGICAL EVENTS 2668 01:39:47,336 --> 01:39:51,740 THAT ARE HAPPENING IN THE 2669 01:39:51,740 --> 01:39:52,207 DISEASE. 2670 01:39:52,207 --> 01:39:52,507 >> GREAT. 2671 01:39:52,507 --> 01:39:53,141 THANK YOU EMPLOY THANK YOU. 2672 01:39:53,141 --> 01:39:55,577 I WILL LEAVE YOU WITH THE OTHER 2673 01:39:55,577 --> 01:39:56,278 QUESTIONS OTHERWISE, I 2674 01:39:56,278 --> 01:39:58,113 UNDERSTAND TO THE AUDIENCE. 2675 01:39:58,113 --> 01:39:59,681 >> THAT IS A GOOD QUESTION, IF I 2676 01:39:59,681 --> 01:40:03,652 MAY READ OUT FROM CHRIS MOLENA, 2677 01:40:03,652 --> 01:40:05,053 ASKING ABOUT THE INJURY MODELS 2678 01:40:05,053 --> 01:40:08,056 THINKING THE RISES AND FALL OFF 2679 01:40:08,056 --> 01:40:10,459 OF RTP1 POSITIVE FIBROBLASTS 2680 01:40:10,459 --> 01:40:11,560 REGULATES AT281 TRANS8 HOURS, 2681 01:40:11,560 --> 01:40:13,862 INDEED ACTUALLY SO THIS IS 2682 01:40:13,862 --> 01:40:16,398 UNPUBLISHED DATA BUT WHAT WE 2683 01:40:16,398 --> 01:40:18,967 FOUND IS THESE SFP1 FIBROBLASTS 2684 01:40:18,967 --> 01:40:20,535 ARE THE FIRST TO EMERGE AND THE 2685 01:40:20,535 --> 01:40:22,304 WAY WE KNOW THAT IS, YOU KNOW IN 2686 01:40:22,304 --> 01:40:25,307 HUMAN IT'S HARD TO KNOW WHICH 1 2687 01:40:25,307 --> 01:40:27,476 COMES FIRST, WHICH 1 BUT THIS 2688 01:40:27,476 --> 01:40:29,077 ANIMAL MODELS WE CAN POST THE 2689 01:40:29,077 --> 01:40:30,946 INJURY AND THAT'S WHERE I LIKE 2690 01:40:30,946 --> 01:40:32,581 THE ABLATION MODEL, WE CAN 2691 01:40:32,581 --> 01:40:35,584 ABLATE THE TYPE 1 CELLS AND THEN 2692 01:40:35,584 --> 01:40:36,485 FOLLOW CHRONOLOGICALLY AND 2693 01:40:36,485 --> 01:40:39,388 THAT'S WHERE WE FOUND SFRP1 + 2694 01:40:39,388 --> 01:40:39,588 FIRST. 2695 01:40:39,588 --> 01:40:42,024 AND IF YOU LOOK AT THE NATURES, 2696 01:40:42,024 --> 01:40:44,526 THEY PRODUCE MANY INFLAMMATORY 2697 01:40:44,526 --> 01:40:46,228 CYTOKINES THAT RECRUIT 2698 01:40:46,228 --> 01:40:47,729 MACROPHAGES, SOME OF THE IMMUNE 2699 01:40:47,729 --> 01:40:50,365 POPULATIONS AS WELL AS THAT ALSO 2700 01:40:50,365 --> 01:40:53,402 STIMULATE THE NEIGHBORING TYPE 2 2701 01:40:53,402 --> 01:40:58,073 CELLS TO TRANSITION TO THE PATH 2702 01:40:58,073 --> 01:40:58,740 POPULATIONS, THE TRANSLATIONAL 2703 01:40:58,740 --> 01:40:59,241 STATES. 2704 01:40:59,241 --> 01:41:02,344 SO WE THINK THAT SFRP1 + 2705 01:41:02,344 --> 01:41:03,545 POPULATION IS ACTUALLY INDUCING 2706 01:41:03,545 --> 01:41:07,549 TYPE 2 CELLS TO INITIATE THE 2707 01:41:07,549 --> 01:41:08,250 EPITHELIAL AREA. 2708 01:41:08,250 --> 01:41:11,186 I HOPE THAT ADDRESS YOUR 2709 01:41:11,186 --> 01:41:11,820 QUESTION CORRECTLY. 2710 01:41:11,820 --> 01:41:13,989 >> I'D LIKE TO ADD A COUPLE -- 2711 01:41:13,989 --> 01:41:15,724 LIKE 1 COMMENT, I JUST WANT TO 2712 01:41:15,724 --> 01:41:17,459 SHARE THE OBSERVATION THAT WE 2713 01:41:17,459 --> 01:41:20,028 HAD, I KNOW THAT TATA, JUST 2714 01:41:20,028 --> 01:41:22,330 MENTIONED THAT IN HE THINKS THAT 2715 01:41:22,330 --> 01:41:26,501 SORT OF LIKE A TRANSITIONAL 2716 01:41:26,501 --> 01:41:28,770 FIBROBLAST COULD AFFECT OR 2717 01:41:28,770 --> 01:41:31,406 INITIATE THE AT2 OR AT1 INJURY, 2718 01:41:31,406 --> 01:41:33,475 AT LEAST IN MY MODEL, THE WORK 2719 01:41:33,475 --> 01:41:35,911 THAT I JUST SHARED IN 2720 01:41:35,911 --> 01:41:39,414 DEVELOPMENTAL MODEL, WE 2721 01:41:39,414 --> 01:41:40,082 BASICALLY PERTUSHED EPITHELIUM 2722 01:41:40,082 --> 01:41:42,818 AND WE SAW THE EMERGENCE OF 2723 01:41:42,818 --> 01:41:47,122 THOSE SFRP 1 POSITIVE AND THE 2724 01:41:47,122 --> 01:41:47,923 RUNX1 POSITIVE FIBROBLAST 2725 01:41:47,923 --> 01:41:50,092 MENTIONED THERE SO AT LEAST IN 2726 01:41:50,092 --> 01:41:52,728 MY MODEL, THE CHANGES IN THE 2727 01:41:52,728 --> 01:41:59,367 EPITHELIUM INDUCE THE CHANGES IN 2728 01:41:59,367 --> 01:41:59,735 FIBROBLAST. 2729 01:41:59,735 --> 01:42:02,838 >> YEAH, SO THOSE ARE BELIEVE 2730 01:42:02,838 --> 01:42:05,006 THE GENETIC MODELS, WHERE ARE 2731 01:42:05,006 --> 01:42:07,809 YOU ACTIVATING AND DELETING PART 2732 01:42:07,809 --> 01:42:12,180 OF THE GENE IN EPITHELIAL SALES. 2733 01:42:12,180 --> 01:42:14,382 SOPHISTICATEDY WOO DID COMPARE 2734 01:42:14,382 --> 01:42:19,387 MDMKNOCK OUT WHICH INDUCES P53, 2735 01:42:19,387 --> 01:42:21,690 AND THAT'S WHAT WE DID AND THAT 2736 01:42:21,690 --> 01:42:22,023 MODEL WE SEE. 2737 01:42:22,023 --> 01:42:23,892 AND IF WE APPROXIMATELY THIS 2738 01:42:23,892 --> 01:42:27,062 CHRONOLOGICAL ORDER WHAT WE SEE 2739 01:42:27,062 --> 01:42:31,933 IS, WE SEE THIS, THE SFRPT1 +, 2740 01:42:31,933 --> 01:42:38,807 AND THEN BECOMES RUNX1 POSITIVE 2741 01:42:38,807 --> 01:42:42,210 BUT THE QUESTION YOU BRING UP 2742 01:42:42,210 --> 01:42:44,012 AND WHO INDUCES WHO? 2743 01:42:44,012 --> 01:42:44,913 >> YES, YES. 2744 01:42:44,913 --> 01:42:46,114 >> IT CAN HAPPEN IN MULTIPLE 2745 01:42:46,114 --> 01:42:49,117 WAYINGS BUT IN A SIMPLE MODEL WE 2746 01:42:49,117 --> 01:42:50,552 THINK IT'S SFRP1 THAT INITIATES 2747 01:42:50,552 --> 01:42:52,020 TAKEN--THEY THE TYPE 2 CELLS. 2748 01:42:52,020 --> 01:42:54,923 THAT'S THE TRIGGER. 2749 01:42:54,923 --> 01:42:58,059 >> I SEE, I SEE. 2750 01:42:58,059 --> 01:43:05,333 >> BECAUSE YOU SEE LIKE VERY 2751 01:43:05,333 --> 01:43:06,301 INTERESTING PLOT INCREASE IN THE 2752 01:43:06,301 --> 01:43:09,738 IMMUNE CELL, IN THE COPD 2753 01:43:09,738 --> 01:43:11,206 PATIENTS IN PARTICULAR, 2754 01:43:11,206 --> 01:43:12,541 T-RESIDENTIAL MEMORY TISSUING 2755 01:43:12,541 --> 01:43:16,044 CELLS, I WONDER WHETHER YOU SEE 2756 01:43:16,044 --> 01:43:19,114 THE PREVIOUS [INDISCERNIBLE] AND 2757 01:43:19,114 --> 01:43:23,351 THE CD8 T-CELL INCREASE THE COPD 2758 01:43:23,351 --> 01:43:23,852 IN THE PATIENT. 2759 01:43:23,852 --> 01:43:27,189 DO YOU SEE ANY MARKER FOR THAT? 2760 01:43:27,189 --> 01:43:33,161 >> FOR THAT IN THE BRONCHIAL 2761 01:43:33,161 --> 01:43:34,095 ABLIT RANS. 2762 01:43:34,095 --> 01:43:35,430 IN COPD I DON'T HAVE IA LOT OF 2763 01:43:35,430 --> 01:43:37,833 PATIENT WHERE IS I COLLECTED 2764 01:43:37,833 --> 01:43:38,567 PARALLEL IMMUNE ENRICHED SAMPLES 2765 01:43:38,567 --> 01:43:40,769 WHICH IS HOW I APPROACHED THE 2766 01:43:40,769 --> 01:43:45,106 MANY OF THE RARE DISEASES 2767 01:43:45,106 --> 01:43:45,774 INCLUDING BRONCHIALITEIS OBLIT 2768 01:43:45,774 --> 01:43:47,242 RANS SO I CAN'T. 2769 01:43:47,242 --> 01:43:50,078 WE DO HAVE SOME EMPUNE CELLS IN 2770 01:43:50,078 --> 01:43:54,716 OUR COPD DATA SETS BUT WE 2771 01:43:54,716 --> 01:43:55,550 SPECIFICALLY DEPLETE 6 CD45 IN 2772 01:43:55,550 --> 01:43:57,752 ORDER TO ENRICH FOR THE 2773 01:43:57,752 --> 01:43:58,153 EPITHELIUM. 2774 01:43:58,153 --> 01:44:01,189 IN THE RARE DISEASES LIKE PH OS, 2775 01:44:01,189 --> 01:44:02,824 WE RUN THOSE IN PARALLEL SO WE 2776 01:44:02,824 --> 01:44:04,726 HAVE 2 DATA SETS WE CAN USE SO I 2777 01:44:04,726 --> 01:44:10,098 CAN'T SAY THAT I'VE LOOKED 2778 01:44:10,098 --> 01:44:20,242 EMPLOY. 2779 01:44:20,742 --> 01:44:21,009 >> THANK YOU. 2780 01:44:21,009 --> 01:44:22,911 NTHERE IS ANOTHER QUESTION FROM 2781 01:44:22,911 --> 01:44:24,546 MAURICEIO IN THE CHAT: DO YOU 2782 01:44:24,546 --> 01:44:26,314 THINK THIS IS ALSO THE CASE IN 2783 01:44:26,314 --> 01:44:28,550 OTHER INJURY MODELS LIKE 2784 01:44:28,550 --> 01:44:30,485 INFLUENZA VIRUS. 2785 01:44:30,485 --> 01:44:32,020 INDEED, ACTUALLY, YOU SEE THE 2786 01:44:32,020 --> 01:44:32,821 SIMILAR TRANSITION STATES THAT 2787 01:44:32,821 --> 01:44:34,055 ARE MATCH NOTHING DIFFERENT 2788 01:44:34,055 --> 01:44:34,956 INJURY MODELS. 2789 01:44:34,956 --> 01:44:40,695 WE HAVE TESTED LPS FLU MODEL, 2790 01:44:40,695 --> 01:44:45,500 HUMAN ACTIVE MODEL, ABLATION 2791 01:44:45,500 --> 01:44:48,270 MODELS IN DIFFERENT. 2792 01:44:48,270 --> 01:44:49,471 >> WE HAVE ANOTHER QUESTION 2793 01:44:49,471 --> 01:44:51,706 SAYING ANY COMMENTS ON THE ROLE 2794 01:44:51,706 --> 01:44:57,746 OF LGR5 CELLS IN ANY OF THESE 2795 01:44:57,746 --> 01:44:58,413 INJURY MODELS. 2796 01:44:58,413 --> 01:45:02,317 >> MAYBE I CAN START, SO LGR5 2797 01:45:02,317 --> 01:45:05,921 POSITIVE CELLS, WHAT WE HAVE 2798 01:45:05,921 --> 01:45:09,391 SEEN, THESE ARE PRESENT IN THE 2799 01:45:09,391 --> 01:45:10,692 PERIBRONCHIAL REGION, NOT IN THE 2800 01:45:10,692 --> 01:45:12,294 SPACE, AT LEAST DATA WE HAVE 2801 01:45:12,294 --> 01:45:16,264 SEEN IN HUMAN TISSUES. 2802 01:45:16,264 --> 01:45:20,001 AND I AM NOT SURE, IN MOUSE 2803 01:45:20,001 --> 01:45:22,370 MODELS OF ANYONE HAS THOSE 2804 01:45:22,370 --> 01:45:25,874 SPECIFIC LGR 5 USING THE LGR 5 2805 01:45:25,874 --> 01:45:27,409 BASED TOOLS BUT THERE ARE OTHER 2806 01:45:27,409 --> 01:45:29,010 MARKERS ASSOCIATED WITH THE 2807 01:45:29,010 --> 01:45:30,512 SIMILAR CELL TYPES AND INDEED, 2808 01:45:30,512 --> 01:45:32,914 THEY DO HAVE A ROLE IN 2809 01:45:32,914 --> 01:45:39,521 EPITHELIAL REPAIR IN THE 2810 01:45:39,521 --> 01:45:39,955 BRONCHIALS. 2811 01:45:39,955 --> 01:45:42,290 >> WE HAVE A QUESTION FROM 2812 01:45:42,290 --> 01:45:42,891 DR. SUSAN [INDISCERNIBLE] IS 2813 01:45:42,891 --> 01:45:44,826 THAT THE ABILITY OF AT2 CELLS 2814 01:45:44,826 --> 01:45:47,262 GIVE RISE TO A TRANSITIONAL CELL 2815 01:45:47,262 --> 01:45:49,331 IN ORDER TO ULTIMATELY BECOME 2816 01:45:49,331 --> 01:45:53,234 AT1 CELLS, IS A GREAT ADVANCE IN 2817 01:45:53,234 --> 01:45:54,703 UNDERSTANDING THE REGENERATION 2818 01:45:54,703 --> 01:45:57,205 OF THE [INDISCERNIBLE] OR 2819 01:45:57,205 --> 01:45:58,606 EPITHELIUM INJURY, CAN ANY OF 2820 01:45:58,606 --> 01:46:00,208 THE SPEAKERS SPEAK TO HOW THEIR 2821 01:46:00,208 --> 01:46:02,177 RESEARCH PROGRAMS ARE ADDRESSING 2822 01:46:02,177 --> 01:46:04,212 THE RESILIENCE AS APPROXIMATE 2823 01:46:04,212 --> 01:46:14,723 PERTAINS TO AT2 SELF-RENEWAL? 2824 01:46:21,529 --> 01:46:24,165 >> DR. HAN, MAYBE YOU WANT TO 2825 01:46:24,165 --> 01:46:24,432 TAKE THAT? 2826 01:46:24,432 --> 01:46:26,601 >> YES, IT COULD BE MORE OF AN 2827 01:46:26,601 --> 01:46:29,371 ABILITY TO PROLIFERATE FOR THE 2828 01:46:29,371 --> 01:46:31,106 AT2 CELLS, I WILL TRANSLATE IT 2829 01:46:31,106 --> 01:46:32,741 THAT WAY, I MEAN OBVIOUSLY THE 2830 01:46:32,741 --> 01:46:34,876 RESEARCH THAT I SHOWED SO FAR IS 2831 01:46:34,876 --> 01:46:38,780 MORE OF THE CELL FATE, AND 2832 01:46:38,780 --> 01:46:39,814 DIFFERENTIATION RATHER THAN 2833 01:46:39,814 --> 01:46:40,148 PROLIFERATION. 2834 01:46:40,148 --> 01:46:47,756 WE HAVE SOME UNPUBLISHED DATA TO 2835 01:46:47,756 --> 01:46:49,491 SUGGEST THAT 1 OF THE ISR 2836 01:46:49,491 --> 01:46:52,694 PATHWAYS ESPECIALLY FOR THE ATF 2837 01:46:52,694 --> 01:46:59,401 4, MAY BE INVOLVED IN THE CAUSAL 2838 01:46:59,401 --> 01:47:01,236 PATHWAY FOR CELL PROLIFERATION 2839 01:47:01,236 --> 01:47:06,207 AS LIKE AN AT2 STEM CELL 2840 01:47:06,207 --> 01:47:06,541 PROLIFERATION. 2841 01:47:06,541 --> 01:47:14,082 BUT, THAT'S ALL I CAN SAY, MAYBE 2842 01:47:14,082 --> 01:47:16,484 DR. [INDISCERNIBLE] CAN FILL IT 2843 01:47:16,484 --> 01:47:17,252 IN. 2844 01:47:17,252 --> 01:47:17,619 >> SURE, SURE. 2845 01:47:17,619 --> 01:47:19,854 THAT'S AGAIN WHERE WE TARTED 2846 01:47:19,854 --> 01:47:20,655 USING ABLATION MODEL. 2847 01:47:20,655 --> 01:47:22,290 WE PUBLISHED SOME OF THE WORK SO 2848 01:47:22,290 --> 01:47:24,826 IF WE ABLATE TYPE 1 CELL, TYPE 2 2849 01:47:24,826 --> 01:47:27,695 CELL, THE FIRST PREFERENCE IS TO 2850 01:47:27,695 --> 01:47:28,163 DIFFERENTIATE. 2851 01:47:28,163 --> 01:47:32,233 SO IF WE JUST LOOK AT THE EVENTS 2852 01:47:32,233 --> 01:47:33,768 OF WHAT ARE THE [INDISCERNIBLE] 2853 01:47:33,768 --> 01:47:36,337 OF TYPE 2 CELLS, FIRST BEGINS 2854 01:47:36,337 --> 01:47:36,704 DIFFERENTIATION. 2855 01:47:36,704 --> 01:47:39,374 IT GENERATES THE TYPE 1 CELLS 2856 01:47:39,374 --> 01:47:41,576 AND THEN, THE REMAINING TYPE 2 2857 01:47:41,576 --> 01:47:43,878 CELLS SURVEYED IN THE 2858 01:47:43,878 --> 01:47:50,151 NEIGHBORING ALVERMEN 2859 01:47:50,151 --> 01:47:52,087 NEIGHBORING ALVOELI, AND WE HAVE 2860 01:47:52,087 --> 01:47:54,622 2 LENGTHS OF EVIDENCE, 1 USING 2861 01:47:54,622 --> 01:47:57,092 CLONAL LABELING EXPERIENCE WHERE 2862 01:47:57,092 --> 01:47:59,060 WE CAN LABEL CLONEALLY TYPE 2 2863 01:47:59,060 --> 01:48:03,164 CELLS AND ELIMINATE SOME OF THEM 2864 01:48:03,164 --> 01:48:06,534 AND THESE 2 MAKE ONLY TYPE 2 2865 01:48:06,534 --> 01:48:06,768 CELLS. 2866 01:48:06,768 --> 01:48:10,472 AND THIS HAS BEEN SHOWN BY 2867 01:48:10,472 --> 01:48:13,041 ANOTHER PAPER RECENTLY BY IT WAS 2868 01:48:13,041 --> 01:48:15,076 A COLLABORATION WITH MAURICEIO 2869 01:48:15,076 --> 01:48:16,678 [INDISCERNIBLE] AND 2870 01:48:16,678 --> 01:48:17,512 [INDISCERNIBLE] USING LIVE 2871 01:48:17,512 --> 01:48:18,346 IMAGING APPROACHES WHERE WE CAN 2872 01:48:18,346 --> 01:48:19,414 SEE THE SAME THING. 2873 01:48:19,414 --> 01:48:23,184 TYPE 2 CELLS FROM 1 ALVEOLAR 2874 01:48:23,184 --> 01:48:24,853 COMPARTMENT MIGRATE INTO OTHER 2875 01:48:24,853 --> 01:48:29,190 COMPARTMENTS, THEY CAN 2876 01:48:29,190 --> 01:48:30,458 ACTUALLYY PENETRATE THROUGH THE 2877 01:48:30,458 --> 01:48:33,661 WALL, THEY CAN GO TO THE CONE TO 2878 01:48:33,661 --> 01:48:36,831 REACH THE NEIGHBORING ALVEOLAR 2879 01:48:36,831 --> 01:48:38,666 SACKS AND THIS IS WHICH THROUGH 2880 01:48:38,666 --> 01:48:40,401 THEY ARE TYPE 2 CELLS RECRUITED. 2881 01:48:40,401 --> 01:48:41,736 HOWEVER, IN MY MIND WHAT WE 2882 01:48:41,736 --> 01:48:45,073 DON'T KNOW IS, WHAT HELPS THE 2883 01:48:45,073 --> 01:48:45,640 TYPE 2 CELL. 2884 01:48:45,640 --> 01:48:48,710 THERE IS ANOTHER TYPE 2 CELL 2885 01:48:48,710 --> 01:48:49,811 MISSING IN NEIGHBORING 2886 01:48:49,811 --> 01:48:50,111 COMPARTMENT. 2887 01:48:50,111 --> 01:48:53,882 WE DON'T KNOW WHAT ARE THE TYPES 2888 01:48:53,882 --> 01:48:56,117 OF SIGNALS THAT THE SECRETERS 2889 01:48:56,117 --> 01:48:58,386 FACTORS THAT ARE COMMUNICATING 2890 01:48:58,386 --> 01:49:02,123 THROUGH THESE CELLS OR 2891 01:49:02,123 --> 01:49:02,757 NEIGHBORING CELLS LIKE 2892 01:49:02,757 --> 01:49:03,958 FIBROBLASTSER OTHER CELLS 2893 01:49:03,958 --> 01:49:04,592 COMMUNICATING, THERE ARE 2894 01:49:04,592 --> 01:49:05,527 DIFFERENT MECH NICHES, WE DON'T 2895 01:49:05,527 --> 01:49:06,027 KNOW THAT. 2896 01:49:06,027 --> 01:49:08,796 SO SEEMS LIKE THE TYPE 2 CELLS, 2897 01:49:08,796 --> 01:49:11,099 AND DIFFERENTIATION ARE TIGHTLY 2898 01:49:11,099 --> 01:49:11,933 CONTROLLED, AT LEAST BASED ON 2899 01:49:11,933 --> 01:49:15,236 SOME OF THESE ABLATION 2900 01:49:15,236 --> 01:49:15,737 EXPERIMENTS WE'VE SEEN. 2901 01:49:15,737 --> 01:49:17,672 DO YOU KNOW WHEN TO REPLICATE, 2902 01:49:17,672 --> 01:49:19,174 THEY KNOW WHEN TO DIFFERENTIATE 2903 01:49:19,174 --> 01:49:21,009 AND THEY HAVE A FIRST PREFERENCE 2904 01:49:21,009 --> 01:49:24,345 IN A BROADER INJURY MODEL, THEY 2905 01:49:24,345 --> 01:49:25,847 MUST DEFERENTIATE BEFORE THE 2906 01:49:25,847 --> 01:49:26,781 REPLICATION NETWORK QUICK 2907 01:49:26,781 --> 01:49:27,115 QUESTION. 2908 01:49:27,115 --> 01:49:29,484 SO YOU THINK THAT WITH ABLATION, 2909 01:49:29,484 --> 01:49:32,954 THE TYPE 2 CELL INITTIAIATES 2910 01:49:32,954 --> 01:49:34,022 DIFFERENTIATION FIRST AND THEN 2911 01:49:34,022 --> 01:49:35,757 TRY TO SELF-RENEW LATER? 2912 01:49:35,757 --> 01:49:37,258 >> THAT'S WHAT WE SEE, AT LEAST 2913 01:49:37,258 --> 01:49:39,427 IN TYPE 1 CELL ABLATION MODEL. 2914 01:49:39,427 --> 01:49:40,628 BECAUSE IN OTHER INJURY MODELS 2915 01:49:40,628 --> 01:49:41,930 IT'S HARD TO GUESS THAT. 2916 01:49:41,930 --> 01:49:43,898 >> I MEAN THAT'S WHAT THE 2917 01:49:43,898 --> 01:49:45,533 [INDISCERNIBLE] PUBLISHED A 2918 01:49:45,533 --> 01:49:47,268 COUPLE YEARS AGO. 2919 01:49:47,268 --> 01:49:49,871 ESSENTIA WILY THAT'S WHAT HE'S 2920 01:49:49,871 --> 01:49:52,173 SEEN TOO, BUT THEN THINKING 2921 01:49:52,173 --> 01:49:54,108 PHILOSOPHICALLY WHY WOULD BODY 2922 01:49:54,108 --> 01:49:55,476 WANT TO DIFFERENTIATE BEFORE 2923 01:49:55,476 --> 01:50:00,348 PROLIFERATE TO RE7 THEIR STEM 2924 01:50:00,348 --> 01:50:00,915 CELL? 2925 01:50:00,915 --> 01:50:02,116 PHILOSOPHICALLY DO YOU ANY 2926 01:50:02,116 --> 01:50:02,784 THOUGHTS ON THAT? 2927 01:50:02,784 --> 01:50:03,985 >> I THINK CONNECTED TO 2928 01:50:03,985 --> 01:50:04,752 PHYSIOLOGY. 2929 01:50:04,752 --> 01:50:05,653 WHAT IS THE MOST IMPORTANT CELL 2930 01:50:05,653 --> 01:50:07,555 TYPE IN THE LUNG IN MY VIEW IT'S 2931 01:50:07,555 --> 01:50:08,890 THE TYPE 1 CELL BECAUSE THAT'S 2932 01:50:08,890 --> 01:50:11,859 THE FUNCTIONAL CELL THAT'S 2933 01:50:11,859 --> 01:50:12,994 PARTICIPATING IN BREATH 2934 01:50:12,994 --> 01:50:13,261 EXCHANGE. 2935 01:50:13,261 --> 01:50:15,163 THAT'S THE FIRST PLACE IT NEEDS 2936 01:50:15,163 --> 01:50:17,065 TO PASS THROUGH BEFORE IT GETS 2937 01:50:17,065 --> 01:50:17,665 TO THE ENDOTHELIUM. 2938 01:50:17,665 --> 01:50:21,069 IT NEEDS TO MAKE THAT GAS ICS 2939 01:50:21,069 --> 01:50:22,337 CHANGING CELL. 2940 01:50:22,337 --> 01:50:23,805 -- GAS EXCHANGING CELL. 2941 01:50:23,805 --> 01:50:26,641 >> DR. JAY WAS GOING TO SAY 2942 01:50:26,641 --> 01:50:27,041 SOMETHING. 2943 01:50:27,041 --> 01:50:29,644 >> OH NO, SIRRA LYNN ASKED A 2944 01:50:29,644 --> 01:50:30,545 VERY THOUGHTFUL QUESTION, IT 2945 01:50:30,545 --> 01:50:34,015 ISN'T IN DETAIL BUT RATHER HAS 2946 01:50:34,015 --> 01:50:35,049 CONCEPTUAL IMPLICATIONS FOR DEC 2947 01:50:35,049 --> 01:50:39,654 AND SHED SOME INJURIES ARE ACUTE 2948 01:50:39,654 --> 01:50:41,256 WHILE THE CHRONIC DISEASE 2949 01:50:41,256 --> 01:50:43,124 DEVELOPMENT PROCESS STIEPS TAKES 2950 01:50:43,124 --> 01:50:44,726 DECADESMENT ARE THERE SHORT 2951 01:50:44,726 --> 01:50:46,828 LIVED VERSUS LONG LASTING 2952 01:50:46,828 --> 01:50:47,862 TRANSITIONAL CELL STATES WHERE 2953 01:50:47,862 --> 01:50:50,098 THE LATTER BECOME A STABLE 2954 01:50:50,098 --> 01:50:50,765 PATHOLOGIC CELL TYPE? 2955 01:50:50,765 --> 01:50:53,301 SO THAT'S A VERY INTRIGUING 2956 01:50:53,301 --> 01:50:54,535 QUESTION AND FOR EXAMPLE, 1 2957 01:50:54,535 --> 01:50:56,237 PLACE WHERE THAT MIGHT COME UP 2958 01:50:56,237 --> 01:51:00,174 IS IN THE IDEA OF FIELD 2959 01:51:00,174 --> 01:51:00,541 CANCERRIZATION. 2960 01:51:00,541 --> 01:51:03,111 WHERE HAVE YOU A SUBCLINICAL 2961 01:51:03,111 --> 01:51:05,079 CLONE THAT THEN EXPANDS AND YOU 2962 01:51:05,079 --> 01:51:06,247 WOULDN'T EVEN KNOW THAT IT'S 2963 01:51:06,247 --> 01:51:09,150 INCREASED AND THERE WOULD BE THE 2964 01:51:09,150 --> 01:51:11,085 SIMPLE MINDED EXPLANATION OF 2965 01:51:11,085 --> 01:51:12,120 ONCOGENIC STRESS THAT WOULD 2966 01:51:12,120 --> 01:51:15,523 CAUSE THAT SO JUST A COMPETITIVE 2967 01:51:15,523 --> 01:51:16,224 CELL COMPETITION MODEL, WHERE 2968 01:51:16,224 --> 01:51:18,726 YOU WOULD GET A BIG FIELD THAT 2969 01:51:18,726 --> 01:51:20,261 HAD LET'S SAY P53 OR KRASE 2970 01:51:20,261 --> 01:51:22,196 MODEL, AND THEN THAT FIELD WOULD 2971 01:51:22,196 --> 01:51:24,732 THEN BE SUBJECT TO MORE 2972 01:51:24,732 --> 01:51:26,467 GENOTOXIC STRESS, SO I THINK 2973 01:51:26,467 --> 01:51:27,635 SARAH THAT'S 1 WAY YOU COULD 2974 01:51:27,635 --> 01:51:28,936 IMAGINE IT, BUT NOW WE'RE 2975 01:51:28,936 --> 01:51:31,472 LOOKINGA THE A DIVERSITY OF 2976 01:51:31,472 --> 01:51:33,508 DIFFERENT CELL TYPES SO IT COULD 2977 01:51:33,508 --> 01:51:37,712 BE FOR EXAMPLE, IN MY CASE, THE 2978 01:51:37,712 --> 01:51:39,013 HILLOCK BASAL COULD EXPAND AND 2979 01:51:39,013 --> 01:51:41,716 THEN IT COULD ACTUALLY ALSO 2980 01:51:41,716 --> 01:51:42,250 BECOME PLASTIC. 2981 01:51:42,250 --> 01:51:44,118 BUT THAT DOESN'T MEAN THAT THAT 2982 01:51:44,118 --> 01:51:46,754 CELL THAT'S BECOME PLASTIC 2983 01:51:46,754 --> 01:51:49,457 DOESN'T RETAIN AN EPIGENETIC 2984 01:51:49,457 --> 01:51:51,426 MEMORY OF ITS HILLOCK STATE. 2985 01:51:51,426 --> 01:51:53,695 IN WHICH CASE THE ENTIRE 2986 01:51:53,695 --> 01:51:56,297 EPITHEMUAL MAY HAVE A 2987 01:51:56,297 --> 01:51:57,365 PREDISPOSITION TO BECOMING 2988 01:51:57,365 --> 01:51:59,133 SQUAMOUS LATER AND BECOMING 2989 01:51:59,133 --> 01:51:59,701 INJURY RESISTANT. 2990 01:51:59,701 --> 01:52:03,504 AS I MENTIONED VERY BRIEFLY THAT 2991 01:52:03,504 --> 01:52:05,139 SAM [INDISCERNIBLE] AND WHO IS 2992 01:52:05,139 --> 01:52:08,576 THE FELLOW AT UC -- PETER 2993 01:52:08,576 --> 01:52:11,045 CAMPBELL HAD PREVIOUSLY 2994 01:52:11,045 --> 01:52:14,716 DESCRIBED THE CELL TYPE THAT 2995 01:52:14,716 --> 01:52:16,117 EMERGED AFTER WHOSE 2996 01:52:16,117 --> 01:52:17,151 PROPORTIONALITY INCREASED AFTER 2997 01:52:17,151 --> 01:52:18,119 THE CESSATION OF SMOKING. 2998 01:52:18,119 --> 01:52:22,123 SO I THINK THAT'S EXACTLY WHAT 2999 01:52:22,123 --> 01:52:22,790 YOU'RE KIND OF TALKING ABOUT, 3000 01:52:22,790 --> 01:52:25,393 AND I THINK THAT'S PROBABLY A 3001 01:52:25,393 --> 01:52:26,561 HILLOCK LIKE CELL OR SOME OTHER 3002 01:52:26,561 --> 01:52:31,699 CELL THAT THEN HAS A SELECTIVE 3003 01:52:31,699 --> 01:52:34,635 ADVANTAGE LATER, BUT THEN THOSE 3004 01:52:34,635 --> 01:52:36,704 SAME CELLS WILL BE ANDROGENIC, 3005 01:52:36,704 --> 01:52:39,741 BUT AT SOME POINT, THE RESILIENT 3006 01:52:39,741 --> 01:52:40,942 CELL ITSELF WHICH EXPANDED 3007 01:52:40,942 --> 01:52:42,777 DURING THE COURSE OF INJURY THEN 3008 01:52:42,777 --> 01:52:44,045 BECOME SUBJECT TO PATHOLOGY. 3009 01:52:44,045 --> 01:52:45,680 SO I THINK IT'S VERY, YOU KNOW 3010 01:52:45,680 --> 01:52:47,782 IF THAT'S THE ONLY CELL LEFT, 3011 01:52:47,782 --> 01:52:49,083 THEN IT'S GOING TO BECOME A 3012 01:52:49,083 --> 01:52:49,317 CANCER. 3013 01:52:49,317 --> 01:52:50,952 BUT I THINK IT'S A VERY 3014 01:52:50,952 --> 01:52:52,754 THOUGHTFUL QUESTION, AND I THINK 3015 01:52:52,754 --> 01:52:54,689 EACH DIFFERENT KIND OF INJURY 3016 01:52:54,689 --> 01:52:56,858 PARADIGM, IT'S GOING TO HAVE A 3017 01:52:56,858 --> 01:52:57,258 DIFFERENT ANSWER. 3018 01:52:57,258 --> 01:52:59,227 AND I LIKE VERY MUCH THE WAY YOU 3019 01:52:59,227 --> 01:53:02,296 PHRASED LIKE, THE ACUTE RESPONSE 3020 01:53:02,296 --> 01:53:03,564 TO INJURY, VERSUS THE CHRONIC, 3021 01:53:03,564 --> 01:53:05,767 BECAUSE IT'S A DISTINCTION WE 3022 01:53:05,767 --> 01:53:09,604 SEE IN THE CLINIC ALL THE TIME 3023 01:53:09,604 --> 01:53:10,338 AND VERY INTERESTING. 3024 01:53:10,338 --> 01:53:12,907 >> JAY, I HAVE A FOLLOW UP 3025 01:53:12,907 --> 01:53:13,174 QUESTION. 3026 01:53:13,174 --> 01:53:15,076 I HAD A FOLLOW UP QUESTION TO 3027 01:53:15,076 --> 01:53:15,810 THAT ACTUALLY. 3028 01:53:15,810 --> 01:53:17,779 >> SERE A THINK SARAH'S TRYING 3029 01:53:17,779 --> 01:53:19,714 TO SAY SOMETHING. 3030 01:53:19,714 --> 01:53:22,550 >> SORRY, SO REAL QUICKLY, I 3031 01:53:22,550 --> 01:53:29,323 THINK MY QUESTION WAS TRIGGERED 3032 01:53:29,323 --> 01:53:31,426 BY TATA, SAYING INJURY RESOLVED, 3033 01:53:31,426 --> 01:53:32,260 TRANSITIONAL CELLS WENT BACK TO 3034 01:53:32,260 --> 01:53:34,328 NORMAL SO THIS IS RELATED AT 3035 01:53:34,328 --> 01:53:36,197 WHAT POINT THIS IS REVERSIBLE 3036 01:53:36,197 --> 01:53:36,798 VERSUS NOT? 3037 01:53:36,798 --> 01:53:39,400 I THINK FOR LOSS OF THE CHRONIC 3038 01:53:39,400 --> 01:53:42,904 DISEASE FIBROTIC OR EMPHYSEMA, 3039 01:53:42,904 --> 01:53:46,007 WE SEE THAT IS TERMINALLY STAGED 3040 01:53:46,007 --> 01:53:47,575 SO THAT MEANS THEY'RE NOT 3041 01:53:47,575 --> 01:53:48,976 REVERSIBLE ANYMORE. 3042 01:53:48,976 --> 01:53:50,745 SO, I THINK THIS IS A MILLION 3043 01:53:50,745 --> 01:53:54,348 DOLLAR QUESTION WHETHER WE CAN 3044 01:53:54,348 --> 01:53:56,517 PUSH THE REVERSIBLE ACTION OF 3045 01:53:56,517 --> 01:53:59,821 THE TRANSITIONAL CELL TYPE, SO I 3046 01:53:59,821 --> 01:54:00,388 WILL STOP HERE. 3047 01:54:00,388 --> 01:54:01,456 THANK YOU BOTH EMPLOY REALLY 3048 01:54:01,456 --> 01:54:02,857 NICE TO SEE EVERYONE. 3049 01:54:02,857 --> 01:54:05,426 >> JOSE DID YOU HAVE A QUESTION. 3050 01:54:05,426 --> 01:54:09,597 >> YEAH, JUST TO KIND OF FOLLOW 3051 01:54:09,597 --> 01:54:11,065 UP ON THAT. 3052 01:54:11,065 --> 01:54:14,635 MAYBE A PROVOCATIVE QUESTION, 3053 01:54:14,635 --> 01:54:15,203 ARE HILLOCK'S REQUIRED? 3054 01:54:15,203 --> 01:54:19,140 LIKE DO YOU NEED THEM IN A 3055 01:54:19,140 --> 01:54:19,807 NORMAL PHYSIOLOGICAL STATE? 3056 01:54:19,807 --> 01:54:25,746 AND HOW EARLY DO YOU SEE THEM, 3057 01:54:25,746 --> 01:54:27,715 DO YOU THINK THEY ARE THE RESULT 3058 01:54:27,715 --> 01:54:30,551 OF MINOR INJURIES THAT OCCUR, 3059 01:54:30,551 --> 01:54:31,619 ALMOST KIND OF MISTAKES THAT 3060 01:54:31,619 --> 01:54:33,454 LEAD TO THAT PATCH WORK EMERGE 3061 01:54:33,454 --> 01:54:35,857 FROM THAT OR IS IT MERELY A 3062 01:54:35,857 --> 01:54:36,624 HOMEOSTATIC STRUCTURE? 3063 01:54:36,624 --> 01:54:37,758 >> SO THESE ARE FASCINATING 3064 01:54:37,758 --> 01:54:38,659 QUESTIONS, YOU KNOW AND I DON'T 3065 01:54:38,659 --> 01:54:43,064 HAVE ALL THE ANSWERS, TO YOUR 3066 01:54:43,064 --> 01:54:44,565 FIRST QUESTION ARE HILLOCKS 3067 01:54:44,565 --> 01:54:45,500 NECESSARY, IT REQUIRES AN 3068 01:54:45,500 --> 01:54:47,034 ABLATION AND IT REQUIRES THE 3069 01:54:47,034 --> 01:54:49,971 ABLATION TO BE SO EXTREME THAT 3070 01:54:49,971 --> 01:54:52,707 YOU KNOW YOU WOULD NEARLY NEED A 3071 01:54:52,707 --> 01:54:53,574 HUNDRED PERCENT EFFICIENCY. 3072 01:54:53,574 --> 01:54:55,309 SO WE CAN'T ANSWER THAT 3073 01:54:55,309 --> 01:54:56,110 QUESTION. 3074 01:54:56,110 --> 01:54:58,212 AND IT WOULD BECOME 3075 01:54:58,212 --> 01:54:58,880 QUANTITATIVE. 3076 01:54:58,880 --> 01:54:59,547 YOU KNOW? 3077 01:54:59,547 --> 01:55:01,315 BECOME A QUANTITATIVE RESCUE OF 3078 01:55:01,315 --> 01:55:02,517 A REGENERATION AND OUR INJURY 3079 01:55:02,517 --> 01:55:04,552 MODELS IN MOUSE ARE SO PRIMITIVE 3080 01:55:04,552 --> 01:55:07,288 THAT THEY CAN NEVER BE 3081 01:55:07,288 --> 01:55:08,122 STANDARDIZED SUFFICIENTLY TO GET 3082 01:55:08,122 --> 01:55:09,857 LIKE, YOU KNOW IF YOU THINK 3083 01:55:09,857 --> 01:55:12,159 ABOUT HDM OR YOU THINK ABOUT 3084 01:55:12,159 --> 01:55:13,928 SO2, YOU WILL NOT PULL OUT GREAT 3085 01:55:13,928 --> 01:55:14,462 ANSWERS FOR THAT. 3086 01:55:14,462 --> 01:55:16,430 SO WE WILL HAVE TO DO DIFFERENT 3087 01:55:16,430 --> 01:55:18,099 KINDS OF EXPERIMENTS WHERE WE 3088 01:55:18,099 --> 01:55:19,600 MARK CELLS AND FOLLOW THEIR 3089 01:55:19,600 --> 01:55:22,003 LINEAGE AND SEE LIKE, HOW MUCH 3090 01:55:22,003 --> 01:55:25,006 THEY'RE ABLE TO COMPETE WITH 3091 01:55:25,006 --> 01:55:25,373 THEIR NEIGHBORS. 3092 01:55:25,373 --> 01:55:28,009 NOW THE SECOND QUESTION IS EVEN 3093 01:55:28,009 --> 01:55:29,510 MORE INTRIGUING JOSE AND I 3094 01:55:29,510 --> 01:55:30,811 THINK, YOU KNOW I'M NOT GOING TO 3095 01:55:30,811 --> 01:55:33,814 BE ABLE TO GIVE YOU A SIMPLE 3096 01:55:33,814 --> 01:55:35,283 ANSWER, BECAUSE IT KEEPS 3097 01:55:35,283 --> 01:55:35,550 CHANGING. 3098 01:55:35,550 --> 01:55:37,952 BUT I WOULD HAVE TOLD YOU BEFORE 3099 01:55:37,952 --> 01:55:39,720 THAT THE HILLOCK PATTERN IS 3100 01:55:39,720 --> 01:55:41,355 STABILIZED AT ABOUT 8 WEEKS. 3101 01:55:41,355 --> 01:55:45,426 BUT IT TURNS OUT THAT IF YOU 3102 01:55:45,426 --> 01:55:46,994 LOOK VERY SUBLY THEN WE CAN GO 3103 01:55:46,994 --> 01:55:50,765 BACK TO 2 WEEKS WHERE THERE'S A 3104 01:55:50,765 --> 01:55:55,536 HILLOCK PATTERN AND BUT THEY'RE 3105 01:55:55,536 --> 01:55:56,637 MUCH SMALLER HILLOCKS. 3106 01:55:56,637 --> 01:55:59,106 AND SO, AN UNDERLYING QUESTION 3107 01:55:59,106 --> 01:56:01,442 BECOMES IS THERE THE COMPETENCY 3108 01:56:01,442 --> 01:56:04,378 TO FORM HILLOCKS THAT IS 3109 01:56:04,378 --> 01:56:05,179 ACTUALLY STEREO TYPICALLY 3110 01:56:05,179 --> 01:56:06,414 DISTRIBUTED THAT, IS TO SAY VERY 3111 01:56:06,414 --> 01:56:08,015 RARE CELLS WHERE IT WOULD BE 3112 01:56:08,015 --> 01:56:09,617 LIKE A NORMAL 3113 01:56:09,617 --> 01:56:11,586 DEVELOPMENTALLENTITY WHERE YOU 3114 01:56:11,586 --> 01:56:14,121 JUST HAVE SCATTERED HILLOCKS 3115 01:56:14,121 --> 01:56:16,157 THAT WERE BILATERALLY SYMMETRIC 3116 01:56:16,157 --> 01:56:17,391 ALONG THE ACIS AND SOMETHING 3117 01:56:17,391 --> 01:56:19,026 HAPPENS AND YOU CAN HAVE A 3118 01:56:19,026 --> 01:56:22,363 MASSIVE EXPANSION OF THAT CELL 3119 01:56:22,363 --> 01:56:23,230 TYPE, LIKE JOHN [INDISCERNIBLE] 3120 01:56:23,230 --> 01:56:24,865 WHO IS ON THE TALK PREVIOUSLY 3121 01:56:24,865 --> 01:56:26,300 SUGGESTED THERE MAY BE SOMETHING 3122 01:56:26,300 --> 01:56:28,736 LIKE THIS AT THE ESOPHAGEAL 3123 01:56:28,736 --> 01:56:30,104 GHASTIC POUNDRY SO THAT REMAINS 3124 01:56:30,104 --> 01:56:30,371 POSSIBLE. 3125 01:56:30,371 --> 01:56:32,106 AND THEN TO THE THIRD COMPONENT. 3126 01:56:32,106 --> 01:56:34,408 YOU ASKED A VERY COMPLICATED 3127 01:56:34,408 --> 01:56:40,014 QUESTION, ALL OF IT INTERESTING. 3128 01:56:40,014 --> 01:56:42,550 I THINK WHY ARE THEY THIS WAY? 3129 01:56:42,550 --> 01:56:45,620 AND IT MIGHT BE AS SIMPLE AS THE 3130 01:56:45,620 --> 01:56:47,455 MOUSE HOLDING ITS NECK IN A 3131 01:56:47,455 --> 01:56:49,390 CERTAIN DIRECTION AND THE 3132 01:56:49,390 --> 01:56:50,424 ESOPHAGUS PRESSING UP AGAINST 3133 01:56:50,424 --> 01:56:51,726 THE TRACHEA IN A CERTAIN WAY 3134 01:56:51,726 --> 01:56:55,062 THAT WOULD BE DIFFERENT IN 3135 01:56:55,062 --> 01:56:56,030 DIFFERENT PEOPLE, DIFFERENT MICE 3136 01:56:56,030 --> 01:56:57,131 FOR THAT MATTER. 3137 01:56:57,131 --> 01:57:00,668 AND I DO THINK AS A QUESTION, 3138 01:57:00,668 --> 01:57:01,836 WELLING TON OR [INDISCERNIBLE] 3139 01:57:01,836 --> 01:57:04,038 ASKED THAT THESE THINGS ARE 3140 01:57:04,038 --> 01:57:06,240 CAUSED TO OUTGROW BY PHYSICAL 3141 01:57:06,240 --> 01:57:13,914 TRANSDUCTION, BY SOME KIND OF 3142 01:57:13,914 --> 01:57:14,715 MECHANO TRANSDUCTION PATHWAY AND 3143 01:57:14,715 --> 01:57:17,718 I THINK THE BEST WAY TO THINK OF 3144 01:57:17,718 --> 01:57:18,886 THEM METAPHORICALLY IS THE 3145 01:57:18,886 --> 01:57:20,187 CALLOUSES ON YOUR HAND. 3146 01:57:20,187 --> 01:57:22,923 THERE'S THE CAPACITY TO FORM 3147 01:57:22,923 --> 01:57:24,325 CALLOUSES AND THEY'RE NOT 3148 01:57:24,325 --> 01:57:25,826 STEREOTYPE, YOU KNOW IT DEPENDS 3149 01:57:25,826 --> 01:57:31,132 ON HOW YOU HOLD THE OAR AS YOUR 3150 01:57:31,132 --> 01:57:33,167 ROWING, BUT EVERY DAY WITH THE 3151 01:57:33,167 --> 01:57:34,902 WEAR AND TEAR, YOUR HAND IS NOT 3152 01:57:34,902 --> 01:57:37,505 AS SMOOTH AS A BABY, SO THROUGH 3153 01:57:37,505 --> 01:57:40,041 WEAR AND TEAR YOU DEVELOP 3154 01:57:40,041 --> 01:57:43,344 POPULATIONS THAT ARE NOT STEREO 3155 01:57:43,344 --> 01:57:45,279 TYPICALLY ARRANGED BUT ARE 3156 01:57:45,279 --> 01:57:45,713 FUNCTIONALLY USEFUL. 3157 01:57:45,713 --> 01:57:48,649 DOES THAT ANSWER YOUR QUESTION 3158 01:57:48,649 --> 01:57:49,183 JOSE? 3159 01:57:49,183 --> 01:57:52,887 >> YES, EXCELLENT. 3160 01:57:52,887 --> 01:57:53,487 THANK YOU. 3161 01:57:53,487 --> 01:57:56,190 NTHERE IS A QUESTION FROM 3162 01:57:56,190 --> 01:57:57,591 [INDISCERNIBLE] CHEN, MAYBE THIS 3163 01:57:57,591 --> 01:57:59,427 IS RELATED TO MARIAS WHAT ARE 3164 01:57:59,427 --> 01:58:01,228 YOUR THOUGHTS ON THE TERMINAL 3165 01:58:01,228 --> 01:58:04,098 CELL CONTRIBUTION TO THE 3166 01:58:04,098 --> 01:58:09,203 ALVEOLAR TRANSITIONAL STAGE LIKE 3167 01:58:09,203 --> 01:58:09,737 IN IBF? 3168 01:58:09,737 --> 01:58:11,372 >> YEAH, SO I THINK IT'S 3169 01:58:11,372 --> 01:58:12,540 POSSIBLE. 3170 01:58:12,540 --> 01:58:16,577 I THINK THERE'S THIS IDEA OF THE 3171 01:58:16,577 --> 01:58:18,179 [INDISCERNIBLE] POPULATION IN 3172 01:58:18,179 --> 01:58:19,680 IBF THAT MULTIPLE GROUPS HAVE 3173 01:58:19,680 --> 01:58:21,315 SHOWN IN SINGLE CELL SEQUENCING, 3174 01:58:21,315 --> 01:58:24,118 SO PEOPLE WHO ARE HERE, WHICH I 3175 01:58:24,118 --> 01:58:26,554 THINK YOU KNOW MIGHT BE A 3176 01:58:26,554 --> 01:58:27,588 DISTINCT POPULATION POTENTIALLY 3177 01:58:27,588 --> 01:58:30,558 FROM THE TRANSITIONAL CELL 3178 01:58:30,558 --> 01:58:33,627 STATES, AND MAY BE RELATED BUT 3179 01:58:33,627 --> 01:58:36,997 MAY ALSO BE DIFFERENT AND IF YOU 3180 01:58:36,997 --> 01:58:38,165 USE SORT OF BIOINFORMATIC 3181 01:58:38,165 --> 01:58:39,366 ANALYSIS, AND IT LOOKS LIKE 3182 01:58:39,366 --> 01:58:41,335 THOSE COULD BE RELATED TO THE 3183 01:58:41,335 --> 01:58:43,137 AIRWAY COUNTERPARTS AT LEAST IN 3184 01:58:43,137 --> 01:58:44,004 HUMAN CELLS. 3185 01:58:44,004 --> 01:58:47,374 BUT TESTING THAT DIRECTLY WILL 3186 01:58:47,374 --> 01:58:48,676 REQUIRE EITHER ORGANOID MODELING 3187 01:58:48,676 --> 01:58:49,376 AND UNDERSTANDING THE SIGNALS 3188 01:58:49,376 --> 01:58:54,081 THAT GO INTO THAT, OR SOME OTHER 3189 01:58:54,081 --> 01:58:55,716 SORT OF ANIMAL MODEL WITH 3190 01:58:55,716 --> 01:58:57,518 LINEAGE TRACING LIKE IN THE 3191 01:58:57,518 --> 01:58:58,586 FERRET MODEL. 3192 01:58:58,586 --> 01:58:59,954 >> THERE WAS A PAPER FROM 3193 01:58:59,954 --> 01:59:02,790 [INDISCERNIBLE] GROUP WHO HAD 3194 01:59:02,790 --> 01:59:04,158 THE [INDISCERNIBLE] LINEAR MODEL 3195 01:59:04,158 --> 01:59:06,327 AND THEY FOUND SOX 2 POSITIVE 3196 01:59:06,327 --> 01:59:07,762 CELLS, ALTHOUGH THEY DIDN'T GET 3197 01:59:07,762 --> 01:59:09,163 TO THE DETAILS, WHICH 1 EXACTLY 3198 01:59:09,163 --> 01:59:12,032 BUT THEY CAN ALSO GENERATE THIS 3199 01:59:12,032 --> 01:59:13,768 TRANSITIONAL STATE WHICH THEN 3200 01:59:13,768 --> 01:59:15,002 EEIVETTUALLY BECOME TYPE 1 CELLS 3201 01:59:15,002 --> 01:59:19,206 ALTHOUGH IT'S TO A LOWER DEGREE, 3202 01:59:19,206 --> 01:59:19,673 NOT MANY CELLS. 3203 01:59:19,673 --> 01:59:21,675 >> AND THE QUESTION IS ARE THOSE 3204 01:59:21,675 --> 01:59:23,677 THE AIRWAY CELLS THAT CONTRIBUTE 3205 01:59:23,677 --> 01:59:26,080 TO THE ALVEOLAR CELLS THAT GO ON 3206 01:59:26,080 --> 01:59:27,014 TO NORMAL DIFFERENTIATION AND 3207 01:59:27,014 --> 01:59:28,949 THE CELLS IN THE HUMAN 3208 01:59:28,949 --> 01:59:30,151 POPULATION THE SAME OR 3209 01:59:30,151 --> 01:59:30,417 DIFFERENT? 3210 01:59:30,417 --> 01:59:31,685 >> YEAH, YEAH, THERE IS A BIG 3211 01:59:31,685 --> 01:59:32,720 DIFFERENCE BETWEEN MOUSE AND 3212 01:59:32,720 --> 01:59:33,921 MUSEUM MAN ACTUALLY, THESE 3213 01:59:33,921 --> 01:59:36,423 TRANSITIONAL STATES BECAUSE THE 3214 01:59:36,423 --> 01:59:39,660 HUMAN EVIDENT BASED CELLS AS THE 3215 01:59:39,660 --> 01:59:42,496 NAME SUGGESTS THEY EXPRESS THESE 3216 01:59:42,496 --> 01:59:44,098 BASE WILL CHARACTERISTIC MARKERS 3217 01:59:44,098 --> 01:59:46,300 BUT IN MICE WE HAVEN'T SEEN ANY 3218 01:59:46,300 --> 01:59:54,742 OF THE MODELS WE TESTED. 3219 01:59:54,742 --> 01:59:55,042 >> YEAH. 3220 01:59:55,042 --> 01:59:56,143 >> TATA, I HAVE A QUESTION, 3221 01:59:56,143 --> 01:59:57,645 FOLLOW UP WHY YOU DESCRIEWB 3222 01:59:57,645 --> 02:00:02,616 EARLY, WHEN YOU HAVE LIKE TYPE 2 3223 02:00:02,616 --> 02:00:05,219 CELL TRENDS ALVEOLAR INTO THE 3224 02:00:05,219 --> 02:00:08,989 OTHER SPACE FOR REPAIR, THAT 3225 02:00:08,989 --> 02:00:10,424 PARTICULAR TYPE 2 CELL MAY BE 3226 02:00:10,424 --> 02:00:11,725 ALREADY IN THE TRANSITION STAGE 3227 02:00:11,725 --> 02:00:15,563 AND THEN TARTED REPAIR PROCESS 3228 02:00:15,563 --> 02:00:17,531 WHILE MAINTAINING TYPE 2 CELL 3229 02:00:17,531 --> 02:00:18,532 FEATURE? 3230 02:00:18,532 --> 02:00:20,134 >> YEAH SO THAT'S ACTUALLY 3231 02:00:20,134 --> 02:00:20,901 REALLY INTERESTING PART. 3232 02:00:20,901 --> 02:00:22,770 THE PRECISE QUESTION WE TESTED 3233 02:00:22,770 --> 02:00:25,072 USING THIS ABLATION MODEL, IF 3234 02:00:25,072 --> 02:00:26,941 YOU ELIMINATE TYPE 2 CELLS, THEY 3235 02:00:26,941 --> 02:00:29,043 MAY GREAT THE REPLICATE, THEY 3236 02:00:29,043 --> 02:00:30,110 MIGRATE AND MAINTAIN AS ONLY 3237 02:00:30,110 --> 02:00:32,046 TYPE 2, WE DON'T SEE ANY 3238 02:00:32,046 --> 02:00:32,880 [INDISCERNIBLE] TO TYPE 1. 3239 02:00:32,880 --> 02:00:34,615 SO THEY KNOW XAKLY WHEN TO 3240 02:00:34,615 --> 02:00:38,652 RESPOND TO EITHER REPLICATE, 3241 02:00:38,652 --> 02:00:39,687 MIGRATE, VERSUS DEFERENTIATE. 3242 02:00:39,687 --> 02:00:41,288 YEAH, HOWEVER, IF YOU DO THE 3243 02:00:41,288 --> 02:00:43,023 SAME THING IN [INDISCERNIBLE] 3244 02:00:43,023 --> 02:00:44,658 MICE IN INJURY MODEL FOR 3245 02:00:44,658 --> 02:00:47,928 EXAMPLE, THEY CAN MIGRATE AND 3246 02:00:47,928 --> 02:00:48,896 REPAIR GENERATE TYPE 1 CELL 3247 02:00:48,896 --> 02:00:58,806 SPACE, SO IT'S ALL ABOUT THE 3248 02:00:58,806 --> 02:00:59,006 NEED. 3249 02:00:59,006 --> 02:01:03,577 >> THANK YOU. 3250 02:01:03,577 --> 02:01:09,617 >> JAY, YOU HAVE A QUESTION FROM 3251 02:01:09,617 --> 02:01:10,985 MAURICIO, ARE THESE STATES 3252 02:01:10,985 --> 02:01:13,087 SIMILAR TO TRANSIENT 3253 02:01:13,087 --> 02:01:13,420 POPULATIONS? 3254 02:01:13,420 --> 02:01:16,090 >> IN AS MUCH AS PATS ARE 3255 02:01:16,090 --> 02:01:16,757 FUNCTIONAL NORMAL INTERMEDIATES, 3256 02:01:16,757 --> 02:01:21,061 I THINK THAT WOULD BE AN 3257 02:01:21,061 --> 02:01:22,329 APPROPRIATE COMPARISON. 3258 02:01:22,329 --> 02:01:25,633 THEY MAY HAVE SOME HOMEOSTATIC 3259 02:01:25,633 --> 02:01:27,334 CONSTANT FUNCTION THOUGH WHICH 3260 02:01:27,334 --> 02:01:28,669 WOULD BE DIFFERENT, SO IN OTHER 3261 02:01:28,669 --> 02:01:31,138 WORDS, YOU COULD HAVE A 3262 02:01:31,138 --> 02:01:33,307 TRANSIENT STATE THAT IS NOT 3263 02:01:33,307 --> 02:01:34,008 FUNCTIONAL, ALTHOUGH THERE'S 3264 02:01:34,008 --> 02:01:36,510 BEEN TALK THAT YOU KNOW THE 3265 02:01:36,510 --> 02:01:40,314 TRAPPED STATE IN DISEASE WILL 3266 02:01:40,314 --> 02:01:41,815 HAVE FUNCTIONAL IMPLICATIONS. 3267 02:01:41,815 --> 02:01:43,851 THE HILLOCK AS FAR AS WE CAN 3268 02:01:43,851 --> 02:01:48,522 TELL DOESN'T HAVE ANY DETAILS 3269 02:01:48,522 --> 02:01:49,957 RIMENTAL STATE FUNCTION AND WE 3270 02:01:49,957 --> 02:01:52,393 LOOKEDDA THE THAT AND 1 OF MY 3271 02:01:52,393 --> 02:01:56,463 POST DOCTORAL FELLOWS CANNED 3272 02:01:56,463 --> 02:01:57,364 CANNED -- 3273 02:01:57,364 --> 02:01:58,265 [INDISCERNIBLE] HAS PUBLISHED 3274 02:01:58,265 --> 02:02:00,467 THAT THERE ARE PATCHES IN THE 3275 02:02:00,467 --> 02:02:03,537 BACK OF THE HUMAN AIRWAY THAT 3276 02:02:03,537 --> 02:02:05,406 WERE BRAHMAATICALLY SIMILAR TO 3277 02:02:05,406 --> 02:02:06,540 HILLOCKS BUT WHEN SHE CULTURES 3278 02:02:06,540 --> 02:02:10,377 THOSE IN A BUNCH OF SIGNALING 3279 02:02:10,377 --> 02:02:12,479 CASCADES SHE SEES A WEAKENED 3280 02:02:12,479 --> 02:02:13,080 BARRIER SO BECAUSE OF THE 3281 02:02:13,080 --> 02:02:14,915 DISTRIBUTION OF THESE CELLS IS 3282 02:02:14,915 --> 02:02:20,054 SO SIMILAR TO THAT OF HILLOCKS, 3283 02:02:20,054 --> 02:02:22,756 IT'S POSSIBLE THAT THEY'RE 3284 02:02:22,756 --> 02:02:24,959 DISEASED HILLOCKS SO MAURICIO, 3285 02:02:24,959 --> 02:02:26,927 I'M HAVING A HARD TIME 3286 02:02:26,927 --> 02:02:28,095 ARTICCULING A SPECIFIC ANSWER TO 3287 02:02:28,095 --> 02:02:29,263 YOUR QUESTION BUT I GUESS WHAT I 3288 02:02:29,263 --> 02:02:30,898 WOULD SAY IS MAYBE YOUR ANALOGY 3289 02:02:30,898 --> 02:02:34,535 IS ACTUALLY QUITE A GOOD 1. 3290 02:02:34,535 --> 02:02:37,705 BECAUSE THE HILLOCKS MAY BE 3291 02:02:37,705 --> 02:02:38,973 SUPER TRANSITION STATE AT BASE 3292 02:02:38,973 --> 02:02:41,041 LINE BUT I SUPPOSE WHAT I'M 3293 02:02:41,041 --> 02:02:43,344 SEEING IS THAT THIS GROUP OF 3294 02:02:43,344 --> 02:02:44,278 EXCELLENT YOUNG INVESTIGATORS 3295 02:02:44,278 --> 02:02:47,214 HAS TAKEN A DISEASE AND SHOWN 3296 02:02:47,214 --> 02:02:50,918 HOW THAT TRANSITION STATE MAY BE 3297 02:02:50,918 --> 02:02:53,020 AN ABERRANT PATHIO LOGICALLY 3298 02:02:53,020 --> 02:02:53,821 SIGNIFICANT ENTITY BUT WE 3299 02:02:53,821 --> 02:02:55,489 HAVEN'T YET DONE THAT WITH THE 3300 02:02:55,489 --> 02:02:56,757 HILLOCK AND I THINK THAT IS WHAT 3301 02:02:56,757 --> 02:02:58,425 WE NEED TO DO SO I THINK WE NEED 3302 02:02:58,425 --> 02:03:00,995 TO LOOK AT COPD AND ASTHMA AND 3303 02:03:00,995 --> 02:03:02,563 ASK FOR THESE ABERRANT HILLOCKS 3304 02:03:02,563 --> 02:03:05,065 THAT COULD BE CAUSING PROBLEMS? 3305 02:03:05,065 --> 02:03:07,034 SO THAT -- AT FIRST I WAS 3306 02:03:07,034 --> 02:03:08,002 CONFUSE BY YOUR QUESTION BUT I 3307 02:03:08,002 --> 02:03:09,603 THINK IT'S A GREAT QUESTION. 3308 02:03:09,603 --> 02:03:13,907 ONE I WILL THINK MORE ABOUT. 3309 02:03:13,907 --> 02:03:17,578 >> THERE IS A QUESTION FROM 3310 02:03:17,578 --> 02:03:18,946 DAVID [INDISCERNIBLE]. 3311 02:03:18,946 --> 02:03:21,815 HE IS ASKING ABOUT GIVEN THE 3312 02:03:21,815 --> 02:03:23,517 EXTENSIVE PLASTICITY OF THESE 3313 02:03:23,517 --> 02:03:25,285 DISTAL LUNG CELLS, IT IS HARD TO 3314 02:03:25,285 --> 02:03:26,387 UNDERSTAND WHERE RESILIENCE 3315 02:03:26,387 --> 02:03:31,158 FALLS AND LUNG DISEASE DEVELOPS, 3316 02:03:31,158 --> 02:03:33,193 FROM MY SOMEWHAT [INDISCERNIBLE] 3317 02:03:33,193 --> 02:03:34,862 PERSPECTIVE, I WOULD ASK WHERE 3318 02:03:34,862 --> 02:03:38,065 DO THESE CELL MECHANISMS FAIL. 3319 02:03:38,065 --> 02:03:46,306 WHERE ARE WEAK LINKS IN CELL 3320 02:03:46,306 --> 02:03:48,242 PLASTICITY? 3321 02:03:48,242 --> 02:03:48,442 MARIA? 3322 02:03:48,442 --> 02:03:51,278 OR SEUNG, DO I WANT TO TAKE ON 3323 02:03:51,278 --> 02:03:51,478 THAT? 3324 02:03:51,478 --> 02:04:00,587 >> YEAH, I DON'T THINK IT'S NOT 3325 02:04:00,587 --> 02:04:01,455 NAIVE AT ALL. 3326 02:04:01,455 --> 02:04:02,790 I THINK THAT -- THE KEY NOTE 3327 02:04:02,790 --> 02:04:04,758 RIGHT WHICH IS THE WHYED THAT IF 3328 02:04:04,758 --> 02:04:06,960 WE REALLY WANTED TO DRILL DOWN 3329 02:04:06,960 --> 02:04:08,128 ON THAT HUMAN SPECIFIC SYSTEM, 3330 02:04:08,128 --> 02:04:12,499 WE EITHER HAVE TO DEVELOP 3331 02:04:12,499 --> 02:04:13,901 LONGITUDINAL COHORTS SO WE CAN 3332 02:04:13,901 --> 02:04:15,436 UNDERSTAND HOW THE CELL 3333 02:04:15,436 --> 02:04:16,336 SIGNALING CHANGES OVER THESE 3334 02:04:16,336 --> 02:04:19,973 DEVELOPMENTS OR WE HAVE TO FIND 3335 02:04:19,973 --> 02:04:21,608 MODELS AND THE MODELS MAY BE 3336 02:04:21,608 --> 02:04:23,377 DIFFERENT FOR EACH CELL TYPE 3337 02:04:23,377 --> 02:04:24,845 INTERACTION, RIGHT? 3338 02:04:24,845 --> 02:04:26,580 THE BEST CELL SYSTEM TO STUDY IN 3339 02:04:26,580 --> 02:04:27,981 THE AT1 OR 2 TRANSITION IS MAY 3340 02:04:27,981 --> 02:04:29,483 NOT BE THE BEST MODEL SYSTEM 3341 02:04:29,483 --> 02:04:32,152 THAT WE STUDY THE DEVELOPMENT OF 3342 02:04:32,152 --> 02:04:34,321 THE BASAL CELL IF IT COMES FROM 3343 02:04:34,321 --> 02:04:41,595 AN AIRWAY BASAL CELL OR 3344 02:04:41,595 --> 02:04:45,666 SECRETATTORY, SO OW HE USE OUR 3345 02:04:45,666 --> 02:04:48,068 MODELS OR LAUNCH LONGITUDINAL 3346 02:04:48,068 --> 02:04:49,837 COHORTS, WILL HELP US UNDERSTAND 3347 02:04:49,837 --> 02:04:52,206 CELLULAR CHARACTERISTICS THAT 3348 02:04:52,206 --> 02:04:53,941 COULD CLUE US INTO CELL 3349 02:04:53,941 --> 02:04:56,009 PLASTICITY OVER TIME AND MAYBE 3350 02:04:56,009 --> 02:04:58,679 WHY I HAD REGENERATE BUT WE ALSO 3351 02:04:58,679 --> 02:04:59,847 MAY BE ABLE TO STUDY THE 3352 02:04:59,847 --> 02:05:01,248 DIFFERENCE IN HOW THESE CELLS 3353 02:05:01,248 --> 02:05:02,649 RESPOND IN ACUTE INJURIES THAT 3354 02:05:02,649 --> 02:05:05,185 WE DON'T BELIEVE GO ON TO POST 3355 02:05:05,185 --> 02:05:05,919 CHRONIC DISEASE VERSUS ACUTE 3356 02:05:05,919 --> 02:05:08,188 INJURIES THAT GO ON TO CHRONIC 3357 02:05:08,188 --> 02:05:09,723 DEC SO THERE ARE INHERENT 3358 02:05:09,723 --> 02:05:20,267 DIFFERENCES IN HOW THE CELLS ARE 3359 02:05:27,074 --> 02:05:27,274 RESHAPED. 3360 02:05:27,274 --> 02:05:29,243 NTHEY HAVE PROPOSE THE EVIDENCE 3361 02:05:29,243 --> 02:05:30,844 BASED SALES FOR [INDISCERNIBLE] 3362 02:05:30,844 --> 02:05:32,412 BASAL CELLS AS WELL. 3363 02:05:32,412 --> 02:05:36,483 THAT'S IN HUMAN THAT'S HARD TO 3364 02:05:36,483 --> 02:05:37,784 ASK QUESTION BECAUSE OF LACK OF 3365 02:05:37,784 --> 02:05:43,724 THESE TOOLS LIKE WE CAN DO THESE 3366 02:05:43,724 --> 02:05:44,925 TRACINGS BUT THERE'S ALSO PAPERS 3367 02:05:44,925 --> 02:05:47,261 FROM THE GROUP USING AGINOID AND 3368 02:05:47,261 --> 02:05:48,662 COCULTURE MODELS WHERE WE 3369 02:05:48,662 --> 02:05:51,932 DEMONSTRATE THAD INDEED TYPE 2 3370 02:05:51,932 --> 02:05:54,902 CELLS CONVERT TO GENERATED THESE 3371 02:05:54,902 --> 02:05:56,336 CELLS AND EVENTUALLY THEY BECOME 3372 02:05:56,336 --> 02:05:57,938 BASAL CELLS, SO THERE IS THAT 3373 02:05:57,938 --> 02:06:01,408 EVIDENCE AT LEAST FROM THE 3374 02:06:01,408 --> 02:06:02,709 CULTURES AND THEY CLEVERLY USE 3375 02:06:02,709 --> 02:06:05,145 THIS MODEL WHERE THE MIX MATCHED 3376 02:06:05,145 --> 02:06:06,547 UNDERLYING FIBROBLASTS LIKE THEY 3377 02:06:06,547 --> 02:06:07,848 USE DIFFERENT FIBROBLASTS AND 3378 02:06:07,848 --> 02:06:11,185 THEY SEE 1 BUT NOT WITH OTHER 3379 02:06:11,185 --> 02:06:12,486 INDICATING WHEN THERE IS EVIDENT 3380 02:06:12,486 --> 02:06:15,022 NEARBY THAT IS INDUCING TYPE 2 3381 02:06:15,022 --> 02:06:16,423 CELLS CONVERSION TO THESE 3382 02:06:16,423 --> 02:06:22,863 BASALOID AND THEN EVENTUALLY 3383 02:06:22,863 --> 02:06:23,630 BASAL CELLS. 3384 02:06:23,630 --> 02:06:26,767 SO NOW SPEAKING 3385 02:06:26,767 --> 02:06:27,634 DR. [INDISCERNIBLE] HAS RAISED 3386 02:06:27,634 --> 02:06:28,335 HAND TO ASK'S QUESTION. 3387 02:06:28,335 --> 02:06:38,679 SO YOU CAN GO AHEAD. 3388 02:06:44,551 --> 02:06:45,886 >> I WAS -- IT WAS PASSED ALONG 3389 02:06:45,886 --> 02:06:47,421 BUYER I WAS READY BUT I WANTED 3390 02:06:47,421 --> 02:06:49,089 TO SAY THERE ARE AT LEAST 3 3391 02:06:49,089 --> 02:06:50,958 PATHWAYS FROM A TYPE 2 CELL IN 3392 02:06:50,958 --> 02:06:52,526 THE HUMAN THAT'S NOT TRUE IN THE 3393 02:06:52,526 --> 02:06:54,328 MOUSE, ONLY 1 IN THE MOUSE, THEY 3394 02:06:54,328 --> 02:06:55,395 WERE ALL CONCERNED ABOUT 3395 02:06:55,395 --> 02:06:56,430 TRANSITIONAL CELLS GOING FROM 3396 02:06:56,430 --> 02:06:58,131 TYPE 2 TO TYPE 1 IN THE MOUSE 3397 02:06:58,131 --> 02:07:04,071 BUT IN THE HUMAN THEY CAN BECOME 3398 02:07:04,071 --> 02:07:05,672 THESE RAS 0 CELLS AND THEY 3399 02:07:05,672 --> 02:07:07,207 BECOME TYPE 1 CELLS. 3400 02:07:07,207 --> 02:07:12,279 SO I GUESS MY QUESTION WAS 3401 02:07:12,279 --> 02:07:14,014 WHETHER OR NOT THERE'S SOME SORT 3402 02:07:14,014 --> 02:07:15,415 OF COMPETITION AS TO WHICH 3403 02:07:15,415 --> 02:07:17,150 PATHWAY FOLLOWS AND WHETHER THE 3404 02:07:17,150 --> 02:07:19,119 DOMINANCE OF THAT PATHWAY JUST 3405 02:07:19,119 --> 02:07:21,989 REFLECTS THE PATHWAY THAT'S THE 3406 02:07:21,989 --> 02:07:30,764 MOST RESILIENT FOR THAT AREA OF 3407 02:07:30,764 --> 02:07:32,266 THE LUNG THE CELLS THAT BEHAVE 3408 02:07:32,266 --> 02:07:33,900 THE BEST IN THOSE CONDITIONS AND 3409 02:07:33,900 --> 02:07:36,336 THAT WILL BE A DIFFERENT WAY OF 3410 02:07:36,336 --> 02:07:38,038 THINKING ABOUT RESILIENCE BUT I 3411 02:07:38,038 --> 02:07:38,872 THINK IT'S PLAUSIBLE ANYWAY, 3412 02:07:38,872 --> 02:07:40,807 THAT'S WHAT I HAD. 3413 02:07:40,807 --> 02:07:41,208 >> GREAT POINT. 3414 02:07:41,208 --> 02:07:41,842 I AGREE WITH YOU. 3415 02:07:41,842 --> 02:07:44,011 I MEAN THIS ACTUALLY CONNECTS 3416 02:07:44,011 --> 02:07:45,545 THE TO LYNN'S QUESTION AND 3417 02:07:45,545 --> 02:07:47,281 DAVID'S QUESTION AS WELL, RIGHT? 3418 02:07:47,281 --> 02:07:48,782 WHEN AND WHERE THESE CELLS 3419 02:07:48,782 --> 02:07:59,293 ACTUALLY TAKE DIFFERENT PARTS 3420 02:08:20,814 --> 02:08:21,415 NOMINAL VERSUS PATHOLOGICAL 3421 02:08:21,415 --> 02:08:23,517 SMRKS AND WE MADE A POINT TO 3422 02:08:23,517 --> 02:08:24,651 PREVIOUS DISCUSSION, WE HAVE 3423 02:08:24,651 --> 02:08:27,087 ALSO SHOWN THE LUNG SLICES THAT 3424 02:08:27,087 --> 02:08:29,856 AT2s CAN GIVE RISE TO BASAL 3425 02:08:29,856 --> 02:08:30,090 CELLS. 3426 02:08:30,090 --> 02:08:34,027 SO YES, THEY USE THE FIBROTIC 3427 02:08:34,027 --> 02:08:35,395 COCKTAILS INCLUDING LPS AND 3428 02:08:35,395 --> 02:08:41,001 OTHER THINGS AND THEY FOUND TYPE 3429 02:08:41,001 --> 02:08:42,969 2, YOU KNOW IT'S LIKELY THAT 3430 02:08:42,969 --> 02:08:44,471 YOU'RE LOOKING AT THE SLICES AND 3431 02:08:44,471 --> 02:08:46,406 YOU FOUND THE BASAL LIKE 3432 02:08:46,406 --> 02:08:56,850 SIGNALLURES IN THE CELL. 3433 02:09:05,292 --> 02:09:06,093 THAT'S IMPORTANT POINT. 3434 02:09:06,093 --> 02:09:09,062 WOULD THIS BE DRIVEN BY CLONE 3435 02:09:09,062 --> 02:09:09,529 SELECTION? 3436 02:09:09,529 --> 02:09:11,431 YEAH, THAT'S RIGHT. 3437 02:09:11,431 --> 02:09:15,469 THEY CAN BE A NONABERRANT STATE, 3438 02:09:15,469 --> 02:09:17,304 THAT'S FINE, YEAH, WE NEED MODEL 3439 02:09:17,304 --> 02:09:27,814 ISES TO TEST IS ESPECIALLY IN 3440 02:09:32,719 --> 02:09:32,986 HUMAN. 3441 02:09:32,986 --> 02:09:34,721 >> OH SORRY, I WAS ON MUTE, 3442 02:09:34,721 --> 02:09:39,626 SORRY FOR THAT EMPLOY. 3443 02:09:39,626 --> 02:09:41,661 >> OKAY, SO THINKING ABOUT YOUR 3444 02:09:41,661 --> 02:09:43,296 POINT OF A DIFFERENT PATHWAY, 3445 02:09:43,296 --> 02:09:44,498 WHICH PATHWAY THE CELL CHOOSE TO 3446 02:09:44,498 --> 02:09:49,035 USE, I WAS THINKING LIKE, A 3447 02:09:49,035 --> 02:09:50,404 MULTIPLE PATHWAY HAS BEEN SHOWN 3448 02:09:50,404 --> 02:09:53,140 FOR THIS TRANSITION PUSH, BUT IN 3449 02:09:53,140 --> 02:09:56,410 MY POINT, MAYBE BIAS LIKE 3450 02:09:56,410 --> 02:09:58,979 DIFFERENT GENETIC VARIANCE AND 3451 02:09:58,979 --> 02:10:00,280 DIFFERENT PREFERENCE, LIKE THE 3452 02:10:00,280 --> 02:10:02,282 WNT AND THE YAPP, AND MANY 3453 02:10:02,282 --> 02:10:03,550 DIFFERENT PATHWAYS BUT I THINK 3454 02:10:03,550 --> 02:10:08,822 OF INDIVIDUAL PEOPLE, THEY MAY 3455 02:10:08,822 --> 02:10:09,756 HAVE DIFFERENT PREFERENCE AND 3456 02:10:09,756 --> 02:10:10,857 WHAT WE'RE DOING, IN THE CELL 3457 02:10:10,857 --> 02:10:13,160 MODEL AND THE MOUSE MODEL, THERE 3458 02:10:13,160 --> 02:10:23,670 ARE ADDITIONAL VERY IMPORTANT. 3459 02:10:24,304 --> 02:10:25,338 >> TO ANSWER YOUR QUESTION, I 3460 02:10:25,338 --> 02:10:26,640 THINK SOMEONE ASKED A QUESTION 3461 02:10:26,640 --> 02:10:27,874 ABOUT THE CLONE IN THESE AND I 3462 02:10:27,874 --> 02:10:29,276 THINK IT'S A VERY, VERY 3463 02:10:29,276 --> 02:10:29,876 THOUGHTFUL AND IMPORTANT 3464 02:10:29,876 --> 02:10:30,143 QUESTION. 3465 02:10:30,143 --> 02:10:31,411 AND I THINK THE PLACE THAT 3466 02:10:31,411 --> 02:10:33,914 PEOPLE REALLY TALKED ABOUT IT IS 3467 02:10:33,914 --> 02:10:37,617 IN CANCER WHERE IT'S OBVIOUS 3468 02:10:37,617 --> 02:10:39,085 IMPORTANCE BUT THE REASON I 3469 02:10:39,085 --> 02:10:40,620 THINK IT'S SUCH A PRESSIENT 3470 02:10:40,620 --> 02:10:42,088 QUESTION IS 1 THE QUESTIONS IN 3471 02:10:42,088 --> 02:10:43,590 DISEASE IN GENERAL BUT IN LUNG 3472 02:10:43,590 --> 02:10:45,959 DISEASE SPECIFICALLY IS WHY IS 3473 02:10:45,959 --> 02:10:46,493 DISEASE PATCHY? 3474 02:10:46,493 --> 02:10:48,195 AND 1 THING I WILL SAY FOR 3475 02:10:48,195 --> 02:10:52,332 EXAMPLE, THERE ARE PARTS OF 3476 02:10:52,332 --> 02:10:53,266 CYSTIC FIBROSIS PATIENT'S LUNGS 3477 02:10:53,266 --> 02:10:55,535 LOOK PERFECT AND THE OLD 3478 02:10:55,535 --> 02:10:56,837 EXPLANATIONS WE GAVE WERE QUITE 3479 02:10:56,837 --> 02:10:57,904 UNSATISFACTORY AND I BEING SAY 3480 02:10:57,904 --> 02:11:01,575 THE SAME THING ABOUT IPF AND WE 3481 02:11:01,575 --> 02:11:04,211 HAVE SOME EXPLANATIONS NOW, 3482 02:11:04,211 --> 02:11:05,812 RIGHT, LIKE PERIPHERY, MECHANO 3483 02:11:05,812 --> 02:11:07,714 TRANSDUCTION BUT NOT THE ENTIRE 3484 02:11:07,714 --> 02:11:08,648 PERIPHERY LOOKS THE SAME AND 3485 02:11:08,648 --> 02:11:11,184 IT'S HARD TO IMAGINE IT'S JUST 3486 02:11:11,184 --> 02:11:13,453 LIKE ABSOLUTELY UNIFORMLY JUST, 3487 02:11:13,453 --> 02:11:14,855 YOU KNOW, PLURAL PRESSURE, 3488 02:11:14,855 --> 02:11:16,356 PULLING ON THE DISTAL LUNG. 3489 02:11:16,356 --> 02:11:22,629 SO I THINK THERE'S MORE THERE. 3490 02:11:22,629 --> 02:11:24,264 AND I WOULD INTERESTED IN ASKING 3491 02:11:24,264 --> 02:11:25,899 ALL OF YOU, I REMEMBER A LONG 3492 02:11:25,899 --> 02:11:27,667 TIME AGO, AND I MY MEMORY IS 3493 02:11:27,667 --> 02:11:30,237 FADING BUT THERE WAS SOME 3494 02:11:30,237 --> 02:11:32,205 QUESTION ABOUT CLONALITY IN IPF 3495 02:11:32,205 --> 02:11:34,808 BASED ON SOME KIND OF 3496 02:11:34,808 --> 02:11:36,309 CHROMOSOMAL ABERRATIONS. 3497 02:11:36,309 --> 02:11:38,311 I THINK IF TIM BLACKWELL IS 3498 02:11:38,311 --> 02:11:39,613 HERE, HE WOULD KNOW ABOUT IT, 3499 02:11:39,613 --> 02:11:41,381 BUT THERE WAS A LITERATURE TO 3500 02:11:41,381 --> 02:11:45,418 SUGGEST THAT THERE WAS CLONALITY 3501 02:11:45,418 --> 02:11:48,054 BASED ON CHROMOSOMAL ABERRATIONS 3502 02:11:48,054 --> 02:11:49,656 IN TELEORDER OF MICRONS RACE 3503 02:11:49,656 --> 02:11:50,490 DEFICIENT DISEASES I THINK AND 3504 02:11:50,490 --> 02:11:51,558 IF YOU DON'T KNOW THAT, YOU 3505 02:11:51,558 --> 02:11:53,293 MIGHT JUST GO BACK AND LOOK AT 3506 02:11:53,293 --> 02:11:55,862 THAT. THERE WAS A LOT OF 3507 02:11:55,862 --> 02:11:56,530 SUGGESTION ABOUT THAT. 3508 02:11:56,530 --> 02:11:59,733 BUT NOW THERE'S SO MUCH ABOUT 3509 02:11:59,733 --> 02:12:02,135 SOMATIC MUTATION AND THERE'S A 3510 02:12:02,135 --> 02:12:04,771 GOOD REASON TO THINK TO THINK 3511 02:12:04,771 --> 02:12:07,841 THAT SOMATIC MUTATIONS COULD 3512 02:12:07,841 --> 02:12:09,643 CAUSE HETEROGENERATED AITY WHICH 3513 02:12:09,643 --> 02:12:10,744 MAY CONTRIBUTE SELECTIVE GROWTH 3514 02:12:10,744 --> 02:12:13,880 ADVANTAGE BUT NOW LET'S THINK 3515 02:12:13,880 --> 02:12:16,516 ABOUT LIKE SELECTIVE IMMUNE 3516 02:12:16,516 --> 02:12:18,051 SUSCEPTIBILITY. 3517 02:12:18,051 --> 02:12:18,618 LIKE IMAGINE THAT. 3518 02:12:18,618 --> 02:12:22,188 AND SO I THINK THAT'S A VERY 3519 02:12:22,188 --> 02:12:22,889 INTERESTING QUESTION. 3520 02:12:22,889 --> 02:12:24,524 >> YEAH, I MEAN IN THAT LINE, AT 3521 02:12:24,524 --> 02:12:25,725 LEAST FROM THE IMMUNE SYSTEMS 3522 02:12:25,725 --> 02:12:27,127 SIDE, THERE ARE A COUPLE OF 3523 02:12:27,127 --> 02:12:29,696 PAPERS NOW, THE CLONAL HEMEAT O 3524 02:12:29,696 --> 02:12:30,463 POETICESIS AND TRANSCRIPTION AND 3525 02:12:30,463 --> 02:12:33,533 OF COURSE, I THINK THAT MIGHT BE 3526 02:12:33,533 --> 02:12:35,902 A VERY [INDISCERNIBLE] 3527 02:12:35,902 --> 02:12:37,337 >> YEAH, EVEN THE FIBROBLASTS OR 3528 02:12:37,337 --> 02:12:39,673 PATS CAN HAVE SOMATIC MUTATION 3529 02:12:39,673 --> 02:12:42,842 THAT RESISTS OR AMPLIFIES ANY 3530 02:12:42,842 --> 02:12:45,946 KIND OF CYTOKINE SIGNAL. 3531 02:12:45,946 --> 02:12:47,080 >> YEAH, THAT'S REALLY IMPORTANT 3532 02:12:47,080 --> 02:12:51,017 BECAUSE THESE STRANSITION STATE, 3533 02:12:51,017 --> 02:12:52,285 THERE IS ABLITERATION IN CANCER 3534 02:12:52,285 --> 02:12:54,487 FIELD AS WELL AS IN HUMAN, 3535 02:12:54,487 --> 02:12:55,555 SIMILARITATESENTIOUS MERGED BUT 3536 02:12:55,555 --> 02:12:57,123 LAKELY DEFINITE FLAVOR BUT THEY 3537 02:12:57,123 --> 02:13:02,996 HAVE OVER LAPPING MOLECULAR 3538 02:13:02,996 --> 02:13:07,767 FEATURES SO WHENY WOO SEE 3539 02:13:07,767 --> 02:13:09,736 NONMALIGNANT DISEASE VERSUS ONO 3540 02:13:09,736 --> 02:13:10,904 GENIC EVEN HAPPENS, I THINK THAT 3541 02:13:10,904 --> 02:13:12,439 WILL BE GOOD, TOO. 3542 02:13:12,439 --> 02:13:12,872 >> YEAH. 3543 02:13:12,872 --> 02:13:14,741 >> GOING BACK TO CLONALITY, HOW 3544 02:13:14,741 --> 02:13:17,811 DO WE ADDRESS IN BLOOD, LIKE THE 3545 02:13:17,811 --> 02:13:24,217 GROUP HAS DONE REALLY NICE WORK 3546 02:13:24,217 --> 02:13:32,492 USING THE SINGLE CELL ATACSEQ, 3547 02:13:32,492 --> 02:13:34,361 WE HAD TO INVENT TOOLS TO ANSWER 3548 02:13:34,361 --> 02:13:36,329 SIMILAR QUESTIONS NBUT YOU WOULD 3549 02:13:36,329 --> 02:13:37,364 THINK DISEASE, RIGHT? 3550 02:13:37,364 --> 02:13:38,131 GENERAL PROPERTY OF THE DISEASE 3551 02:13:38,131 --> 02:13:40,100 MIGHT BE SELECTION OF PATHOLOGIC 3552 02:13:40,100 --> 02:13:43,169 CLONES THAT GROW TOO BIG. 3553 02:13:43,169 --> 02:13:43,370 RIGHT? 3554 02:13:43,370 --> 02:13:44,237 ANALOGY AGAIN TO THE CANCER 3555 02:13:44,237 --> 02:13:46,439 FIELD AND THAT IS WHEN YOU HAVE 3556 02:13:46,439 --> 02:13:48,041 SELECTIVE, LIKE ADVANTAGE FOR AN 3557 02:13:48,041 --> 02:13:49,009 A PERRENT CLONE THAT IS WHEN 3558 02:13:49,009 --> 02:13:51,811 YOU HAVE A DISEASE. 3559 02:13:51,811 --> 02:13:53,313 IT'S AN THE PATCHY WORST PART OF 3560 02:13:53,313 --> 02:13:56,616 THE DEC WHERE YOU SEE THE MOST 3561 02:13:56,616 --> 02:13:59,119 MANIFEST EXAMPLE OF IT. 3562 02:13:59,119 --> 02:14:03,390 >> THE EXPANSION IS MORE LIKE 3563 02:14:03,390 --> 02:14:05,825 RELEVANT TO IPF COMPARED TO 3564 02:14:05,825 --> 02:14:06,159 COPD? 3565 02:14:06,159 --> 02:14:08,128 >> I THINK IT WILL APPLY 3566 02:14:08,128 --> 02:14:08,361 EQUALLY. 3567 02:14:08,361 --> 02:14:12,165 I THINK IT'S SUCH A GENERAL 3568 02:14:12,165 --> 02:14:16,269 CONCEPT THAT IT COULD APPLY TO 3569 02:14:16,269 --> 02:14:18,538 ULTIMATELIA OF DISEASE, REALLY. 3570 02:14:18,538 --> 02:14:19,939 >> IF I COULD ENTER INTO IT 3571 02:14:19,939 --> 02:14:22,409 DISCUSSION A LITTLE BIT ABOUT 3572 02:14:22,409 --> 02:14:24,377 PATCHY DISEASE, YOU KNOW, WE 3573 02:14:24,377 --> 02:14:31,918 HAVEN'T TALKED ABOUT THE 3574 02:14:31,918 --> 02:14:33,153 ENVIRONMENT AND DISTRIBUTION AND 3575 02:14:33,153 --> 02:14:37,424 I CAN'T HELP BUT THINK THAT SOME 3576 02:14:37,424 --> 02:14:38,258 OF THE PATCHINESS, CERTAINLY NOT 3577 02:14:38,258 --> 02:14:39,793 ALL OF THIS, I HAVE BEEN VERY 3578 02:14:39,793 --> 02:14:41,327 INTERESTED IN THIS ISSUE OF 3579 02:14:41,327 --> 02:14:45,699 SOMATIC MUTATIONS BUT SOME OF 3580 02:14:45,699 --> 02:14:47,033 THE PATCHINESS MAY BE DUE TO 3581 02:14:47,033 --> 02:14:53,339 WHAT WE'RE INHALING AND HOW 3582 02:14:53,339 --> 02:14:56,109 THOSE MICROSCOPIC RESPONSES ARE 3583 02:14:56,109 --> 02:14:57,477 ARE PLAYING OUT IN SPECIFIC 3584 02:14:57,477 --> 02:15:02,215 REGIONS OF THE LUNG, 3585 02:15:02,215 --> 02:15:04,584 SIMULTANEOUSLY OR CO INSURE 3586 02:15:04,584 --> 02:15:09,089 MARKET DENTALLY ACROSS DIFFERENT 3587 02:15:09,089 --> 02:15:10,123 AREAS OF HETEROGENEOUS LUNG. 3588 02:15:10,123 --> 02:15:11,658 SO IT'S IMPORTANT TO THINK ABOUT 3589 02:15:11,658 --> 02:15:14,194 THE ENVIRONMENTAL COMPONENT OF 3590 02:15:14,194 --> 02:15:16,096 THIS AS WELL. 3591 02:15:16,096 --> 02:15:17,964 >> I THINK DAVID, I AGREE WITH 3592 02:15:17,964 --> 02:15:20,600 YOU COMPLETELY AND FURTHER MOW I 3593 02:15:20,600 --> 02:15:23,036 WOULD AMPLIFY YOUR COMMENT BY 3594 02:15:23,036 --> 02:15:24,671 SAYING THERE'S ACTUALLY VERY 3595 02:15:24,671 --> 02:15:27,640 GOOD DATA TO SUGGEST YOU'RE A 3596 02:15:27,640 --> 02:15:28,908 HUNDRED% RIGHT, INCLUDING THINGS 3597 02:15:28,908 --> 02:15:30,076 LIKE PARTICLE DEPOSITION WHERE 3598 02:15:30,076 --> 02:15:31,945 YOU CAN ACTUALLY PRECISELY 3599 02:15:31,945 --> 02:15:33,847 QUANTIFY EXACTLY WHAT YOU'RE 3600 02:15:33,847 --> 02:15:34,080 SAYING. 3601 02:15:34,080 --> 02:15:35,381 AND THEN THERE MUST BE A WHOLE 3602 02:15:35,381 --> 02:15:36,449 BUNCH OF OTHER THINGS LIKE WHEN 3603 02:15:36,449 --> 02:15:41,254 YOU HAVE AN UNKNOWN ANTIGEN IN 3604 02:15:41,254 --> 02:15:42,489 SARCODOSEIS, BUT ALMOST 3605 02:15:42,489 --> 02:15:44,457 CERTAINLY ANTIGEN DRIVEN THAT IT 3606 02:15:44,457 --> 02:15:45,492 WOULD DEPOSIT IT IN DIFFERENT 3607 02:15:45,492 --> 02:15:46,559 PARTS OF THE LUNG. 3608 02:15:46,559 --> 02:15:48,728 SO I THINK YOUR STATEMENT DAVID 3609 02:15:48,728 --> 02:15:50,230 HAS MORE EVIDENCE THAN ANYTHING 3610 02:15:50,230 --> 02:15:55,368 I SUGGESTED WHICH IS JUST PURELY 3611 02:15:55,368 --> 02:15:55,769 THEY--THE RETINAL 3612 02:15:55,769 --> 02:15:56,136 LOCATIONICICAL. 3613 02:15:56,136 --> 02:15:57,470 BUT WE HAVEN'T LOOKED SO WHY 3614 02:15:57,470 --> 02:16:03,843 WOULDN'T TB THE CASE TO SOMATIC 3615 02:16:03,843 --> 02:16:05,411 MOSAICISM ISN'T THE CASE? 3616 02:16:05,411 --> 02:16:05,912 >> YEAH. 3617 02:16:05,912 --> 02:16:07,280 >> READING FROM THE COMMENTS 1 3618 02:16:07,280 --> 02:16:09,649 FROM SARAH LYNN, HOPE WE WILL 3619 02:16:09,649 --> 02:16:11,317 DISCUSSION ENGINEER TRACE MARKER 3620 02:16:11,317 --> 02:16:14,354 IN HUMAN CELLS IN THE TECHNOLOGY 3621 02:16:14,354 --> 02:16:15,855 SESSION LATER, SO, I THINK 3622 02:16:15,855 --> 02:16:17,824 THAT'S A GOOD SESSION TO DISCUSS 3623 02:16:17,824 --> 02:16:19,859 ABOUT SOME OF THIS. 3624 02:16:19,859 --> 02:16:21,761 HOW DO WE PROBE WHO'S HAPPENING 3625 02:16:21,761 --> 02:16:22,428 IN THE HUMAN LUNG. 3626 02:16:22,428 --> 02:16:24,297 I MEAN WE HAVE SOME OF THE 3627 02:16:24,297 --> 02:16:25,365 SPIRITUAL STRUGGLES ORDER OF 3628 02:16:25,365 --> 02:16:27,801 MICRONSETRY AND SOME OF THE LYNN 3629 02:16:27,801 --> 02:16:30,170 CLINICAL MEASUREMENTS BUT MORE 3630 02:16:30,170 --> 02:16:31,671 FROM A CELLULAR AND TISSUE 3631 02:16:31,671 --> 02:16:33,106 LEVEL, HOW DO WE GET TO THAT? 3632 02:16:33,106 --> 02:16:36,509 I THINK THAT'S A GOOD SESSION TO 3633 02:16:36,509 --> 02:16:38,011 TALK ABOUT EVEN ENVIRONMENTAL 3634 02:16:38,011 --> 02:16:39,212 EXPOSURE, YOU KNOW CAN BE 3635 02:16:39,212 --> 02:16:40,647 MEASURED HOW MUCH 1 WAS EXPOSED 3636 02:16:40,647 --> 02:16:42,982 IN THE LAST 10 YEARS, LET'S SAY 3637 02:16:42,982 --> 02:16:44,851 OR THROUGHOUT THEIR LIFE, CAN WE 3638 02:16:44,851 --> 02:16:47,987 GET SOME READ OUTS FROM THE 3639 02:16:47,987 --> 02:16:51,057 BIOMARKER POINT OF VIEW. 3640 02:16:51,057 --> 02:16:54,227 >> BACK TO SOMATIC MUTATION, I 3641 02:16:54,227 --> 02:16:56,196 WANT TO DROP DOWN A MEASURE HERE 3642 02:16:56,196 --> 02:16:58,631 BECAUSE SHE'S DONE A LOT OF 3643 02:16:58,631 --> 02:17:00,466 PHENOMENAL WORK RELATED TO 3644 02:17:00,466 --> 02:17:01,968 SOMATIC MUTATION IN 3645 02:17:01,968 --> 02:17:03,770 [INDISCERNIBLE] IS IPF. 3646 02:17:03,770 --> 02:17:04,737 YEAH, I THINK, JOHN I DON'T KNOW 3647 02:17:04,737 --> 02:17:09,142 IF YOU WANT TO UNMUTE YOURSELF 3648 02:17:09,142 --> 02:17:12,779 BUT SHE POST HER COMMENT THAT 3649 02:17:12,779 --> 02:17:17,383 THE SOMATIC MUTATION IN IPF IS 3650 02:17:17,383 --> 02:17:18,084 CLEARLY EVIDENT. 3651 02:17:18,084 --> 02:17:18,751 JOHN'S HERE,. 3652 02:17:18,751 --> 02:17:20,587 >> YEAH, THANK YOU SO, RIGHT NOW 3653 02:17:20,587 --> 02:17:22,655 BECAUSE OF THE LIMITED LUNG 3654 02:17:22,655 --> 02:17:24,958 TISSUE WE'VE USED RNA SEQ AND 3655 02:17:24,958 --> 02:17:26,492 MATCHED BLOOD WHOLE GENOME 3656 02:17:26,492 --> 02:17:27,861 SEQUENCING TO CULTURE MUTATIONS 3657 02:17:27,861 --> 02:17:29,395 AND WE SEE ACTUALLY EVIDENTLY 3658 02:17:29,395 --> 02:17:30,697 IPT GREATER CREASING SOMATIC 3659 02:17:30,697 --> 02:17:32,966 MUTATIONS IN IERK PF LUNGS AND 3660 02:17:32,966 --> 02:17:34,000 PRELIMINARY ANALYSIS OF SINGLE 3661 02:17:34,000 --> 02:17:39,539 CELL BASED STUDIES SO THAT THE 3662 02:17:39,539 --> 02:17:42,075 MUTATION [INDISCERNIBLE] SO 3663 02:17:42,075 --> 02:17:43,810 CTHC1 CELLS, THOSE ARE THE CELL 3664 02:17:43,810 --> 02:17:48,781 TYPES THAT CARRY MOST OF THE 3665 02:17:48,781 --> 02:17:49,048 MUTATIONS. 3666 02:17:49,048 --> 02:17:49,716 ACTUALLY THAT'S INTERESTING HAVE 3667 02:17:49,716 --> 02:17:51,718 YOU DONE ANY REGIONAL SAMPLES TO 3668 02:17:51,718 --> 02:17:54,287 SEE IF THERE ARE RECURRENT OTHER 3669 02:17:54,287 --> 02:17:56,489 SIMILAR PATTERNS THAT EMERGED? 3670 02:17:56,489 --> 02:17:59,525 >> YEAH, SO, I'M COLLABORATING 3671 02:17:59,525 --> 02:18:01,494 WITH DR. SCHWARTZ, SO WE HOPE TO 3672 02:18:01,494 --> 02:18:02,896 SAMPLE DIFFERENT AREAS WITH A 3673 02:18:02,896 --> 02:18:03,897 DIFFERENT DEGREE OF FIBROSIS, 3674 02:18:03,897 --> 02:18:06,332 BUT THE 1S WE CAN CALL SOMATIC 3675 02:18:06,332 --> 02:18:07,967 MUTATIONS NOW ARE CLONEALLY 3676 02:18:07,967 --> 02:18:09,602 EXPANDED 1S BECAUSE WE'RE 3677 02:18:09,602 --> 02:18:11,704 CALLING FROM RNA SEQ, AND WE CAN 3678 02:18:11,704 --> 02:18:13,239 ONLY CLONE LARGE MUTATIONS AND 3679 02:18:13,239 --> 02:18:15,375 THOSE GENES WE SEE THAT ARE 3680 02:18:15,375 --> 02:18:16,843 ENRICHED FOR MUTATIONS ARE 3681 02:18:16,843 --> 02:18:20,513 NORMAL GENES IMPORTANT FOR IPF, 3682 02:18:20,513 --> 02:18:23,116 MUK5, 4, B, 16 OR EMT RELATED 3683 02:18:23,116 --> 02:18:23,449 GENES. 3684 02:18:23,449 --> 02:18:25,919 >> YEAH, I MEAN, I ASK THE 3685 02:18:25,919 --> 02:18:28,087 REGIONAL SAMPLING BECAUSE IF YOU 3686 02:18:28,087 --> 02:18:30,290 TAKE IN UNAFFECTED REGION AND 3687 02:18:30,290 --> 02:18:32,125 LET'S SAY FIBROTIC REGION, YOU 3688 02:18:32,125 --> 02:18:35,895 KNOW IF THERE ARE PATTERNS THAT 3689 02:18:35,895 --> 02:18:37,196 OVERLAP PATTERNS THEN IT CAN 3690 02:18:37,196 --> 02:18:39,432 SUGGEST, IT WON'T BE DEFINITELY 3691 02:18:39,432 --> 02:18:40,967 BUT IT CAN SUGGEST CLONALITY IF 3692 02:18:40,967 --> 02:18:48,841 THERE ARE DIFFERENCES, YEAH. 3693 02:18:48,841 --> 02:18:50,176 CAN WE MAKE A DNLIZATION, 3694 02:18:50,176 --> 02:18:52,445 BECAUSE WE'RE CANNED TO MAKE A 3695 02:18:52,445 --> 02:18:53,613 NEW INTRODUCTION AND IT MADE ME 3696 02:18:53,613 --> 02:18:55,148 REALIZE THAT SOME OF US HAVE A 3697 02:18:55,148 --> 02:18:56,215 CLINICAL BACKGROUND AND SOME OF 3698 02:18:56,215 --> 02:18:59,819 US HAVE A Ph.D. BACKGROUND AND 3699 02:18:59,819 --> 02:19:01,554 WE'RE BOTH TRYING TO CONVERGE ON 3700 02:19:01,554 --> 02:19:04,290 THIS BUT NO 1 PERSON CAN DO 3701 02:19:04,290 --> 02:19:04,590 EVERYTHING. 3702 02:19:04,590 --> 02:19:06,693 AND EVEN WHEN YOU CAN BOTH LOOK 3703 02:19:06,693 --> 02:19:08,461 AT THE OTHER TO TRY TO IMPORT 3704 02:19:08,461 --> 02:19:11,030 SOMETHING, IT WOULD BE VERY 3705 02:19:11,030 --> 02:19:12,565 INTERESTING FOR EXAMPLE, TO FUSE 3706 02:19:12,565 --> 02:19:14,100 LIKE A CLINICAL RESEARCHER, WHO 3707 02:19:14,100 --> 02:19:18,137 IS ACTUALLY DOING A CLINICAL 3708 02:19:18,137 --> 02:19:19,305 TRIAL AND COMBINING IT WITH 3709 02:19:19,305 --> 02:19:20,707 SOMEONE MORE ON THE BASIC SIDE 3710 02:19:20,707 --> 02:19:22,842 THINKING ABOUT DISEASE AND MAYBE 3711 02:19:22,842 --> 02:19:26,045 THAT IS A DIRECTION WE SHOULD GO 3712 02:19:26,045 --> 02:19:28,414 IN TO ACTUALLY ENCOURAGE 3713 02:19:28,414 --> 02:19:30,350 COLLABORATION ACROSS THE 3714 02:19:30,350 --> 02:19:32,385 CLINICAL RESEARCHERS AND THE 3715 02:19:32,385 --> 02:19:32,885 BASIC RESEARCHERS. 3716 02:19:32,885 --> 02:19:35,188 IT'S NOT EASY TO DO BUT IT'S THE 3717 02:19:35,188 --> 02:19:37,857 KIND OF THING, THE NIH CAN DO, 3718 02:19:37,857 --> 02:19:43,830 THE VERY OTHER FEW ORGANIZATIONS 3719 02:19:43,830 --> 02:19:44,063 CAN. 3720 02:19:44,063 --> 02:19:46,165 YEAH, THANKS WE ARE RUNNING LATE 3721 02:19:46,165 --> 02:19:46,966 FOR THE SCHEDULE. 3722 02:19:46,966 --> 02:19:49,335 THANKS EVERYONE FOR THESE LIKE 3723 02:19:49,335 --> 02:19:50,603 VERY INTRIGUING DISCUSSION AND 3724 02:19:50,603 --> 02:19:52,939 THANK ALL OF SPEAKERS, IT'S 3725 02:19:52,939 --> 02:19:55,108 REALLY GREAT OPENING SESSION FOR 3726 02:19:55,108 --> 02:20:00,380 OUR 2 DAY SYMPOSIUM. 3727 02:20:00,380 --> 02:20:03,583 OUR BREAK TIME IS OH HALF HOUR, 3728 02:20:03,583 --> 02:20:05,885 SO, TEAM WE NEED TO COME BACK AT 3729 02:20:05,885 --> 02:20:09,789 HALF AN HOUR LATER, IT'S 1:15 3730 02:20:09,789 --> 02:20:11,290 STARTING SESSION 2. 3731 02:20:11,290 --> 02:20:11,524 NYES. 3732 02:20:11,524 --> 02:20:14,727 WE WILL BE BACK AT 1:15. 3733 02:20:14,727 --> 02:20:15,194 THANK YOU. 3734 02:20:15,194 --> 02:20:17,263 WE ALSO HAVE LOTS OF DISCUSSION, 3735 02:20:17,263 --> 02:20:20,299 WE DIDN'T HAVE TIME BUT WE ARE 3736 02:20:20,299 --> 02:20:22,335 COMING BACK, CONTINUING 3737 02:20:22,335 --> 02:20:24,404 TOMORROW, AND WE HAVE STRATEGIC 3738 02:20:24,404 --> 02:20:27,907 SCHEDULE TOMORROW, IN THE LAST 3739 02:20:27,907 --> 02:20:28,141 SECTION. 3740 02:20:28,141 --> 02:20:28,775 >> THANKS EVERYONE. 3741 02:20:28,775 --> 02:20:35,033 >> THANK YOU EVERYONE. 3742 02:20:35,033 --> 02:20:38,670 WE WILL HEAR FROM 4 SPEAKERS 3743 02:20:38,670 --> 02:20:41,806 TODAY. 3744 02:20:41,806 --> 02:20:42,407 NEXT SLIDE, PLEASE. 3745 02:20:42,407 --> 02:20:44,909 WHO WILL TRY TO TALK ABOUT THE 3746 02:20:44,909 --> 02:20:45,643 NEW TECHNOLOGIES THEY ARE 3747 02:20:45,643 --> 02:20:47,378 DEVELOPING AND HOW THEY CAN BE 3748 02:20:47,378 --> 02:20:48,813 USED TO STUDY PROGENITOR AND 3749 02:20:48,813 --> 02:20:50,281 TEMCELL BEHAVIOR IN THE LUNG AND 3750 02:20:50,281 --> 02:20:51,482 DURING THE DISCUSSION WE WILL 3751 02:20:51,482 --> 02:20:53,785 FOCUS ON THE CRITICAL RESEARCH 3752 02:20:53,785 --> 02:20:58,489 GAPS, AND WHAT WE DO TO ADDRESS 3753 02:20:58,489 --> 02:20:59,257 THAT. 3754 02:20:59,257 --> 02:21:04,929 NEXT PLEASE. 3755 02:21:04,929 --> 02:21:06,931 NEXT PLEASE. 3756 02:21:06,931 --> 02:21:09,600 I THINK THESE SLIDES WILL BE FOR 3757 02:21:09,600 --> 02:21:10,101 DISCUSSION. 3758 02:21:10,101 --> 02:21:14,105 WE WILL GO TO SPEAKER #1 EMPLOY 3759 02:21:14,105 --> 02:21:19,444 FIRST SPEAKER IS DR. MING 3760 02:21:19,444 --> 02:21:23,681 XIA GU, PHYSICIAN SCIENTIST AT 3761 02:21:23,681 --> 02:21:25,983 CUSTOM CENTER AT CHILDRENS, SHE 3762 02:21:25,983 --> 02:21:29,087 IS IN THE PEDIATRICS DIVISION 3763 02:21:29,087 --> 02:21:32,990 THERE, SHE WILL TALK TO US ABOUT 3764 02:21:32,990 --> 02:21:36,594 IPSC PROGENITOR CELLS AND HOW WE 3765 02:21:36,594 --> 02:21:40,231 CAN USE ORGANOID MODELS? 3766 02:21:40,231 --> 02:21:41,032 THANK YOU FOR THE KIND 3767 02:21:41,032 --> 02:21:42,700 INTRODUCTION AND THANK YOU FOR 3768 02:21:42,700 --> 02:21:44,402 HAVING ME TODAY. 3769 02:21:44,402 --> 02:21:46,604 I REALLY, REALLY ENJOYED THE 3770 02:21:46,604 --> 02:21:47,739 MORNING SESSION AND ESPECIALLY 3771 02:21:47,739 --> 02:21:50,074 THE DISCUSSION AND THE QUESTIONS 3772 02:21:50,074 --> 02:21:52,477 RAISED BY THE PANEL IS VERY 3773 02:21:52,477 --> 02:21:53,845 INSIGHTFUL AND THOUGHTFUL AND 3774 02:21:53,845 --> 02:21:58,483 FOR US, WE ARE INTERESTED IN 3775 02:21:58,483 --> 02:21:59,617 DEVELOPING HUMAN INDUCED 3776 02:21:59,617 --> 02:22:01,686 PLURIPOTENT STEM CELLS TO 3777 02:22:01,686 --> 02:22:02,887 ORGANOID MODELS TO HOPEFULLY 3778 02:22:02,887 --> 02:22:04,288 ANSWER SOME OF THE REMAINING 3779 02:22:04,288 --> 02:22:06,224 QUESTIONS RAISED BY THE PANEL 3780 02:22:06,224 --> 02:22:09,861 THIS MORNING AND ALSO TO PROVIDE 3781 02:22:09,861 --> 02:22:12,930 A HUMAN PERSPECTIVE IN DISEASE 3782 02:22:12,930 --> 02:22:16,501 DEVELOPMENT. 3783 02:22:16,501 --> 02:22:17,435 AND POSSIBLY UNDERSTANDING, SOME 3784 02:22:17,435 --> 02:22:24,142 FOR EXAMPLE, THE PATCHY BIOLOGY 3785 02:22:24,142 --> 02:22:26,778 MENTIONED EARLIER AND 3786 02:22:26,778 --> 02:22:29,847 POTENTIALLY CRISR THE SYSTEM AND 3787 02:22:29,847 --> 02:22:32,250 INTRODUCE SOMATIC MUTATIONS AND 3788 02:22:32,250 --> 02:22:36,721 UNDERSTAND CLONAL EXPANSION IN 3789 02:22:36,721 --> 02:22:37,889 INVITRO MODELING SYSTEM. 3790 02:22:37,889 --> 02:22:39,257 ALL RIGHT, NEXT. 3791 02:22:39,257 --> 02:22:41,526 SO TODAY, DUE TO THE TIME LIMIT, 3792 02:22:41,526 --> 02:22:44,395 I WILL JUST INTERVIEWS 1 OF OUR 3793 02:22:44,395 --> 02:22:46,831 RECEIPT STUDIES FOCUSING ON 3794 02:22:46,831 --> 02:22:48,800 ALVEOLAR CAPILLARY DYSPLASIA 3795 02:22:48,800 --> 02:22:49,934 WITH MISALIGNMENT OF PULMONARY 3796 02:22:49,934 --> 02:22:53,404 VAINS WHICH IS A CONGENITAL LUNG 3797 02:22:53,404 --> 02:22:58,142 DISORDER WITH NO CURE AND AS YOU 3798 02:22:58,142 --> 02:23:01,879 CAN SEE FROM THE STAINING, THE 3799 02:23:01,879 --> 02:23:06,050 DECREASED NUMBER OF PULMONARY 3800 02:23:06,050 --> 02:23:08,953 CAPILLARIES AND ADJACENT TO 3801 02:23:08,953 --> 02:23:12,757 SMALL PULMONARY ARTERIES AND 3802 02:23:12,757 --> 02:23:14,258 LOBULAR UNDERDEVELOPMENT THIS IS 3803 02:23:14,258 --> 02:23:17,695 CAUSED A MUTATION IN THE FOX F1 3804 02:23:17,695 --> 02:23:19,530 AND EXPRESSED IN ENDOTHELIAL AND 3805 02:23:19,530 --> 02:23:21,466 MESSENTERIEN CHIME AT 3806 02:23:21,466 --> 02:23:24,902 POPULATIONS AND IT LED TO STUDY 3807 02:23:24,902 --> 02:23:28,840 ACD/MPV IN A CULTURE DISH. 3808 02:23:28,840 --> 02:23:29,040 NEXT. 3809 02:23:29,040 --> 02:23:31,709 THIS CONDITION IS CAUSED BY A 3810 02:23:31,709 --> 02:23:33,878 MUTATION IN FOX F1 SO THROUGH 3811 02:23:33,878 --> 02:23:37,381 THE COLLABBUATION WITH THE LUNG 3812 02:23:37,381 --> 02:23:39,183 MAP GROUP HERE THEY HELPED ME 3813 02:23:39,183 --> 02:23:41,052 LOOK INTO THE EXPRESSION PATTERN 3814 02:23:41,052 --> 02:23:43,387 OF FOX F1. 3815 02:23:43,387 --> 02:23:44,088 NEXT. 3816 02:23:44,088 --> 02:23:45,857 SO THE MAGENTA COLOR INDICATES 3817 02:23:45,857 --> 02:23:48,359 THE CELLS EXPRESSING FOX F1 3818 02:23:48,359 --> 02:23:50,194 DURING LUNG DEVELOPMENT AND 3819 02:23:50,194 --> 02:23:51,462 CLEARLY THERE'S AN ENRICHMENT IN 3820 02:23:51,462 --> 02:23:54,065 THOSE 2 CAPE ILLEGALSARY 3821 02:23:54,065 --> 02:23:55,199 ENDOTHELIAL CELLS, CAP 1 AND 2. 3822 02:23:55,199 --> 02:23:59,237 AND I ALSO WANTED TO DRAW 3823 02:23:59,237 --> 02:24:01,005 ATTENTION TO THE [INDISCERNIBLE] 3824 02:24:01,005 --> 02:24:02,406 POPULATION, AT1 AND 2 AS THERE'S 3825 02:24:02,406 --> 02:24:06,911 NO EXPRESSION OF FOX F1 IN THOSE 3826 02:24:06,911 --> 02:24:08,246 EPITHELIAL CELLS. 3827 02:24:08,246 --> 02:24:10,147 NEXT. 3828 02:24:10,147 --> 02:24:14,986 SO THE INTERESTING PHENOTYPE 3829 02:24:14,986 --> 02:24:20,358 USED IN THESE SINGLE NUCLEI 3830 02:24:20,358 --> 02:24:26,464 RNA-ATAC-SEQ CASES IS THAT 3831 02:24:26,464 --> 02:24:32,803 MINZHE AND JEFF, NOT ONLY FOUND 3832 02:24:32,803 --> 02:24:34,605 A REDUCTION IN THE CAPILLARY 3833 02:24:34,605 --> 02:24:38,075 CELLS, THEY ALSO OBSERVED 3834 02:24:38,075 --> 02:24:39,777 ABNORMALITIES IN EPITHELIAL 3835 02:24:39,777 --> 02:24:42,046 DIFFERENTIATION AS SHOWNOT RIGHT 3836 02:24:42,046 --> 02:24:43,648 HAND SIDE, THEY FOUND AND THIS 3837 02:24:43,648 --> 02:24:46,250 IS ALSO A PHENOTYPE SEEN IN A 3838 02:24:46,250 --> 02:24:49,787 VARIETY OF LONG INJURY MODELS. 3839 02:24:49,787 --> 02:24:51,522 THERE'S ACCUMULATION OF THIS 3840 02:24:51,522 --> 02:24:53,190 INTERMEDIATE CELL TYPE OF BOTH 3841 02:24:53,190 --> 02:24:58,029 AT1 AND 2, SIGNATURES IN THE 3842 02:24:58,029 --> 02:25:00,131 CASES AND A REDUCTION IN AT1 3843 02:25:00,131 --> 02:25:04,302 CELL POPULATION IN THE PATIENT 3844 02:25:04,302 --> 02:25:06,304 WHICH INDICATES THAT THESE 3845 02:25:06,304 --> 02:25:08,306 ABNORMALITIES IN THE EPITHELIAL 3846 02:25:08,306 --> 02:25:12,143 CELLS ARE LIKELY CAUSED BY THE 3847 02:25:12,143 --> 02:25:13,210 ABNORMAL CAPILLARY DEVELOPMENT 3848 02:25:13,210 --> 02:25:15,613 AS THE EPITHELIAL CELLS DO NOT 3849 02:25:15,613 --> 02:25:18,416 EXPRESS FOX F1, THEREFORE WE AIM 3850 02:25:18,416 --> 02:25:21,319 TO DEVELOP A NEXT GENERATION OF 3851 02:25:21,319 --> 02:25:22,687 VASCULARIZED LUNG ORGANOID 3852 02:25:22,687 --> 02:25:29,927 MODELS TO STUDY THE ALVEOLI 3853 02:25:29,927 --> 02:25:34,932 CAPILLARIES AND CROSS TOCK IN 3854 02:25:34,932 --> 02:25:38,469 ACD/MPV. 3855 02:25:38,469 --> 02:25:39,070 NEXT. 3856 02:25:39,070 --> 02:25:44,442 SO DEVELOPING SUCH COMPLEX 3857 02:25:44,442 --> 02:25:46,611 ORGANNAL MODEL IS DIFFICULT 3858 02:25:46,611 --> 02:25:48,379 BECAUSE DURING AT1 AND 2 3859 02:25:48,379 --> 02:25:49,447 EPITHELIAL CELLS ARE DERIVED 3860 02:25:49,447 --> 02:25:52,416 FROM THE EBD O THERMAL LIPIAGE 3861 02:25:52,416 --> 02:25:54,085 WHEREAS THE VASCULAR ARE DERIVE 3862 02:25:54,085 --> 02:25:58,389 FRIDAY THE MESODERM AND IN THE 3863 02:25:58,389 --> 02:26:00,458 DEFERENTIATION, TO REQUIRES HIGH 3864 02:26:00,458 --> 02:26:02,994 MBP, WITH ACTIVATION WERE 3865 02:26:02,994 --> 02:26:04,128 GENERATING [INDISCERNIBLE] 3866 02:26:04,128 --> 02:26:06,230 ENDODERM REQUIRES LOW BMP BUT 3867 02:26:06,230 --> 02:26:09,700 HIGH TGF BETA AND FGF. 3868 02:26:09,700 --> 02:26:13,104 THAT MADE US TO FIRST TRY TO 3869 02:26:13,104 --> 02:26:14,505 BALANCE ALL THESE SIGNALING 3870 02:26:14,505 --> 02:26:17,975 PATHWAYS SO WE CAN MAINTAIN BOTH 3871 02:26:17,975 --> 02:26:20,044 MESODERM AND ENDODERM 3872 02:26:20,044 --> 02:26:22,546 POPULATIONS IN THE SAME SPHEROID 3873 02:26:22,546 --> 02:26:24,649 TO EVENTUALLY VASCULARIZE THE 3874 02:26:24,649 --> 02:26:26,517 ORGANOIDS. 3875 02:26:26,517 --> 02:26:27,618 NEXT, SLIDE, PLEASE. 3876 02:26:27,618 --> 02:26:29,487 SO, THE NEXT COUPLE OF SLIDES, 3877 02:26:29,487 --> 02:26:32,256 I'M GOING TO BRIEFLY SUMMARIZE 3878 02:26:32,256 --> 02:26:33,858 THIS WORK SPEARHEADED BY SIMON 3879 02:26:33,858 --> 02:26:36,827 IN THE LAB TOGETHER WITH 3880 02:26:36,827 --> 02:26:37,728 [INDISCERNIBLE] VICTOR, SO WHAT 3881 02:26:37,728 --> 02:26:39,930 THEY FOUND IN THE PAST 4 YEARS 3882 02:26:39,930 --> 02:26:41,032 OR SO, THEY'VE BEEN TRYING TO 3883 02:26:41,032 --> 02:26:47,004 REALLY HARD TO MAINTAIN MULTIPLE 3884 02:26:47,004 --> 02:26:50,408 LINEAGES IN A SINGLE SPHEROIDS 3885 02:26:50,408 --> 02:26:52,843 TO MAINTAIN DURING DEVELOPMENTAL 3886 02:26:52,843 --> 02:26:53,077 PROCESS. 3887 02:26:53,077 --> 02:26:54,478 SO OUR FIRST POPULATION IS WHEN 3888 02:26:54,478 --> 02:26:56,814 SIMON FOR THE INCREASE THE BMP 3889 02:26:56,814 --> 02:27:02,153 ACTIVATION DURING THE FIRST 3 3890 02:27:02,153 --> 02:27:03,187 DAYS OF SPHOAROID 3891 02:27:03,187 --> 02:27:04,355 DIFFERENTIATION, HE FOUND HE 3892 02:27:04,355 --> 02:27:05,990 COULD INCREASE THE POPULATION OF 3893 02:27:05,990 --> 02:27:09,060 THE MESODERMAL CELLS AND SHOW 3894 02:27:09,060 --> 02:27:12,730 ONCE THEY MEET HERE AT THE 3895 02:27:12,730 --> 02:27:17,601 BOTTOM, AND AT THE SAME TIME 3896 02:27:17,601 --> 02:27:19,737 MAINTAIN THE ENDOTERM POPULATION 3897 02:27:19,737 --> 02:27:22,206 STAYING POS 5 FOR FOX F2 IN THE 3898 02:27:22,206 --> 02:27:25,943 GREEN, SO USING THIS FINE TUNING 3899 02:27:25,943 --> 02:27:28,679 METHOD, WE MAINTAINED THE BOTH 3900 02:27:28,679 --> 02:27:30,281 ENDODERM AND MESODERM LINEAGES 3901 02:27:30,281 --> 02:27:31,949 THROUGH THE SAME SPHEROIDS 3902 02:27:31,949 --> 02:27:33,584 THROUGH DIFFERENTIATION AND FOR 3903 02:27:33,584 --> 02:27:37,054 THE NEXT 4 DAYS OUR SORE, WE 3904 02:27:37,054 --> 02:27:38,556 PUSHED THE ENDODERM 3905 02:27:38,556 --> 02:27:39,156 MALPOPPULATION FORWARD THE 3906 02:27:39,156 --> 02:27:43,894 EPITHEL YIEWM, AT THE SAM TIME 3907 02:27:43,894 --> 02:27:47,431 MAINTAINING METRICS SENK MALAND 3908 02:27:47,431 --> 02:27:48,833 ENDOTHELIAL CELLS, IF YOU CLICK 3909 02:27:48,833 --> 02:27:53,137 ON THE IMAGE ON THE RIGHT SIDE, 3910 02:27:53,137 --> 02:27:55,072 IT'S A 3D MODEL. 3911 02:27:55,072 --> 02:28:00,511 IN THE MITTED YOU'RE SEEING THE 3912 02:28:00,511 --> 02:28:02,446 FOREGUT, AND THEN ALSO THE 3913 02:28:02,446 --> 02:28:04,949 MESODERM POPULATION AND ALSO 3914 02:28:04,949 --> 02:28:07,485 CD31 POSITIVE BLOOD VESSELS IN 3915 02:28:07,485 --> 02:28:07,685 WHITE. 3916 02:28:07,685 --> 02:28:14,725 ALL RIGHT, NEXT SLIDES. 3917 02:28:14,725 --> 02:28:17,828 AND THEN, WE FURTHER 3918 02:28:17,828 --> 02:28:19,196 DIFFERENTIATED THE FOREGUT 3919 02:28:19,196 --> 02:28:24,068 LINEAGE TOWARD THE LUNG 3920 02:28:24,068 --> 02:28:26,937 PROGENITOR ORGANOID WITH 3921 02:28:26,937 --> 02:28:28,305 MESSENTERIEN CHIME AND 3922 02:28:28,305 --> 02:28:28,606 VASCULATURE. 3923 02:28:28,606 --> 02:28:31,809 SO THIS A BRIGHT VIEW LINEAGE OF 3924 02:28:31,809 --> 02:28:33,043 ORGANOIDS AND YOU CAN APPRECIATE 3925 02:28:33,043 --> 02:28:35,513 THAT MAJORITY OF THE CELLS ARE 3926 02:28:35,513 --> 02:28:45,823 ENDOTHELIAL CELLS. 3927 02:28:59,103 --> 02:29:01,505 COMPARED TO -- THEY HAVE THE 3928 02:29:01,505 --> 02:29:04,441 POSITIVE EPITHELIAL CELLS IN THE 3929 02:29:04,441 --> 02:29:06,777 MIDDLE, FOX P1 POS55 TELES IN 3930 02:29:06,777 --> 02:29:08,145 THE CD31 POSITIVE VESSELS AND ON 3931 02:29:08,145 --> 02:29:11,982 THE RIGHT HAND SIDE THESE ARE 3932 02:29:11,982 --> 02:29:13,250 VASCULARIZED ORGANOIDS AFTER 21 3933 02:29:13,250 --> 02:29:15,920 DAYS OF DIFFERENTIATION FROM 3934 02:29:15,920 --> 02:29:19,089 HUMAN IPSCs, AND THEY 3935 02:29:19,089 --> 02:29:20,691 SELF-ARAINCHL INTO THIS 3936 02:29:20,691 --> 02:29:22,860 STRUCTURE WITH THE EPITHELIAL 3937 02:29:22,860 --> 02:29:25,095 CELLS IN THE MIDDLE AND 3938 02:29:25,095 --> 02:29:27,965 MESENCHYMAL CELLS IN THE 3939 02:29:27,965 --> 02:29:29,433 EMTHELIUM AND THAT'S ALSO 3940 02:29:29,433 --> 02:29:32,136 WRAPPED BY THE CD31 POSITIVE 3941 02:29:32,136 --> 02:29:34,939 VESSELS. 3942 02:29:34,939 --> 02:29:36,073 NEXT SLIDE, PLEASE. 3943 02:29:36,073 --> 02:29:38,409 AND TOO, FOR THE MODEL OF THE 3944 02:29:38,409 --> 02:29:40,044 ALVEOLAR STRUCTURE WE 3945 02:29:40,044 --> 02:29:45,316 DISTALLIZED THE ORGANOIDS USING 3946 02:29:45,316 --> 02:29:46,450 THE PARTICLE DEVELOPED BY 3947 02:29:46,450 --> 02:29:47,051 [INDISCERNIBLE] GROUP AND WE 3948 02:29:47,051 --> 02:29:48,686 FOUND THAT THE CELLS AT A 3949 02:29:48,686 --> 02:29:50,754 POSITIVE FOR DISTAL MARKER FOX 9 3950 02:29:50,754 --> 02:29:53,390 AND ALSO AT1 AND AT2 MARKER 3951 02:29:53,390 --> 02:29:58,596 GENES IN THESE ORGANOIDS AFTER 3952 02:29:58,596 --> 02:30:02,600 DISTALLIZATION. 3953 02:30:02,600 --> 02:30:03,267 NEXT SLIDES. 3954 02:30:03,267 --> 02:30:10,908 AND THIS IS A 3D RECONSTRUCTION, 3955 02:30:10,908 --> 02:30:12,042 [INDISCERNIBLE] THIS IS TO GIVE 3956 02:30:12,042 --> 02:30:14,144 YOU KNOW OVERVIEW OF THE 3957 02:30:14,144 --> 02:30:15,379 INTERACTION OF THE ENDOTHELIUM 3958 02:30:15,379 --> 02:30:15,946 AND EPITHELIAL CELLS. 3959 02:30:15,946 --> 02:30:18,716 WE ARE ABLE TO,A CHIEF IN THESE 3960 02:30:18,716 --> 02:30:20,184 ORGANOID MODELS SO IT'S SOMEWHAT 3961 02:30:20,184 --> 02:30:21,385 SIMILAR TO THE LUNG STRUCTURE 3962 02:30:21,385 --> 02:30:25,756 WITH THE EPITHELIAL CELLS IN 3963 02:30:25,756 --> 02:30:28,025 ORANGE, AND WE INTRODUCED A 3964 02:30:28,025 --> 02:30:30,127 DESCENT AMOUNT OF THE CD31 3965 02:30:30,127 --> 02:30:31,729 POSITIVE BLOOD VESSELS AND I 3966 02:30:31,729 --> 02:30:33,664 ALSO WANT TO IMAGINE THESE ARE 3967 02:30:33,664 --> 02:30:38,135 FEASIBLE AND THEY HAVE LUMEN 3968 02:30:38,135 --> 02:30:40,938 THAT'S RECAPITULATING A 3969 02:30:40,938 --> 02:30:42,406 CAPILLARY SIZE. 3970 02:30:42,406 --> 02:30:44,909 NEXT SLIDE, TO CHARKTIZE THE 3971 02:30:44,909 --> 02:30:46,310 ORGANOIDS WE PERFORM SINGLE 3972 02:30:46,310 --> 02:30:47,745 CELL RNASEQ TO THE ORGANOIDS BUT 3973 02:30:47,745 --> 02:30:50,047 AS YOU CAN SEE FROM THE DOT 3974 02:30:50,047 --> 02:30:51,815 PLOTS WE HAVE A VARIETY OF CELL 3975 02:30:51,815 --> 02:30:54,585 TYPES IN THESE ORGANOIDS. 3976 02:30:54,585 --> 02:30:57,021 IN ADDITION TO THE EPITHELIAL 3977 02:30:57,021 --> 02:30:58,889 CELLS IN OBSERVED IN THE 3978 02:30:58,889 --> 02:31:00,624 CONVENTIONAL ORGANOIDS, WE NOW 3979 02:31:00,624 --> 02:31:01,825 HAVE MESENCHYMAL IN THE 3980 02:31:01,825 --> 02:31:03,560 ENDOTHELIAL CELLS AND I ALSO 3981 02:31:03,560 --> 02:31:05,930 WANT TO MENTION THAT AS YOU CAN 3982 02:31:05,930 --> 02:31:10,134 SEE FROM THE ORANGE GENES, 3983 02:31:10,134 --> 02:31:12,970 HPGD IN KITS THESE ARE LONG 3984 02:31:12,970 --> 02:31:14,371 SPECIFIC ENDOTHELIAL CELL 3985 02:31:14,371 --> 02:31:16,974 MACROIGEP GENES EXPRESSED IN 3986 02:31:16,974 --> 02:31:19,376 THESE ORGANOIDS AND FOX F1 ARE 3987 02:31:19,376 --> 02:31:21,612 ALSO ENRICHED IN THESE 3988 02:31:21,612 --> 02:31:22,446 MESENCHYMAL CELLS WHICH 3989 02:31:22,446 --> 02:31:25,482 INDICATES WHEN WE CO DEVELOPED 3990 02:31:25,482 --> 02:31:27,885 MESSENTERY ILLEGALS DERM WITH 3991 02:31:27,885 --> 02:31:29,353 THE TISSUE RELEVANT ENDODERMAL 3992 02:31:29,353 --> 02:31:30,788 POPULATION THAT MESSY DERMAL 3993 02:31:30,788 --> 02:31:32,856 CELLS INCLUDING THE VASC O 3994 02:31:32,856 --> 02:31:35,192 ENDOTHELIUM AND THE MESENCHYMAL 3995 02:31:35,192 --> 02:31:35,993 CELLS GAINED ORGAN SPECIFICITY 3996 02:31:35,993 --> 02:31:37,828 WHICH WILL HELP US BETTER 3997 02:31:37,828 --> 02:31:39,229 ADDRESS THE DISEASE IN THE HUMAN 3998 02:31:39,229 --> 02:31:41,298 DEVELOPMENT IN THE TISSUES 3999 02:31:41,298 --> 02:31:46,470 SPECIFIC MANNER. 4000 02:31:46,470 --> 02:31:47,805 NEXT SLIDE PLEASE. 4001 02:31:47,805 --> 02:31:50,507 WHAT'S MORE INTERESTING TO US, 4002 02:31:50,507 --> 02:31:53,177 IS THAT WE FOUND, WE'RE NOT ONLY 4003 02:31:53,177 --> 02:31:54,812 GENERATING DIFFERENT CELL TYPES 4004 02:31:54,812 --> 02:31:56,347 IN THESE ORGANOIDS, THE CELL 4005 02:31:56,347 --> 02:31:59,049 PROPORTION IS ALSO VERY SIMILAR 4006 02:31:59,049 --> 02:32:02,586 TO WHAT'S BEING SHOWN IN HUMAN 4007 02:32:02,586 --> 02:32:05,723 FETAL LUNG BASE ON THE RNA SEQ 4008 02:32:05,723 --> 02:32:07,124 THAT'S PUBLICLY AVAILABLE, SO 4009 02:32:07,124 --> 02:32:09,193 COMPARED WITH THE CONVENTIONAL 4010 02:32:09,193 --> 02:32:12,696 LUNG ORGANOID SHOWING ON THE 4011 02:32:12,696 --> 02:32:16,166 LEFT-HAND SIDE, THEY HAVE 4012 02:32:16,166 --> 02:32:21,338 EPITHELIAL CELLS UNCONTROLLED 4013 02:32:21,338 --> 02:32:21,772 DIFFERENTIATION, AND 4014 02:32:21,772 --> 02:32:22,740 CONTAMINATION IN THE SYSTEM, SO 4015 02:32:22,740 --> 02:32:26,076 IN THE MITSD THEE ARE THE 4016 02:32:26,076 --> 02:32:27,244 VASCULARIZED LUNG ORGANOIDS THAT 4017 02:32:27,244 --> 02:32:28,345 WE GENERATED AND FIRST OF ALL WE 4018 02:32:28,345 --> 02:32:30,547 HAVE A LARGER MOUND OF 4019 02:32:30,547 --> 02:32:33,083 MESENCHYMAL POPULATION, DUE TO 4020 02:32:33,083 --> 02:32:34,551 THE MAINTENANCE OF THE 4021 02:32:34,551 --> 02:32:35,719 MESODERMAL POPULATION IN THE 4022 02:32:35,719 --> 02:32:39,256 SPHEROIDS AND WE ALSO HAVE THE 4023 02:32:39,256 --> 02:32:40,657 ENDOTHELIAL CELLS AS YOU CAN SEE 4024 02:32:40,657 --> 02:32:44,094 IN YELLOW HERE IN THESE 4025 02:32:44,094 --> 02:32:44,828 ORGANOIDS AND PROPORTIONALLY 4026 02:32:44,828 --> 02:32:46,663 THEY ARE QUITE SIMILAR TO HUMAN 4027 02:32:46,663 --> 02:32:48,365 FETAL LUNG. 4028 02:32:48,365 --> 02:32:50,768 WE ALSO HAVE MIN NUM 4029 02:32:50,768 --> 02:32:54,071 CONTAMINATION OF THE INTESTINE 4030 02:32:54,071 --> 02:32:55,806 EPITHELIAL CELLS IN THESE LUNG 4031 02:32:55,806 --> 02:32:58,509 ORGANOIDS. 4032 02:32:58,509 --> 02:32:59,209 NEXT SLIDE PLEASE. 4033 02:32:59,209 --> 02:33:01,879 BECAUSE IN THESE ORGANOIDS ARE 4034 02:33:01,879 --> 02:33:04,581 STILL IN SPHEROIDS, WHICH IS 4035 02:33:04,581 --> 02:33:05,916 DIFFERENT FROM THE ALVEOLAR 4036 02:33:05,916 --> 02:33:08,452 STRUCTURE, SO WE'RE ALSO TRYING 4037 02:33:08,452 --> 02:33:10,087 TO BETTER YOU KNOW DRIVE THE 4038 02:33:10,087 --> 02:33:14,191 CELL FATE COMMITMENTS AS WELL AS 4039 02:33:14,191 --> 02:33:15,626 RECAPITULATING THE ALVEOLAR 4040 02:33:15,626 --> 02:33:17,428 STRUCTURES USING ENGINEERING 4041 02:33:17,428 --> 02:33:20,164 APPROACHES, SO THROUGH 4042 02:33:20,164 --> 02:33:21,532 COLLABORATION, [INDISCERNIBLE] 4043 02:33:21,532 --> 02:33:23,700 AT WOMEN'S WE ASSOCIATED THESE 4044 02:33:23,700 --> 02:33:26,003 ORGANOIDS AND THEN RECEDE THEM 4045 02:33:26,003 --> 02:33:31,608 ON A LUNG OR CHIP MODEL MADE BY 4046 02:33:31,608 --> 02:33:37,414 [INDISCERNIBLE]. 4047 02:33:37,414 --> 02:33:38,582 SO NEXT SLIDE. 4048 02:33:38,582 --> 02:33:40,684 WE STAINED BOTH ENDOTHELIAL AND 4049 02:33:40,684 --> 02:33:42,953 EPITHELIAL CELLS IN THESE 4050 02:33:42,953 --> 02:33:45,255 SCAFFOLDS, AND YOU CAN 4051 02:33:45,255 --> 02:33:47,558 APPRECIATE THAT THEY NOW FORM -- 4052 02:33:47,558 --> 02:33:49,493 ALTHOUGH THEY WERE BEING 4053 02:33:49,493 --> 02:33:52,329 DISASSOCIATED INTO SINGLE CELL 4054 02:33:52,329 --> 02:33:53,964 SUSPENSION, AND THEN RECEIVED ON 4055 02:33:53,964 --> 02:33:57,034 THE LONG SCAFFOLD, THEY ACTUALLY 4056 02:33:57,034 --> 02:33:58,969 AGAIN, SELF-PATTERN INTO THIS 4057 02:33:58,969 --> 02:34:00,337 STRUCTURE WHICH IS ALSO SIMILAR 4058 02:34:00,337 --> 02:34:02,439 TO A MOUSE LONG STRUCTURE, SO IN 4059 02:34:02,439 --> 02:34:03,841 THE MIDDLE, THESE ARE ALL 4060 02:34:03,841 --> 02:34:06,009 EPITHELIAL CELLS AND THAT'S 4061 02:34:06,009 --> 02:34:08,779 WRAPPED UP BY THE CD10 POSITIVE 4062 02:34:08,779 --> 02:34:11,281 BLOOD VESSELS AND THIS WORK IS 4063 02:34:11,281 --> 02:34:12,683 STILL PRELIMINARY AND WE'RE NOW 4064 02:34:12,683 --> 02:34:15,519 ALSO TRYING TO FURTHER OPTIMIZE 4065 02:34:15,519 --> 02:34:22,259 THE SYSTEM AT THIS POINT. 4066 02:34:22,259 --> 02:34:22,826 NEXT SLIDE, PLEASE. 4067 02:34:22,826 --> 02:34:26,463 NOW WE HAVE A VASCULARIZED 4068 02:34:26,463 --> 02:34:28,832 KD--SALLY WHO MODEL, WE SUES 4069 02:34:28,832 --> 02:34:31,735 THAT TO SEE IF WE COULD 4070 02:34:31,735 --> 02:34:32,436 RECAPITULATE SOME OF THE 4071 02:34:32,436 --> 02:34:33,937 PHENOTYPES IN PATIENT LUNG 4072 02:34:33,937 --> 02:34:37,141 TISSUES USING THESE ORGANOID 4073 02:34:37,141 --> 02:34:38,809 MODELS. 4074 02:34:38,809 --> 02:34:41,345 THROUGH COLLABORATION WITH 4075 02:34:41,345 --> 02:34:44,815 DR. KOTTON AND DR. ROTTIER, WE 4076 02:34:44,815 --> 02:34:45,449 OBLIGATIONS STAINED IPSCS FROM 4077 02:34:45,449 --> 02:34:46,483 THESE PATIENTS AND THEY CARRY 4078 02:34:46,483 --> 02:34:49,319 DIFFERENT TYPES OF MUTATIONS. 4079 02:34:49,319 --> 02:34:52,589 ONE IS A BIG CHUNK 4080 02:34:52,589 --> 02:34:54,191 [INDISCERNIBLE] IN THE MUTATIONS 4081 02:34:54,191 --> 02:34:57,694 AND BINDING DOMAIN OF THE FOX 4082 02:34:57,694 --> 02:35:01,832 HEAD 1 PROTEIN. 4083 02:35:01,832 --> 02:35:02,499 NEXT SLIDE. 4084 02:35:02,499 --> 02:35:04,635 SO FIRST, WE EXAMINED THE 4085 02:35:04,635 --> 02:35:06,370 ENDOTHELIAL POPULATION IN THESE 4086 02:35:06,370 --> 02:35:11,208 ORGANOIDS AND WE FOUND IN THOSE 4087 02:35:11,208 --> 02:35:12,676 ACD/MPV, ORGANOIDS THERE'S 4088 02:35:12,676 --> 02:35:14,444 REDUCTION IN THE CD31 POSITIVE 4089 02:35:14,444 --> 02:35:16,280 CELLS AND ALSO REDUCED MEMBERS 4090 02:35:16,280 --> 02:35:18,148 OF CAP 1 AND CAP 2 ENDOTHELIAL 4091 02:35:18,148 --> 02:35:25,722 CELLS IN THE SYSTEM. 4092 02:35:25,722 --> 02:35:26,290 NEXT SLIDE. 4093 02:35:26,290 --> 02:35:27,491 MORE IMPORTANTLY BECAUSE WE HAVE 4094 02:35:27,491 --> 02:35:29,226 MULTIPLE CELL TYPES IN THESE 4095 02:35:29,226 --> 02:35:31,094 ORGANOIDS THAT ARE 4096 02:35:31,094 --> 02:35:32,829 RECAPITULATING THE CELL-CELL 4097 02:35:32,829 --> 02:35:35,966 INTERACTION WE OBSERVED 4098 02:35:35,966 --> 02:35:38,035 ABNORMALITY IN THE EPITHELIAL 4099 02:35:38,035 --> 02:35:40,637 POPULATION ALTHOUGH THEY DON'T 4100 02:35:40,637 --> 02:35:46,109 EXPRESS FOX F1, SO IN THE 4101 02:35:46,109 --> 02:35:47,444 ACD/MPV ORGANOIDS THERE'S 4102 02:35:47,444 --> 02:35:49,346 ACCUMULATION OF THE INTERMEDIATE 4103 02:35:49,346 --> 02:35:59,690 CELL TYPE AT1/AT2. 4104 02:36:04,194 --> 02:36:04,795 NEXT. 4105 02:36:04,795 --> 02:36:10,133 -- OBSERVED IN THE CONVENTIONAL 4106 02:36:10,133 --> 02:36:10,400 ORGANOIDS. 4107 02:36:10,400 --> 02:36:13,237 NEXT, PLEASE. 4108 02:36:13,237 --> 02:36:23,347 SO IN SUMMARY, WE DEVELOPED 4109 02:36:23,347 --> 02:36:24,514 MESODERM ENDODERM MULTILINEAGE 4110 02:36:24,514 --> 02:36:27,918 LUNG ORGANOIDS AND WE ALSO 4111 02:36:27,918 --> 02:36:29,653 ADOPTED LUNG SPECIFIC GENE 4112 02:36:29,653 --> 02:36:32,522 SIGNATURES AND THESE ORGANOIDS 4113 02:36:32,522 --> 02:36:37,828 CAN BE FURTHER PATTERNED ON A 4114 02:36:37,828 --> 02:36:41,131 IMRKS ELMA SCAFFOLD TO 4115 02:36:41,131 --> 02:36:42,232 CAPITULATE THE HUMAN ALVERMEN 4116 02:36:42,232 --> 02:36:45,168 INFECTED O LIAISON SYSTEM AND 4117 02:36:45,168 --> 02:36:46,737 ALSO THESE ORGANOID PROVIDE 4118 02:36:46,737 --> 02:36:49,006 HUMAN-SPECIFIC MODEL TO STUDY 4119 02:36:49,006 --> 02:36:50,907 THE DYNAMIC CELL-CELL 4120 02:36:50,907 --> 02:36:53,110 INTERACTIONS AND CELL FATE 4121 02:36:53,110 --> 02:36:55,212 TRANSITION DURING LUNG 4122 02:36:55,212 --> 02:36:58,115 DEVELOPMENT AND DISEASE SUCH AS 4123 02:36:58,115 --> 02:37:00,450 ACDMPV, NEXT, IF I STILL HAVE A 4124 02:37:00,450 --> 02:37:01,652 MINUTE OR SO, I THINK THIS IS 4125 02:37:01,652 --> 02:37:03,820 SORT OF TRYING TO SET THE STAGE 4126 02:37:03,820 --> 02:37:06,123 FOR THE DISCUSSION LATER, AFTER 4127 02:37:06,123 --> 02:37:07,658 THE SESSION, WHAT ARE THE NEXT 4128 02:37:07,658 --> 02:37:08,659 STEPS, RIGHT? 4129 02:37:08,659 --> 02:37:11,628 I THINK SARAH ALSO MENTIONED IN 4130 02:37:11,628 --> 02:37:16,700 THE MORNING WE CAN APPLY SOME 4131 02:37:16,700 --> 02:37:17,501 ENGINEERING APPROACHES OR 4132 02:37:17,501 --> 02:37:23,373 BIOLOGY APPROACHES TO TRACE THE 4133 02:37:23,373 --> 02:37:24,374 CELLS POSSIBLY INVITRO AND TRY 4134 02:37:24,374 --> 02:37:25,342 TO ANSWER SOME QUESTIONS THAT 4135 02:37:25,342 --> 02:37:28,078 ARE DIFFICULT TO BE ANSWERED IN 4136 02:37:28,078 --> 02:37:28,879 MOUSE MODELS. 4137 02:37:28,879 --> 02:37:32,516 SO FOR US, THE NEXT GOAL OR 4138 02:37:32,516 --> 02:37:36,987 FUTURE DIRECTIONS IS TO BETTER 4139 02:37:36,987 --> 02:37:39,723 -- TO GENERATE A BETTER LUNG 4140 02:37:39,723 --> 02:37:41,692 ORGANOID MODEL THAT CLOSELY 4141 02:37:41,692 --> 02:37:43,327 RESEMBLES THE HUMAN LUNG 4142 02:37:43,327 --> 02:37:44,161 STRUCTURE AND DEVELOPMENTAL 4143 02:37:44,161 --> 02:37:44,594 PARALYSIS. 4144 02:37:44,594 --> 02:37:46,496 SO THERE ARE SEVERAL PIECES IN 4145 02:37:46,496 --> 02:37:47,764 MY OPINIONS THAT ARE STILL 4146 02:37:47,764 --> 02:37:49,466 MISSING IN THE CURRENT SYSTEMS 4147 02:37:49,466 --> 02:37:52,069 AND I'M ALSO HAPPY TO TALK ABOUT 4148 02:37:52,069 --> 02:37:54,771 THAT LATER INCLUDING, YOU KNOW 4149 02:37:54,771 --> 02:37:56,973 USING LUNG SPECIFIC ECM TO DRIVE 4150 02:37:56,973 --> 02:37:58,475 SOME OF THE LUNG PLATE 4151 02:37:58,475 --> 02:38:01,044 DETERMINATION AND USE REPORTER 4152 02:38:01,044 --> 02:38:04,648 OR TRACER TO VISUALIZE THE CELL 4153 02:38:04,648 --> 02:38:05,582 DIFFERENTIATIONS, THAT'S NOT 4154 02:38:05,582 --> 02:38:09,319 ENTIRELY A BLACK BOX TO US AND 4155 02:38:09,319 --> 02:38:12,356 IT'S BETTER CONTROLLED AND A 4156 02:38:12,356 --> 02:38:12,989 POTENTIAL REPRODUCE ABILITY OF 4157 02:38:12,989 --> 02:38:16,226 THE SYSTEM AND ALSO INCORPORATE 4158 02:38:16,226 --> 02:38:18,028 A PROPER GRADIENT OF THE MORPHIA 4159 02:38:18,028 --> 02:38:20,230 GENERATED TO INDUCE CELL 4160 02:38:20,230 --> 02:38:22,399 PATTERNS PROLIFERATION AND 4161 02:38:22,399 --> 02:38:23,333 LASTLY, RESULTS OF SOMETHING 4162 02:38:23,333 --> 02:38:24,634 WE'RE TRYING TO OPTIMIZE IN THE 4163 02:38:24,634 --> 02:38:27,371 CURRENT SYSTEM IS TO INTRODUCE 4164 02:38:27,371 --> 02:38:30,540 BIOPHYSICAL CUES SUCH AS FLOW, 4165 02:38:30,540 --> 02:38:33,043 IN THE VASCULATURE OR MECHANICAL 4166 02:38:33,043 --> 02:38:34,644 FORCE THROUGH THE STRETCHING OF 4167 02:38:34,644 --> 02:38:37,814 THE MEMBRANE TO UNDERSTAND HOW 4168 02:38:37,814 --> 02:38:39,850 THOSE FACTORS PLAY A ROLE IN 4169 02:38:39,850 --> 02:38:41,518 LUNG DEVELOPMENT OR IN RESPONSE 4170 02:38:41,518 --> 02:38:44,888 TO LUNG INJURIES. 4171 02:38:44,888 --> 02:38:50,026 I THINK THAT'S IT. 4172 02:38:50,026 --> 02:38:50,827 NEXT. 4173 02:38:50,827 --> 02:38:51,762 I THINK ACKNOWLEDGMENTS SLIDE. 4174 02:38:51,762 --> 02:38:53,330 THESE ARE THE PEOPLE CONTRIBUTED 4175 02:38:53,330 --> 02:38:55,699 TO MAIORITY OF THE WORK THAT I 4176 02:38:55,699 --> 02:39:00,404 TALKED ABOUT TODAY. 4177 02:39:00,404 --> 02:39:01,338 SIMON, VICTOR, AND NICOLE. 4178 02:39:01,338 --> 02:39:03,673 I ALSO WANT TO THANK TALL MY 4179 02:39:03,673 --> 02:39:07,611 COLLABORATORS AT CHILDREN'S AND 4180 02:39:07,611 --> 02:39:08,145 OTHER UNIVERSITIES. 4181 02:39:08,145 --> 02:39:09,579 HAPPY TO TAKE QUESTIONS LATER 4182 02:39:09,579 --> 02:39:09,746 ON. 4183 02:39:09,746 --> 02:39:13,016 THANK YOU VERY MUCH. 4184 02:39:13,016 --> 02:39:19,756 >> THANK YOU DR. GU FOR THAT 4185 02:39:19,756 --> 02:39:22,526 PHENOMENAL TALK NEXT WE HAVE 4186 02:39:22,526 --> 02:39:23,927 DR. BIN ZHOU, I THINK THE 4187 02:39:23,927 --> 02:39:25,328 DESCRIPTION HERE IS NOT CORRECT, 4188 02:39:25,328 --> 02:39:27,130 HE IS A DISTINGUISHED PROFESSOR 4189 02:39:27,130 --> 02:39:28,698 AT THE CHINESE ACADEMY OF 4190 02:39:28,698 --> 02:39:30,700 SCIENCES HERE TO TALK TO US 4191 02:39:30,700 --> 02:39:33,336 ABOUT USING MULTIPLE REPORTER 4192 02:39:33,336 --> 02:39:35,272 SYSTEMS FOR HIGH FIDELITY 4193 02:39:35,272 --> 02:39:37,374 LINEAGE TRACING IN THE LUNG. 4194 02:39:37,374 --> 02:39:38,542 >> OKAY, THANK YOU FOR THE 4195 02:39:38,542 --> 02:39:38,875 INTRODUCTION. 4196 02:39:38,875 --> 02:39:42,045 CAN YOU HEAR ME? 4197 02:39:42,045 --> 02:39:43,246 CAN YOU HEAR ME? 4198 02:39:43,246 --> 02:39:48,585 >> YES, WE CAN HEAR YOU 4199 02:39:48,585 --> 02:39:48,852 DR. ZHOU. 4200 02:39:48,852 --> 02:39:50,153 >> OKAY, TODAY I WILL INTRODUCE 4201 02:39:50,153 --> 02:39:55,392 YOU SOME STORY ON THE RECOMBIN 4202 02:39:55,392 --> 02:39:57,761 ACES LINEAGE TRACING TO APPLYING 4203 02:39:57,761 --> 02:40:01,364 IT TO STARTING OF LUNG 4204 02:40:01,364 --> 02:40:04,067 EPITHELIAL CELL IN LUNG 4205 02:40:04,067 --> 02:40:09,906 REGENERATION REPAIR. 4206 02:40:09,906 --> 02:40:10,106 NEXT. 4207 02:40:10,106 --> 02:40:20,650 SO MY LAB INTRODUCED THE CRE-LOX 4208 02:40:23,386 --> 02:40:29,693 P AND DRE-ROX SO WE CAN MORE 4209 02:40:29,693 --> 02:40:30,760 PRECISELY DO LINEAGE TRACING. 4210 02:40:30,760 --> 02:40:34,064 NEXT, IN THE LUNG THERE HAS BEEN 4211 02:40:34,064 --> 02:40:40,670 A DEBATE ON THE ROLE OF 4212 02:40:40,670 --> 02:40:41,371 BRONCHIAL ALVEOLAR STEM CELL 4213 02:40:41,371 --> 02:40:46,676 BASE THAT IS LOCATED IN THE DARK 4214 02:40:46,676 --> 02:40:49,646 JUNCTION BETWEEN THE BRONCHIOLES 4215 02:40:49,646 --> 02:40:54,851 AND ALVERMEN INFECTED O LIE, SO 4216 02:40:54,851 --> 02:40:56,720 WE WANT TO PRECISE TARGET THIS 4217 02:40:56,720 --> 02:41:01,858 BASE IN VIVO. 4218 02:41:01,858 --> 02:41:02,826 NEXT. 4219 02:41:02,826 --> 02:41:05,595 WE FOUND THAT THIS BASCs, 4220 02:41:05,595 --> 02:41:09,299 LABELED BY [INDISCERNIBLE] CAN 4221 02:41:09,299 --> 02:41:11,167 CONTRIBUTE TO THE BRONCHIAL 4222 02:41:11,167 --> 02:41:13,136 EPITHELIAL CELLS OF THE 4223 02:41:13,136 --> 02:41:14,804 BRONCHIAL INJURY. 4224 02:41:14,804 --> 02:41:17,874 ALL CONTRIBUTED TO ALVEOLAR 4225 02:41:17,874 --> 02:41:20,677 EPITHELIAL CELLS AFTER ALVEOLAR 4226 02:41:20,677 --> 02:41:22,646 INJURY. 4227 02:41:22,646 --> 02:41:24,314 SO THIS MAKES MULTIPOTENT STEM 4228 02:41:24,314 --> 02:41:27,918 CELLS IN 4229 02:41:27,918 --> 02:41:29,719 CELLS IN VIVO. 4230 02:41:29,719 --> 02:41:30,954 NEXT. 4231 02:41:30,954 --> 02:41:33,657 FOR THE ORIGINS OF ALVEOLAR OR 4232 02:41:33,657 --> 02:41:37,160 AT2 CELLS IN HOMEOSTASIS AND 4233 02:41:37,160 --> 02:41:38,461 DISEASES, THERE HAS BEEN MULTILE 4234 02:41:38,461 --> 02:41:42,966 SOURCES IN ADDITION TO THE AT2 4235 02:41:42,966 --> 02:41:44,134 CELL PROLIFERATION OR CELL 4236 02:41:44,134 --> 02:41:49,339 RENEWAL THAT HAS BEEN REPORTED 4237 02:41:49,339 --> 02:41:51,608 THAT CLUB CELLS IN THE BRONCHIAL 4238 02:41:51,608 --> 02:41:56,279 CAN TRIBUTE TO AT2 CELLS, 4239 02:41:56,279 --> 02:41:57,480 BASCs HAVE BEEN REPORTED TO 4240 02:41:57,480 --> 02:41:59,716 CONTRIBUTE TO AT2 CELLS OR EVEN 4241 02:41:59,716 --> 02:42:04,754 THOSE AT1 CELLS CAN REVERSE BACK 4242 02:42:04,754 --> 02:42:08,558 AND DIFFERENTIATE TO ITS 4243 02:42:08,558 --> 02:42:12,796 PARENTAL AT2 CELLS. 4244 02:42:12,796 --> 02:42:13,697 NEXT. 4245 02:42:13,697 --> 02:42:15,966 NEXT, HOWEVER, THERE ARE SOME 4246 02:42:15,966 --> 02:42:18,034 ISSUES ON THE LINEAGE TRACING 4247 02:42:18,034 --> 02:42:21,104 FOR THIS PREVIOUS STUDIES. 4248 02:42:21,104 --> 02:42:29,446 THE MARKERS FOR AT1, LIKE HOPX, 4249 02:42:29,446 --> 02:42:30,847 OR AGER, WE FOUND THESE MARKERS 4250 02:42:30,847 --> 02:42:33,950 ARE NOT THAT SPECIFIC FOR AT1 4251 02:42:33,950 --> 02:42:37,354 CELLS FOR EXAMPLE, HOPX TARGET 4252 02:42:37,354 --> 02:42:43,059 NOT ONLY AT1 CELLS BUT ALSO A 4253 02:42:43,059 --> 02:42:48,832 PORTION OF CLUB CELLS. 4254 02:42:48,832 --> 02:42:51,635 ATM IS BASED AND THE AT2 CELLS 4255 02:42:51,635 --> 02:42:55,839 IN ADDITION TO AT1 CELLS, AND 4256 02:42:55,839 --> 02:43:03,446 THE CONVENTIONAL TOOLS FOR CLUB 4257 02:43:03,446 --> 02:43:05,949 CELLS LIKE ACTB1, TARGET BOTH 4258 02:43:05,949 --> 02:43:08,685 CLUB CELLS AND SFTPC WHICH HAS 4259 02:43:08,685 --> 02:43:10,920 BEEN WIDELY USED FOR TARGETING 4260 02:43:10,920 --> 02:43:13,323 AT2 CELLS ACTUALLY TARGET 4261 02:43:13,323 --> 02:43:15,291 BASCs AS WELL, SO ALL THESE 4262 02:43:15,291 --> 02:43:19,295 TOOLS ARE NOT EXCLUSIVELY 4263 02:43:19,295 --> 02:43:20,463 TARGETED. 4264 02:43:20,463 --> 02:43:23,199 ONE CELL TYPE. 4265 02:43:23,199 --> 02:43:24,100 NEXT. 4266 02:43:24,100 --> 02:43:32,676 SO WE WANT TO APPLY DUAL 4267 02:43:32,676 --> 02:43:34,277 RECOMBIN ACES AND CELL TYPES FOR 4268 02:43:34,277 --> 02:43:38,014 EXAMPLE, WE FIRST USED DUAL 4269 02:43:38,014 --> 02:43:42,218 RECOMBINNATE TO TARGET AT1 AS I 4270 02:43:42,218 --> 02:43:45,021 INTRODUCED HOPX AND AGER ARE NOT 4271 02:43:45,021 --> 02:43:45,955 SPECIFIC TO AT1. 4272 02:43:45,955 --> 02:43:49,459 BUT THE COMBINATION OF THEM, WE 4273 02:43:49,459 --> 02:43:53,897 USE INTERSECTIONAL PART OF 4274 02:43:53,897 --> 02:43:57,967 AT-HOPX AND AGER FOR THE CELLS 4275 02:43:57,967 --> 02:43:59,102 EXPRESSING BOTH MARKERS WE FOUND 4276 02:43:59,102 --> 02:44:02,405 THAT THEY ARE QUITE SPECIFIC, 4277 02:44:02,405 --> 02:44:05,375 RESTRICTED TO AT1 CELL LINEAGES. 4278 02:44:05,375 --> 02:44:09,846 SO, WE USE IRPT SECTIONAL 4279 02:44:09,846 --> 02:44:15,952 GENETICS TO TARGET AT1 CELLS BY 4280 02:44:15,952 --> 02:44:23,159 HOPX BY EXPRESSING HOPX AND 4281 02:44:23,159 --> 02:44:25,061 AGER, USING THOSE DOUBLE LOX, 4282 02:44:25,061 --> 02:44:31,301 AND CROSS IT WITH HOPX AND AGER 4283 02:44:31,301 --> 02:44:33,670 AND CRE, SO AFTER 4284 02:44:33,670 --> 02:44:35,138 [INDISCERNIBLE] INJECTION, THEY 4285 02:44:35,138 --> 02:44:37,440 REMOVE IT LEADING TO EXPRESSION 4286 02:44:37,440 --> 02:44:45,515 OF TD-TOMATO. 4287 02:44:45,515 --> 02:44:47,150 NEXT. 4288 02:44:47,150 --> 02:44:49,652 THE IMAGES ON THE UPPER PANEL IS 4289 02:44:49,652 --> 02:44:52,288 A STRATEGY USING HOPX CREA, YOU 4290 02:44:52,288 --> 02:44:59,629 CAN USE THAT AFTER THE BLE 4291 02:44:59,629 --> 02:45:01,865 OMYCIN INJURY, YOU CAN SEE THE 4292 02:45:01,865 --> 02:45:04,567 TDTOMATO, CAN YOUEE THAT SOME 4293 02:45:04,567 --> 02:45:07,637 EXTENSION NUMBER OF CLUB CELLS 4294 02:45:07,637 --> 02:45:10,974 IN THE BRONCHIALS ALSO LABELED 4295 02:45:10,974 --> 02:45:13,042 BY HOPX CRE, SO WE CAN CANNOT 4296 02:45:13,042 --> 02:45:16,479 TELL YOU THESE TDTOMATO POSITIVE 4297 02:45:16,479 --> 02:45:21,117 OR AT2 CELLS ARE DERIVED FROM 4298 02:45:21,117 --> 02:45:25,989 AT1 CELLS OR FROM CLUB CELLS. 4299 02:45:25,989 --> 02:45:29,459 IN THE IMAGE S ON THE LOWER 4300 02:45:29,459 --> 02:45:32,228 PANEL, WE FOUND THAT THIS TD 4301 02:45:32,228 --> 02:45:35,532 TOMATO POSITIVE CELLS LABELED BY 4302 02:45:35,532 --> 02:45:37,534 THE DUAL RECOMBIN ACES ARE 4303 02:45:37,534 --> 02:45:42,338 SPECIFIC AT-1 CELLS AND THEY DO 4304 02:45:42,338 --> 02:45:46,276 NOT CONTRIBUTE TO HOP SFTC AT2 4305 02:45:46,276 --> 02:45:50,613 CELLS AFTER THE BLEOMYCIN 4306 02:45:50,613 --> 02:45:51,414 INJURY. 4307 02:45:51,414 --> 02:45:54,517 NEXT. 4308 02:45:54,517 --> 02:45:56,085 WE ALSO PERFORMED PNEUMONECT 4309 02:45:56,085 --> 02:46:00,089 ME INJURY AND FOUND THAT AT1 4310 02:46:00,089 --> 02:46:04,327 CELLS DO NOT CONTRIBUTE TO AT2 4311 02:46:04,327 --> 02:46:10,500 CELLS COMPARED WITH HOPX, CREE, 4312 02:46:10,500 --> 02:46:16,706 AND CONTROL. 4313 02:46:16,706 --> 02:46:18,374 NEXT. 4314 02:46:18,374 --> 02:46:20,910 THEN WE USED DURANNAL RECOMBIN 4315 02:46:20,910 --> 02:46:22,445 ACE TO SPECIFICALLY LABEL CLUB 4316 02:46:22,445 --> 02:46:26,749 CELLS, AT2 CELLS AND THE BASCs 4317 02:46:26,749 --> 02:46:29,185 SIMULTANEOUSLY IN 1 MOUSE, IN 1 4318 02:46:29,185 --> 02:46:29,385 MOUSE. 4319 02:46:29,385 --> 02:46:35,859 WE USE TRIP O LIGHT REPORTER AND 4320 02:46:35,859 --> 02:46:40,730 ACROSS WITH SDG1 AC1 CRE AND 4321 02:46:40,730 --> 02:46:44,133 STP3, IN THIS MODEL, CLUB CELLS 4322 02:46:44,133 --> 02:46:50,640 IS LABELED BY TD TOMATO, AT2 4323 02:46:50,640 --> 02:46:51,341 CELLS ARE LABELED BY 4324 02:46:51,341 --> 02:46:53,977 [INDISCERNIBLE] IS THE BASE THAT 4325 02:46:53,977 --> 02:46:58,848 EXPRESS BOTH SFTPC AND SFTPC, 4326 02:46:58,848 --> 02:47:05,355 AND ADG101 ARE LABELED BY 4327 02:47:05,355 --> 02:47:06,289 TD TOMATO AND [INDISCERNIBLE] 4328 02:47:06,289 --> 02:47:10,927 EMPLOY SO THEY'RE SHOWING THE 4329 02:47:10,927 --> 02:47:13,229 YFP, SO WE COULD LABEL THESE 3 4330 02:47:13,229 --> 02:47:15,031 DIFFERENT POPULATIONS WITH 3 4331 02:47:15,031 --> 02:47:18,301 DIFFERENT COLORS. 4332 02:47:18,301 --> 02:47:18,902 NEXT. 4333 02:47:18,902 --> 02:47:21,471 NEXT, SO THIS A DETAILED 4334 02:47:21,471 --> 02:47:24,908 STRATEGY, WE LABELED. 4335 02:47:24,908 --> 02:47:26,976 WE USED TRIPOLITE REPORTER SO 4336 02:47:26,976 --> 02:47:32,548 THIS COULD RESPOND TO CRE OR DRE 4337 02:47:32,548 --> 02:47:34,150 RESULLING IN TD TOMATO KREEN AND 4338 02:47:34,150 --> 02:47:37,921 WE CALL THEM CLUB TRACER, AT2 4339 02:47:37,921 --> 02:47:39,389 TRACER AND BASC TRACER AND IN 4340 02:47:39,389 --> 02:47:40,890 THE RIGHT, LEFT, AND RIGHT LOWER 4341 02:47:40,890 --> 02:47:46,763 PANEL YOU CAN SEE THAT WE CAN 4342 02:47:46,763 --> 02:47:48,131 LABEL THIS DISTINCT EPITHELIAL 4343 02:47:48,131 --> 02:47:50,533 POPULATION THAT WOULD BE 4344 02:47:50,533 --> 02:47:56,839 DIFFERENT COLORS FOR US AND THE 4345 02:47:56,839 --> 02:47:57,273 REPORTERS. 4346 02:47:57,273 --> 02:47:57,974 NEXT. 4347 02:47:57,974 --> 02:48:01,377 THEN WE INDUCED MICE TO INDUCE 4348 02:48:01,377 --> 02:48:03,913 MICE INJURY COMPARED WITH THE 4349 02:48:03,913 --> 02:48:05,949 KD--SALLY SHAM INJURY, COMPARED 4350 02:48:05,949 --> 02:48:07,617 WITH THE SHAM, THE UPPER PANEL 4351 02:48:07,617 --> 02:48:11,921 IS THE SHAM, YOU CAN SEE THE 4352 02:48:11,921 --> 02:48:14,457 COLORED CELLS ARE TD TOMATO 4353 02:48:14,457 --> 02:48:16,859 POSITIVE, THE AT2 CELLS ARE 4354 02:48:16,859 --> 02:48:20,063 GREEN, AND THE BASE WITH THE 4355 02:48:20,063 --> 02:48:23,032 REGION EXPRESSING BOTH TD TOMATO 4356 02:48:23,032 --> 02:48:28,438 AND THE CSGREEN, THEY ARE OF THE 4357 02:48:28,438 --> 02:48:33,176 BLEOMYCIN INJURY, WE OBSERVE 4358 02:48:33,176 --> 02:48:36,779 THAT SUBSET OF SFTP2 CELLS 4359 02:48:36,779 --> 02:48:40,483 EXPRESS YFP OR EXPRESS TD TOMATO 4360 02:48:40,483 --> 02:48:45,021 INDICATING THEY ARE DERIVED FROM 4361 02:48:45,021 --> 02:48:45,822 THE CLUB CELLS. 4362 02:48:45,822 --> 02:48:48,925 ON THE RIGHT PANEL THESE ARE THE 4363 02:48:48,925 --> 02:48:52,228 DATA QUANTIFICATION DATA FOR THE 4364 02:48:52,228 --> 02:48:57,333 CELL AT2 CELLS THAT DERIVED FROM 4365 02:48:57,333 --> 02:49:03,239 CLUB, BASCs OR SELF-RENEW 4366 02:49:03,239 --> 02:49:03,940 AFTER BLEOMYCIN. 4367 02:49:03,940 --> 02:49:04,841 NEXT. 4368 02:49:04,841 --> 02:49:07,477 SO WE FOUND THAT AFTER BLEOMYCIN 4369 02:49:07,477 --> 02:49:12,281 INJURY, IN ADDITION TO THE 4370 02:49:12,281 --> 02:49:15,018 SELF-RENEWAL OF AT2, AIT 2 4371 02:49:15,018 --> 02:49:18,087 CELLS, CLUB CELLS AND BASCs 4372 02:49:18,087 --> 02:49:21,724 CAN DIFFERENTIATE INTO AT2 CELLS 4373 02:49:21,724 --> 02:49:23,793 AND OUR TRIPLE COLOR LABELED IT 4374 02:49:23,793 --> 02:49:31,734 GENETIC LINEAGE TRACING PRECISE 4375 02:49:31,734 --> 02:49:32,235 QUANTIFICATION OF THEIR 4376 02:49:32,235 --> 02:49:37,573 CONTRIBUTION OF THE INJURY. 4377 02:49:37,573 --> 02:49:38,107 NEXT. 4378 02:49:38,107 --> 02:49:48,618 WE CAN AWLINGS MANIPULATE THE 4379 02:49:48,918 --> 02:49:52,055 SYSTEM AND OVER EXPRESS P21 AND 4380 02:49:52,055 --> 02:49:54,357 GFP, SO THAT REGENERATIVE 4381 02:49:54,357 --> 02:49:56,592 ABILITY OF BASCs AND AT2 CELLS 4382 02:49:56,592 --> 02:50:00,229 ARE IMPAIRED AS THEY CANNOT 4383 02:50:00,229 --> 02:50:02,465 PROLIFERATE ANYMORE AFTER INJURY 4384 02:50:02,465 --> 02:50:05,001 BECAUSE THEY OVEREXPRESS 4385 02:50:05,001 --> 02:50:09,572 PROLIFERATION INHIBITOR MARKER 4386 02:50:09,572 --> 02:50:10,206 P21. 4387 02:50:10,206 --> 02:50:10,807 NEXT. 4388 02:50:10,807 --> 02:50:16,879 IN THIS MODEL, WE FOUND THAT AWE 4389 02:50:16,879 --> 02:50:18,981 SUBSTANTIAL NUMBER OF TD TOMATO 4390 02:50:18,981 --> 02:50:23,119 POSITIVE CELLS WERE AT2, WERE 4391 02:50:23,119 --> 02:50:24,787 SFTPC, POSITIVE, AT2 CELLS, THEY 4392 02:50:24,787 --> 02:50:27,490 CONTRIBUTE TO AT2 CELLINGS AFTER 4393 02:50:27,490 --> 02:50:33,930 4 WEEKS. 4394 02:50:33,930 --> 02:50:35,131 NEXT. 4395 02:50:35,131 --> 02:50:39,235 AT 8 MONTHS, WE FOUND THAT AS A 4396 02:50:39,235 --> 02:50:43,106 MAJORITY OF AT2 CELLS ARE NOW 4397 02:50:43,106 --> 02:50:45,741 TDTOMATO INDICATING THAT UNDER 4398 02:50:45,741 --> 02:50:50,480 SPECIAL CONDITIONS WHEN AT2 CELL 4399 02:50:50,480 --> 02:50:55,218 REGENERATIVE ABILITY IS 4400 02:50:55,218 --> 02:50:55,785 IMPAIRED, CLUB CELLS CAN 4401 02:50:55,785 --> 02:50:58,321 CONTRIBUTE TO THE MAIORITY OF 4402 02:50:58,321 --> 02:51:04,293 AT2 CELLS CELLS SUGGESTING THEH 4403 02:51:04,293 --> 02:51:06,796 PLASTICITY FOR REGENERATION FOR 4404 02:51:06,796 --> 02:51:14,303 CLUB CELLS TO AT2 CELLS. 4405 02:51:14,303 --> 02:51:15,071 NEXT. 4406 02:51:15,071 --> 02:51:18,808 WE CAN ALSO MANIPULATE THE 4407 02:51:18,808 --> 02:51:22,678 GENETIC SYSTEM TO STUDY THE 4408 02:51:22,678 --> 02:51:26,215 MOLECULAR MECHANISMS OF CLUB 4409 02:51:26,215 --> 02:51:28,284 SALES, OR BASCs, THEY ARE 4410 02:51:28,284 --> 02:51:29,919 DIFFERENTIATION INTO AT2 CELLS. 4411 02:51:29,919 --> 02:51:32,121 WE, BY SINGLE CELL RNASEQUENCE 4412 02:51:32,121 --> 02:51:35,057 OF THESE TRACES, WE FOUND THE 4413 02:51:35,057 --> 02:51:37,593 DYNAMIC CHANGE OF NOTCH 4414 02:51:37,593 --> 02:51:42,932 SIGNALING PATHWAYS, SO WE DELETE 4415 02:51:42,932 --> 02:51:47,570 NOTCH TRANSCRIPTION FACTOR RPG 4416 02:51:47,570 --> 02:51:50,806 IN BASCs AND CLUB CELLS AND 4417 02:51:50,806 --> 02:51:54,076 EVALUATED THESE 2 POPULATIONS 4418 02:51:54,076 --> 02:51:57,780 DIFFERENTIATION ABILITY TO AT2 4419 02:51:57,780 --> 02:52:02,818 CELLS, AND THE UP PANEL, WE USE 4420 02:52:02,818 --> 02:52:06,923 THIS USE THIS FLOX AS ELIMINATED 4421 02:52:06,923 --> 02:52:13,262 CONTROL AND WE USE RBGFLOX AS A 4422 02:52:13,262 --> 02:52:14,997 KNOCK OUT AND WE FOUND TO 4423 02:52:14,997 --> 02:52:18,067 COMPARED TO THE CONTROL IN THE 4424 02:52:18,067 --> 02:52:22,872 MUTANT THERE ARE INCREASED WILD 4425 02:52:22,872 --> 02:52:24,807 [INDISCERNIBLE] CLONES AND 4426 02:52:24,807 --> 02:52:27,743 REDUCED TD TOMATO POSITIVE 4427 02:52:27,743 --> 02:52:29,445 CLONES FOR AT-2 CELL 4428 02:52:29,445 --> 02:52:31,280 CONTRIBUTION ON THE RIGHT PANEL, 4429 02:52:31,280 --> 02:52:34,350 WE CAN SEE THE QUANTIFICATION 4430 02:52:34,350 --> 02:52:38,521 DATA OF THIS IMMUNOSTAINING DATA 4431 02:52:38,521 --> 02:52:40,623 AND ALSO THE FACTS DATA SHOWING 4432 02:52:40,623 --> 02:52:43,759 THAT AFTER NOTCH KNOCK OUT, THE 4433 02:52:43,759 --> 02:52:46,395 CONTRIBUTION OF CLUB SALES TO 4434 02:52:46,395 --> 02:52:48,998 AT2 SALES AND SIGNIFICANTLY 4435 02:52:48,998 --> 02:52:51,834 REDUCE THE AND 1 OF THE 4436 02:52:51,834 --> 02:52:56,372 CONTRIBUTIONS TO AT2 CELLS ARE 4437 02:52:56,372 --> 02:53:01,777 INCREASED SUGGESTING THAT NOTCH 4438 02:53:01,777 --> 02:53:03,512 SIGNALING DISTINCTLY REGULATED 4439 02:53:03,512 --> 02:53:06,015 THESE 2 PROGENITOR CELLS, 4440 02:53:06,015 --> 02:53:11,020 DEFERENTIATION TO AT2 CELLS. 4441 02:53:11,020 --> 02:53:12,989 NEXT. 4442 02:53:12,989 --> 02:53:13,256 NEXT. 4443 02:53:13,256 --> 02:53:15,524 IN SUMMARY, OUR STUDY SHOWED 4444 02:53:15,524 --> 02:53:19,095 THAT THE AT1 CELLS ARE QUITE 4445 02:53:19,095 --> 02:53:21,597 STABLE DIFIENTIATIONS, THEY DO 4446 02:53:21,597 --> 02:53:26,602 NOT REVERSE BACK TO THEIR 4447 02:53:26,602 --> 02:53:28,638 PARENTAL CELLS UNDERSPECIFIC 4448 02:53:28,638 --> 02:53:32,174 INJURY, DURING HOMEIO STASES WE 4449 02:53:32,174 --> 02:53:36,512 FOUND THAT IN ADDITION TO THE 4450 02:53:36,512 --> 02:53:40,049 AT2 CELLS SELF-RENEW CLUB CELLS 4451 02:53:40,049 --> 02:53:41,250 AND BASCs CAN CONTRIBUTE TO 4452 02:53:41,250 --> 02:53:43,219 AT2 CELL SAYS AND THEY ARE 4453 02:53:43,219 --> 02:53:44,754 DIFFERENTIATION TO THE AT2 CELLS 4454 02:53:44,754 --> 02:53:46,789 THAT ARE DISTINCTLY REGULATED BY 4455 02:53:46,789 --> 02:53:51,060 NOTCH SIGNALING. 4456 02:53:51,060 --> 02:53:51,327 NEXT. 4457 02:53:51,327 --> 02:53:56,165 IT HAS BEEN REPORTED THAT UNDER 4458 02:53:56,165 --> 02:53:58,801 SPECIAL CONDITIONS AT1 CELLS CAN 4459 02:53:58,801 --> 02:54:02,471 DIFFERENTIATE INTO AT2 CELLS AND 4460 02:54:02,471 --> 02:54:05,408 EVEN AT1 CELLS CAN CONTRIBUTE TO 4461 02:54:05,408 --> 02:54:10,446 THE LUNG ADEN O CARCINOMAS IF 4462 02:54:10,446 --> 02:54:13,616 THEY EXPRESS KRAS, SO WE IN 4463 02:54:13,616 --> 02:54:16,118 FUTURE RE, VALENTINEDUATEED 4464 02:54:16,118 --> 02:54:18,988 THESE STUDIES BY USING DUAL 4465 02:54:18,988 --> 02:54:24,894 RECOMBIN ACES MEDIATED LINEAGE 4466 02:54:24,894 --> 02:54:26,429 TRACING TO UNDERSTAND THE 4467 02:54:26,429 --> 02:54:30,199 PLASTICITY OF WHAT AT1 CELLS AND 4468 02:54:30,199 --> 02:54:36,605 THE SPECIAL CIRCUMSTANCES. 4469 02:54:36,605 --> 02:54:36,939 NEXT. 4470 02:54:36,939 --> 02:54:38,708 AND FINALLY I WOULD LIKE TO 4471 02:54:38,708 --> 02:54:41,811 THANK MY STUDENTS, 4472 02:54:41,811 --> 02:54:44,647 COLLABORATORS, AND FUNDERS. 4473 02:54:44,647 --> 02:54:45,781 THANK YOU. 4474 02:54:45,781 --> 02:54:47,383 THANK YOU DR. ZHOU. 4475 02:54:47,383 --> 02:54:51,987 I HAD THE PLEASURE TO INTRODUCE 4476 02:54:51,987 --> 02:54:54,256 DR. RUOBING WANG WHO IS A AN 4477 02:54:54,256 --> 02:54:56,459 ASIFT ANT PULL MONITORROLOGYIST 4478 02:54:56,459 --> 02:54:59,228 ASSISTANT AT HARVARD MEDICAL 4479 02:54:59,228 --> 02:55:00,396 SCHOOL. 4480 02:55:00,396 --> 02:55:02,164 DR. WANG DOES FANTASTIC WORK IN 4481 02:55:02,164 --> 02:55:03,432 IPSCs CELLS AND SHE WILL TALK 4482 02:55:03,432 --> 02:55:09,271 TO US ABOUT LEVERAGES IPS AIR 4483 02:55:09,271 --> 02:55:12,875 WAY TO INVESTIGATE PULMONARY 4484 02:55:12,875 --> 02:55:14,009 IONOSIGHTS AND CYSTIC FIBROSIS. 4485 02:55:14,009 --> 02:55:15,244 >> THANK YOU VERY MUCH. 4486 02:55:15,244 --> 02:55:16,512 EXCITED TO BE HERE ESPECIALLY 4487 02:55:16,512 --> 02:55:17,947 SINCE SOME OF THE WORK REALLY 4488 02:55:17,947 --> 02:55:20,116 KICKED OFF MY OWN CAREER AND AS 4489 02:55:20,116 --> 02:55:21,117 A PEDIATRIC PULL 4490 02:55:21,117 --> 02:55:22,017 MONITORROLOGYIST, I WAS INSPIRED 4491 02:55:22,017 --> 02:55:23,586 BY THE PATIENTS I TOOK CARE OF 4492 02:55:23,586 --> 02:55:24,687 TO EMBARK ON A RESEARCH YOWRNY 4493 02:55:24,687 --> 02:55:28,691 AND I WAS ASKED TO PEEK ABOUT 4494 02:55:28,691 --> 02:55:30,659 IPS AIRWAY, IONOSIGHTS AND 4495 02:55:30,659 --> 02:55:32,328 CYSTIC FIBROSIS, SO I WILL TRY 4496 02:55:32,328 --> 02:55:34,130 TO INTEGRATE ALL 3 IN THE 15 4497 02:55:34,130 --> 02:55:34,663 MINUTE TALK. 4498 02:55:34,663 --> 02:55:36,132 NEXT PLEASE, AS A CLINICIAN I 4499 02:55:36,132 --> 02:55:37,733 REALIZE MANY OF THE LUNG 4500 02:55:37,733 --> 02:55:38,501 DISEASES ARE POORLY UNDERSTOOD 4501 02:55:38,501 --> 02:55:43,706 AND 1 OF THE REASONS IS LACK OF 4502 02:55:43,706 --> 02:55:46,342 EASY TO USE MODEL SYSTEMS AND 4503 02:55:46,342 --> 02:55:49,745 HERE'S 1, AND FOR THE AIR WAY ON 4504 02:55:49,745 --> 02:55:51,814 THE BASAL CELLS THAT GIVE RISE 4505 02:55:51,814 --> 02:55:53,582 TO MAJOR TYPES OF SECRETEATORY 4506 02:55:53,582 --> 02:55:57,153 CELLS AS WELL AS CELL TYPES SUCH 4507 02:55:57,153 --> 02:55:57,520 AS IONOSIGHTS. 4508 02:55:57,520 --> 02:55:59,255 SO TODAY MY FOCUS IS 4509 02:55:59,255 --> 02:56:00,423 CYSTIC FIBROSIS BUT I WOULD LOVE 4510 02:56:00,423 --> 02:56:03,392 TO BROADEN THE STUDY TO OTHER 4511 02:56:03,392 --> 02:56:13,869 PEDIATRIC DISEASES AS WELL. 4512 02:56:35,090 --> 02:56:36,058 NEXT PLEASE. 4513 02:56:36,058 --> 02:56:40,696 -- TO MOW AND YOU HAD -- HUMAN 4514 02:56:40,696 --> 02:56:42,331 AIR WAYS AND IDENTIFIED THESE 4515 02:56:42,331 --> 02:56:44,533 CELL TYPES THAT ARE HIGH IN CTR 4516 02:56:44,533 --> 02:56:49,305 BUT LESS THAN 1% OF AIRWAY 4517 02:56:49,305 --> 02:56:53,876 CELLS, AND THEY WERE CALLED THE 4518 02:56:53,876 --> 02:56:54,710 PULMONARY IONOCYTES AND IT'S 4519 02:56:54,710 --> 02:56:56,278 BEEN A SUBJECT OF ONGOING 4520 02:56:56,278 --> 02:56:57,480 RESEARCH AND I ALWAYS INCLUDE 4521 02:56:57,480 --> 02:57:00,115 THIS AS 1 OF MY CP PATIENTS AND 4522 02:57:00,115 --> 02:57:01,617 APPRECIATE THE HYPER REAMIC 4523 02:57:01,617 --> 02:57:03,586 MUCOSA AND THE TENACIOUS MUCUS 4524 02:57:03,586 --> 02:57:04,653 AND ENVIRONMENT LIKE THIS SETS 4525 02:57:04,653 --> 02:57:06,856 UP FOR A CHRONIC CYCLE OF 4526 02:57:06,856 --> 02:57:08,123 INFLAMMATION AND INFECTION, 4527 02:57:08,123 --> 02:57:11,126 LEADING TO LUNG STRUCTURAL 4528 02:57:11,126 --> 02:57:13,329 DAMAGE AND SHORTENING LIFE SPAN 4529 02:57:13,329 --> 02:57:13,896 EMPLOY NEXT, PLEASE. 4530 02:57:13,896 --> 02:57:16,298 AND AS MANY KNOW THERE'S A BREAK 4531 02:57:16,298 --> 02:57:18,100 THROUGH IN CF TREATMENT IN THE 4532 02:57:18,100 --> 02:57:21,170 FORM OF SMALL MOLECULE THAT 4533 02:57:21,170 --> 02:57:23,138 TARGETS THE CF MODULES, THAT 4534 02:57:23,138 --> 02:57:24,673 BEING SAID, GAPS STILL REMAIN, 4535 02:57:24,673 --> 02:57:27,076 FOR THOSE THAT DON'T HAVE 4536 02:57:27,076 --> 02:57:29,945 MODULATORS OR CAN'T RESPOND TO 4537 02:57:29,945 --> 02:57:31,814 THEM, THE FUTURE MAY BE IN GENE 4538 02:57:31,814 --> 02:57:35,417 CELL THERAPY AND WE ALSO NEED 4539 02:57:35,417 --> 02:57:36,819 PERSONALIZED DRUG AND RESPONSE 4540 02:57:36,819 --> 02:57:39,922 PLATFORMS SO ALL THOO NEEDS 4541 02:57:39,922 --> 02:57:40,723 PATIENT-SPECIFIC NONINVASIVE 4542 02:57:40,723 --> 02:57:41,790 HUMAN MODEL SYSTEM WHICH CAN BE 4543 02:57:41,790 --> 02:57:43,959 APPLIED TO CF BUT OTHER DISEASES 4544 02:57:43,959 --> 02:57:44,693 AS WELL. 4545 02:57:44,693 --> 02:57:45,160 NEXT. 4546 02:57:45,160 --> 02:57:50,366 SO MANY RESEARCHERS DO WORK WITH 4547 02:57:50,366 --> 02:57:51,901 IMMORTALIZED CELL LINES AND BUT 4548 02:57:51,901 --> 02:57:53,536 THEY DON'T REPRESENT ALL THE 4549 02:57:53,536 --> 02:57:55,404 RELEVANT CELL TYPES AND THE 4550 02:57:55,404 --> 02:57:56,438 PRIMARY BRORVEGGIAL HUMAN CELLS 4551 02:57:56,438 --> 02:57:57,940 ARE STILL THE GOLD STANDARD 4552 02:57:57,940 --> 02:57:59,708 BECAUSE BECAUSE THEY'RE STILL 4553 02:57:59,708 --> 02:58:00,910 INVASIVE THERE'S LIMITED ACCESS 4554 02:58:00,910 --> 02:58:02,044 FOR DIVERSE POPULATIONS AND 4555 02:58:02,044 --> 02:58:03,646 THEY'RE TAKEN FROM DISEASE 4556 02:58:03,646 --> 02:58:04,246 ENVIRONMENT WHICH MAY AFFAIRS 4557 02:58:04,246 --> 02:58:07,449 TEAM LEADERRER THE BEHAVIOR OF 4558 02:58:07,449 --> 02:58:07,683 CELLS. 4559 02:58:07,683 --> 02:58:08,017 NEXT, PLEASE. 4560 02:58:08,017 --> 02:58:10,819 SO ALL THIS TO SAY THAT INDUCED 4561 02:58:10,819 --> 02:58:13,455 PLURIPOTENT STEM CELL CAN BE A 4562 02:58:13,455 --> 02:58:15,858 PLOSM ELEMENTARY MODEL SYSTEM, 4563 02:58:15,858 --> 02:58:17,726 EVERYONE HERE KNOWS IPSCs, WE 4564 02:58:17,726 --> 02:58:19,695 HEARD A WONDERFUL TALK ABOUT IT 4565 02:58:19,695 --> 02:58:22,164 TAKING SOMATIC CELLS FROM 4566 02:58:22,164 --> 02:58:23,666 PATIENTS INTRODUCING FOREFACTORS 4567 02:58:23,666 --> 02:58:24,967 WE CAN DIFFERENTIATE A SOMATIC 4568 02:58:24,967 --> 02:58:26,902 CELL BACK TO THE EMBRYONIC STEM 4569 02:58:26,902 --> 02:58:30,239 CELL LIKE STATE AND IPSCs CAN 4570 02:58:30,239 --> 02:58:31,774 BE DIFFERENTIATED TO VARIOUS 4571 02:58:31,774 --> 02:58:36,011 CELL TYPES AND COUPLE IT TO THE 4572 02:58:36,011 --> 02:58:37,780 EDITING TECHNOLOGIES AND TARGET 4573 02:58:37,780 --> 02:58:40,115 BETTER YEENS. 4574 02:58:40,115 --> 02:58:42,384 SO IT'S PATIENT SPECIFIC, 4575 02:58:42,384 --> 02:58:44,453 CONTAINS HOST PROGRAMS, 4576 02:58:44,453 --> 02:58:45,421 NONEVASIVE, NEED TCCs OF BLOOD 4577 02:58:45,421 --> 02:58:48,290 AND YOU HAVE AN INEXHAUSTIBLE 4578 02:58:48,290 --> 02:58:51,860 RENEWAL SUPPLY. 4579 02:58:51,860 --> 02:58:55,764 IT'S EASE OF GENE EDITING AND 4580 02:58:55,764 --> 02:58:56,799 ACCESS TO DEVELOPMENTAL MINE 4581 02:58:56,799 --> 02:58:58,167 SOLES AND IT OFFERS A RETINAL 4582 02:58:58,167 --> 02:58:59,835 LOCATION SET THAT OTHER GENETICS 4583 02:58:59,835 --> 02:59:02,004 MAY OR MAY NOT HAVE. 4584 02:59:02,004 --> 02:59:06,508 I WAS FORTUNATE TO CONTRIBUTE TO 4585 02:59:06,508 --> 02:59:09,678 PROTOCOL BY MANY GROUPS OVER 4586 02:59:09,678 --> 02:59:11,680 DECADES, IT'S A STEP WISE 4587 02:59:11,680 --> 02:59:14,183 PROTOCOL THAT AIMS TO 4588 02:59:14,183 --> 02:59:16,852 RECAPITULATE IN VIVO LUNG 4589 02:59:16,852 --> 02:59:17,286 DEVELOPMENT. 4590 02:59:17,286 --> 02:59:20,089 THE FIRST 14 DAYS ARE ON 2 D, WE 4591 02:59:20,089 --> 02:59:23,292 MAKE IPSCs AND INHIBITING TGF 4592 02:59:23,292 --> 02:59:25,794 BETA AND PUT IN THE FOREGUT, AND 4593 02:59:25,794 --> 02:59:29,331 THEN WE MAKE LUNG PROGENITORS 4594 02:59:29,331 --> 02:59:39,742 WHICH ARE PURIFIED ON 3D 4595 02:59:42,211 --> 02:59:43,345 MATRIgE R, AND THESE ARE PURE 4596 02:59:43,345 --> 02:59:45,648 PIED AND PLAYED ON TO 4597 02:59:45,648 --> 02:59:47,883 INTERLEUKIN INTERPHASE TO,A LOW 4598 02:59:47,883 --> 02:59:49,118 FOR DEFERENTIATION TO MATURE AIR 4599 02:59:49,118 --> 02:59:51,353 WAYS AND WE CAN PRESS, WE CAN 4600 02:59:51,353 --> 02:59:54,189 PRAY THE ANIMATION, SO AFTER 3 4601 02:59:54,189 --> 02:59:55,924 WEEKS AT THE ISHT FACE, THIS IS 4602 02:59:55,924 --> 02:59:58,560 A BIRD'S EYE VIEW OF 1 OF THE 4603 02:59:58,560 --> 03:00:01,330 AIR WAY CULTURES YOU CAN SEE THE 4604 03:00:01,330 --> 03:00:03,265 BEATING CILIA, MEETING YOU THINK 4605 03:00:03,265 --> 03:00:04,633 IS A MUCUS HURRICANE AND THE 4606 03:00:04,633 --> 03:00:08,470 SECTION OF THE AIR WAY SHOWS A 4607 03:00:08,470 --> 03:00:09,672 PSEUDOSTRATIFIED EPITHELIUM THAT 4608 03:00:09,672 --> 03:00:10,506 MORPHOLOGICALLY VERY SIMILAR TO 4609 03:00:10,506 --> 03:00:15,044 A PRIMARY AIR WAY. 4610 03:00:15,044 --> 03:00:16,812 NEXT, PLEASE. 4611 03:00:16,812 --> 03:00:19,281 TO CHARACTERIZE THE POETIC 4612 03:00:19,281 --> 03:00:20,816 LECULAR PHENOTYPE, WE 4613 03:00:20,816 --> 03:00:23,018 PERFORMED SINGLE RNA SEQ, WHICH 4614 03:00:23,018 --> 03:00:25,320 SHOWED THAT WE GENERATED THE 4615 03:00:25,320 --> 03:00:26,455 RELEVANT CELL TYPES, MAININGOR 4616 03:00:26,455 --> 03:00:30,793 AND RARE AND THESE CELL TYPES 4617 03:00:30,793 --> 03:00:31,427 ARE TRANSCRIPTOMICLY SILL 4618 03:00:31,427 --> 03:00:33,962 SIMILAR TO AIR WAYS, ON THIS 4619 03:00:33,962 --> 03:00:36,565 MAP, WE HAVE 5 DIFFERENT LINES. 4620 03:00:36,565 --> 03:00:40,469 WE SEE GENERATIONS OF BASAL 4621 03:00:40,469 --> 03:00:41,603 CELLS, SECRETORY CELLS, IMMUNE 4622 03:00:41,603 --> 03:00:43,572 DYSFUNCTION MATURE CELLS AND 4623 03:00:43,572 --> 03:00:45,741 CILIATED, AND WE HAVE THE ION SO 4624 03:00:45,741 --> 03:00:49,078 SIGHTS THAT EXPRESS FOX 1 THAT 4625 03:00:49,078 --> 03:00:55,617 EXPRESS THE ISNI GENES AND THE 4626 03:00:55,617 --> 03:00:56,585 IONOCYTES CONSIST OF 1% OF THE 4627 03:00:56,585 --> 03:00:59,955 POPULATION AND WELL IS NO 4628 03:00:59,955 --> 03:01:01,423 CONTAMINATION FROM NONLUNG 4629 03:01:01,423 --> 03:01:02,925 LINEAGES USING THIS PROTOCOL. 4630 03:01:02,925 --> 03:01:06,095 ON THE RIGHT WE SEE STAINING OF 4631 03:01:06,095 --> 03:01:13,368 THE IPSCs IONOCYTESS ON THIS 4632 03:01:13,368 --> 03:01:16,004 AND THE LUNG FUNCTION AND AIR 4633 03:01:16,004 --> 03:01:17,372 WAY AND HOW THEY'RE 4634 03:01:17,372 --> 03:01:18,841 COMMUNICATING TO OTHER AIRWAY 4635 03:01:18,841 --> 03:01:29,184 CELL TYPES.L TYPES. 4636 03:01:34,723 --> 03:01:35,991 NEXT, PLEASE. 4637 03:01:35,991 --> 03:01:42,898 -- SHOWED THAT MICE DEFICIENT 4638 03:01:42,898 --> 03:01:44,733 IONOCYTES DEMONSTRATE VISCOSITY 4639 03:01:44,733 --> 03:01:51,573 AND MOST PUB LIKELY PUBLISHED, 4640 03:01:51,573 --> 03:01:56,145 THAT FERRETS SHOW BETTER, OTHERS 4641 03:01:56,145 --> 03:01:59,648 SHOWING THE IONOCYTES ARE 4642 03:01:59,648 --> 03:02:03,652 FUNCTIONAL BUT THEY ABSORB 4643 03:02:03,652 --> 03:02:04,319 CHLORIDES. 4644 03:02:04,319 --> 03:02:05,087 NEXT, PLEASE. 4645 03:02:05,087 --> 03:02:07,756 AND THEN, SO TO INTERROGATE THE 4646 03:02:07,756 --> 03:02:08,957 FUNCTION OF IONOCYTES TO ADD TO 4647 03:02:08,957 --> 03:02:11,493 THIS BODY OF LITERATURE USING 4648 03:02:11,493 --> 03:02:13,295 OUR SYSTEM, GIVEN IT'S ABILITY 4649 03:02:13,295 --> 03:02:16,398 TO DO GENE EDITING WE TEAMED UP 4650 03:02:16,398 --> 03:02:18,167 WITH OUR GENE EDITOR 4651 03:02:18,167 --> 03:02:21,069 [INDISCERNIBLE] AND KNOCKED OUT 4652 03:02:21,069 --> 03:02:23,772 THE FOX I1 AND DIFFERENTIATED 4653 03:02:23,772 --> 03:02:26,041 BOTH FOX 1 KNOCK OUT AND GENETIC 4654 03:02:26,041 --> 03:02:28,510 WILD-TYPE 2 AIRWAYS AND WE FOUND 4655 03:02:28,510 --> 03:02:31,180 THAT FOX 1 KNOCK OUT OF IPS AIR 4656 03:02:31,180 --> 03:02:35,017 WAY CULTURED IN THE LIQUID, 4657 03:02:35,017 --> 03:02:36,351 BEGAN TO CF HUMAN HAIR WAY, WITH 4658 03:02:36,351 --> 03:02:38,620 THE DEVELOP AM OF THESE THICK 4659 03:02:38,620 --> 03:02:40,823 MUCUS, IN FACT, AFTER ABOUT 3 4660 03:02:40,823 --> 03:02:43,125 WEEKS OF CULTURE AT INTERLEUKIN 4661 03:02:43,125 --> 03:02:44,426 INTERPHASE OUR TEAM HAS DAILY 4662 03:02:44,426 --> 03:02:47,029 WASHED OFF THE MUCUS TO SEE THE 4663 03:02:47,029 --> 03:02:48,397 CELLS UNDERNEATH. 4664 03:02:48,397 --> 03:02:54,670 AND WE ALSO SAW SIGNIFICANT 4665 03:02:54,670 --> 03:02:56,104 INCREASE IN MUC 5 B AND THE 4666 03:02:56,104 --> 03:02:56,972 CULLURES AND IT'S SIMILAR TO 4667 03:02:56,972 --> 03:02:58,941 WHAT'S SEEN IN THE FOX 1 4668 03:02:58,941 --> 03:02:59,575 KNOCKOUT MICE. 4669 03:02:59,575 --> 03:03:01,777 AND NOT SHOWN HERE BUT WE ALSO 4670 03:03:01,777 --> 03:03:04,379 SEE A SIGNIFICANT DECREASE IN 4671 03:03:04,379 --> 03:03:06,582 CILIATED CELLS WHICH FITS IN DAT 4672 03:03:06,582 --> 03:03:09,451 WITH WITH IONOCYTES AND OTHER 4673 03:03:09,451 --> 03:03:12,254 ORGANISMS THAT IONOCYTES MAY 4674 03:03:12,254 --> 03:03:15,858 COMMUNICATE TO IMPAIR CELLULAR 4675 03:03:15,858 --> 03:03:16,425 DIS 4676 03:03:16,425 --> 03:03:16,725 DYSFUNCTION. 4677 03:03:16,725 --> 03:03:18,126 SO WHAT IS THE FUNCTION IN 4678 03:03:18,126 --> 03:03:19,895 EMERGING ITS OF ION TRANSPORT SO 4679 03:03:19,895 --> 03:03:22,664 WE PERFORMED SHORT CIRCUIT 4680 03:03:22,664 --> 03:03:24,233 ANALYSIS, AND FOX 1 WILD-TYPE 4681 03:03:24,233 --> 03:03:26,268 AIR WAYS, SO ON THE VERY LEFT, 4682 03:03:26,268 --> 03:03:28,837 WE SHOW IMAGES OF THE SUCCESSFUL 4683 03:03:28,837 --> 03:03:30,672 KNOCKING OF THOSE IONOCYTES, THE 4684 03:03:30,672 --> 03:03:33,342 RED CELLS ARE ON THE WILD-TYPE 4685 03:03:33,342 --> 03:03:34,743 CULTURE ARE BSND POSITIVE, AND 4686 03:03:34,743 --> 03:03:38,680 THE KNOCK OUT CULTURES HAVE NO 4687 03:03:38,680 --> 03:03:41,116 IONOCYTES, SO THE FIRST CHAMBER 4688 03:03:41,116 --> 03:03:42,918 SHORT CIRCUIT TRACING IS 4689 03:03:42,918 --> 03:03:44,119 COMPARING THE FOX 1 WILD-TYPE 4690 03:03:44,119 --> 03:03:44,753 AND KNOCK OUT. 4691 03:03:44,753 --> 03:03:46,421 AND THE RED TRAITSING YOU SEE IS 4692 03:03:46,421 --> 03:03:50,325 THE KNOCK OUT HAS A 4693 03:03:50,325 --> 03:03:52,594 SIGNIFICANTLY DECREASED CHLORIDE 4694 03:03:52,594 --> 03:03:55,230 TRANSPORT AND CF2 R DEPENDENT AS 4695 03:03:55,230 --> 03:03:57,065 COMPARE TO THE BLUE WILD-TYPE 4696 03:03:57,065 --> 03:03:58,567 TRACING AND THERE THIS IS 4697 03:03:58,567 --> 03:03:59,768 SIMILAR TO THE KNOCK OUT FERIT 4698 03:03:59,768 --> 03:04:02,070 AND WE ALSO GENERATED A DOCKSY 4699 03:04:02,070 --> 03:04:04,072 PSYCHE LINE INDUCIBLE FOX 1 4700 03:04:04,072 --> 03:04:05,340 OVEREXPRESSING LINE IN THE KNOCK 4701 03:04:05,340 --> 03:04:07,509 OUT BACKGROUND, AND SO THE 4702 03:04:07,509 --> 03:04:08,844 SECOND WAS IN CHAMBER TRACINGOT 4703 03:04:08,844 --> 03:04:09,411 RIGHT, WE SHOWED THAT WEB 4704 03:04:09,411 --> 03:04:11,480 CONNECTED WERE ABLE TO RESTORE 4705 03:04:11,480 --> 03:04:13,415 THIS DEFICIENT CHLORIDE 4706 03:04:13,415 --> 03:04:14,283 TRANSPORT. 4707 03:04:14,283 --> 03:04:16,351 AND ALL THIS POINTS TO THE FACT 4708 03:04:16,351 --> 03:04:19,755 THAT IONON SIGHTS WERE IMPORTANT 4709 03:04:19,755 --> 03:04:23,325 TO AIR WAY TRANSPORT AND 4710 03:04:23,325 --> 03:04:25,394 FUNCTION IN A HUMAN SYSTEM. 4711 03:04:25,394 --> 03:04:25,727 NEXT. 4712 03:04:25,727 --> 03:04:30,565 WE DID A MIXING STUDY, WE 4713 03:04:30,565 --> 03:04:35,270 COMBINED FOX EXPRESSING IPSC 4714 03:04:35,270 --> 03:04:36,972 BASAL CELLS WITH A DURING 4715 03:04:36,972 --> 03:04:38,974 SEEDING AND THE MIXED CULTURES 4716 03:04:38,974 --> 03:04:40,475 WERE ALLOWED TO DIFFERENTIATE 4717 03:04:40,475 --> 03:04:42,778 AND THEN DOCKSY PSYCHE LYNN WAS 4718 03:04:42,778 --> 03:04:45,414 ADDED 5 DAYS AT IRENFACE AND TO 4719 03:04:45,414 --> 03:04:47,683 SAY THAT THE WILD-TYPE IONOCYTES 4720 03:04:47,683 --> 03:04:52,254 JUST 5% TO A CFIPS AIRWAY SEEMED 4721 03:04:52,254 --> 03:04:55,457 TO RESTORE THE CFTR MEDIAN 4722 03:04:55,457 --> 03:04:57,326 TRANSPORT AND POINTING TO A 4723 03:04:57,326 --> 03:04:59,861 THERAPEUTIC POTENTIAL OF THE 4724 03:04:59,861 --> 03:05:05,567 PULMONARY IONOCYTES. 4725 03:05:05,567 --> 03:05:06,335 NEXT, PLEASE. 4726 03:05:06,335 --> 03:05:08,103 SO BECAUSE THESE ARE SO FEW IN 4727 03:05:08,103 --> 03:05:09,404 NUMBERS WE NEED MONITOR THE 4728 03:05:09,404 --> 03:05:15,644 NUMBERS AND STUDY THE PATHWAYS 4729 03:05:15,644 --> 03:05:18,280 THAT LEAD TO MODULATION. 4730 03:05:18,280 --> 03:05:19,881 THERE'S A CRITICAL TIME AND 4731 03:05:19,881 --> 03:05:21,183 DIFFERENTIATION WHERE NOTCH LED 4732 03:05:21,183 --> 03:05:22,818 TO A SIGNIFICANT INCREASE IN ION 4733 03:05:22,818 --> 03:05:26,655 SIGHT MEMBERS MEMBER -- NUMBERT 4734 03:05:26,655 --> 03:05:27,889 IS AN ONGOING AREA OF RESEARCH 4735 03:05:27,889 --> 03:05:28,457 AS WELL. 4736 03:05:28,457 --> 03:05:28,890 NEXT, PLEASE. 4737 03:05:28,890 --> 03:05:30,225 AND SO WE ALSO ASKED WHETHER WE 4738 03:05:30,225 --> 03:05:33,562 CAN USE THE SYSTEM TO MODEL 4739 03:05:33,562 --> 03:05:34,963 CYSTIC FIBROSIS, THE DEFEC IN 4740 03:05:34,963 --> 03:05:36,598 ION AND FLUID TRANSPORT AND WE 4741 03:05:36,598 --> 03:05:38,600 IMENERATED -- WE HAVE PLULT PEL 4742 03:05:38,600 --> 03:05:48,810 IPSCs IN OUR LAB AND WE 4743 03:05:48,810 --> 03:05:49,544 GENERATED BOTH. 4744 03:05:49,544 --> 03:05:54,616 AS YOU SEE IN BLUE HAS NO 4745 03:05:54,616 --> 03:05:55,784 DEPENDENT CURRENT WHERE THE 4746 03:05:55,784 --> 03:05:56,852 CORRECTED CURRENT IN THE 4747 03:05:56,852 --> 03:05:59,054 CONTROLS WERE IN THE RANGE OF 4748 03:05:59,054 --> 03:05:59,888 PRIMARY HUMAN BRONCHIAL 4749 03:05:59,888 --> 03:06:01,590 EPITHELIAL CELLS AND WE'RE ALSO 4750 03:06:01,590 --> 03:06:04,593 ABLE TO DOWN THE BASAL CELLS AS 4751 03:06:04,593 --> 03:06:09,765 A 3D ORGANOID STAGE AND THE 4752 03:06:09,765 --> 03:06:11,066 BASAL CELLS MAINTAIN CAPABLE AS 4753 03:06:11,066 --> 03:06:14,970 WELL AS THIS DEFECT IN CF-ION 4754 03:06:14,970 --> 03:06:15,237 TRANSPORT. 4755 03:06:15,237 --> 03:06:16,204 NEXT PLEASE. 4756 03:06:16,204 --> 03:06:18,940 SO IN THE LAST FEW MINUTES, 4757 03:06:18,940 --> 03:06:20,575 ANOTHER GAP WE MENTION SIDE WE 4758 03:06:20,575 --> 03:06:22,144 NEED PATHOGEN IS DRUG RESPONSE, 4759 03:06:22,144 --> 03:06:23,512 NEXT, PLEASE, SO DURING THE 4760 03:06:23,512 --> 03:06:26,281 PANDEMIC AS EVERYBODY DID, WE 4761 03:06:26,281 --> 03:06:30,185 PIVOTED OUR PLATFORM TO MODELS 4762 03:06:30,185 --> 03:06:35,157 SARS-COV-2, AND TEAMED UP WITH 4763 03:06:35,157 --> 03:06:38,960 VIROLOGISTS FROM THE NIAID WITH 4764 03:06:38,960 --> 03:06:40,128 CULTURES FROM SARS-COV-2 WE 4765 03:06:40,128 --> 03:06:40,929 FOUND OURSELVES PERMISSIVE TO 4766 03:06:40,929 --> 03:06:45,000 THE VIRUS AND ON THE LEFT IS THE 4767 03:06:45,000 --> 03:06:47,402 VOLCAN O PLOT SHOWING THE IPS C 4768 03:06:47,402 --> 03:06:49,805 AIR WAYS AND LIKE PRIMARY AIR 4769 03:06:49,805 --> 03:06:51,106 WAYS THESE EXHIBIT VERY ROBUST 4770 03:06:51,106 --> 03:06:53,708 TYPE 1 AND TYPE 3 INTERFERON 4771 03:06:53,708 --> 03:06:55,844 RESPONSE AS WELL AS PLEURAL 4772 03:06:55,844 --> 03:06:56,645 INFLAMMATORY RESPONSE AND TO THE 4773 03:06:56,645 --> 03:06:58,613 RIGHT WE ALSO LOOKED AT THE 4774 03:06:58,613 --> 03:07:00,115 FEASIBILITY OF THE THIS PLATFORM 4775 03:07:00,115 --> 03:07:01,883 TO SCREEN FOR COVID-19. 4776 03:07:01,883 --> 03:07:04,219 THERAPEUTIC COMPOUNDS AND HERE 4777 03:07:04,219 --> 03:07:06,188 I'M SHOWING REMDESAVIR BUT ALSO 4778 03:07:06,188 --> 03:07:08,156 TESTED SEVERAL OTHER COMPOUNDS 4779 03:07:08,156 --> 03:07:11,059 IN THIS FASHION AS WELL. 4780 03:07:11,059 --> 03:07:11,726 NEXT. 4781 03:07:11,726 --> 03:07:14,763 AND BECAUSE THE IPSC SYSTEM 4782 03:07:14,763 --> 03:07:15,897 OFFERS THIS REDUCTIONIST 4783 03:07:15,897 --> 03:07:17,399 PERSONALIZED MODEL SYSTEM AND 4784 03:07:17,399 --> 03:07:19,067 WHEN COUPLED GENE EDITING ALLOW 4785 03:07:19,067 --> 03:07:20,902 US TO TEASE OUT THE EFFECT OF A 4786 03:07:20,902 --> 03:07:22,404 SPECIFIC GENE ON PATHOGEN 4787 03:07:22,404 --> 03:07:22,671 RESPONSE. 4788 03:07:22,671 --> 03:07:25,907 IN THIS CASE WE INFECTED CF AND 4789 03:07:25,907 --> 03:07:28,510 THE CFTR, WITH THE SARS-COV-2 4790 03:07:28,510 --> 03:07:31,646 AND WE FOUND THAT CF EPITHELIUM 4791 03:07:31,646 --> 03:07:34,216 HAD A SIGNIFICANTLY HIGHER VIRAL 4792 03:07:34,216 --> 03:07:36,518 BURDEN WITH THE EPITHELIUM WITH 4793 03:07:36,518 --> 03:07:37,719 DISORGANIZED SEALIA AND THE 4794 03:07:37,719 --> 03:07:39,221 GREEN HERE IS SARS-COV-2 AND 4795 03:07:39,221 --> 03:07:43,058 PROTEIN AND THEN THE RED IS 4796 03:07:43,058 --> 03:07:45,227 [INDISCERNIBLE] CELLS SO THE CF 4797 03:07:45,227 --> 03:07:46,962 LOOKS MUCH SICKER BUT THEN 4798 03:07:46,962 --> 03:07:50,298 INTERESTING, WHEN WE TREATED THE 4799 03:07:50,298 --> 03:07:56,238 CF AIRWAYS WITH THE MODULATOR IN 4800 03:07:56,238 --> 03:07:59,875 THE COMBINATION, WE FOUND THAT 4801 03:07:59,875 --> 03:08:00,809 THE CFTMODDULATOR HAD 4802 03:08:00,809 --> 03:08:01,743 SIGNIFICANT REDUCTION OF 4803 03:08:01,743 --> 03:08:04,546 INFECTION AND A MUCH BETTER 4804 03:08:04,546 --> 03:08:07,649 LOOKING AIRWAY EPITHELIUM. 4805 03:08:07,649 --> 03:08:08,150 NEXT, PLEASE. 4806 03:08:08,150 --> 03:08:10,218 SO WE WANTED TO MAKE SURE IT'S 4807 03:08:10,218 --> 03:08:12,954 NOT A SARS, JUST A ONLY 4808 03:08:12,954 --> 03:08:13,288 PHENOMENON. 4809 03:08:13,288 --> 03:08:15,056 WE WANT TO LOOK AT OTHER VIRUSES 4810 03:08:15,056 --> 03:08:18,860 AS WELL AND FOR THIS WE TEAMED 4811 03:08:18,860 --> 03:08:19,995 UP WITH [INDISCERNIBLE]. 4812 03:08:19,995 --> 03:08:22,564 AND WE INFECTED OUR IPSCs WITH 4813 03:08:22,564 --> 03:08:25,901 H1N1 AND SO THAT AIRWAY HAD 4814 03:08:25,901 --> 03:08:27,235 INCREASE INFECTION COMPARED TO 4815 03:08:27,235 --> 03:08:31,506 CANNED WHAT AIRWAY AND HERE THE 4816 03:08:31,506 --> 03:08:35,343 GREEN CELLS ARE IN NUCLEOTIDES 4817 03:08:35,343 --> 03:08:37,212 CLARPROTEIN AND WHEN WE HAVE THE 4818 03:08:37,212 --> 03:08:39,080 MODULOR TRI CASTA THERE WAS A 4819 03:08:39,080 --> 03:08:43,351 SIGNIFICANT REDUCTION IN 4820 03:08:43,351 --> 03:08:43,785 INFECTION. 4821 03:08:43,785 --> 03:08:44,052 NEXT. 4822 03:08:44,052 --> 03:08:45,453 NEXT, SO IN SUMMARY, I THINK I 4823 03:08:45,453 --> 03:08:47,589 HOPE TO HAVE SHOWN YOU THAT WE 4824 03:08:47,589 --> 03:08:49,858 HAVE ESTABLISHED IPSC AIRWAY 4825 03:08:49,858 --> 03:08:52,360 THAT CAN BE DIFFERENTIATED INTO 4826 03:08:52,360 --> 03:08:54,095 COMMON AND RARE AIRWAY CELL 4827 03:08:54,095 --> 03:08:56,031 TYPES TO STUDY THEIR BIOLOGY AND 4828 03:08:56,031 --> 03:08:59,701 WE CF AND WERE ABLE TO CAPTURE 4829 03:08:59,701 --> 03:09:02,504 THE DEFECT IN CF ION TRANSPORT. 4830 03:09:02,504 --> 03:09:04,706 WE HAVE GENERATED IONOCYTES, AND 4831 03:09:04,706 --> 03:09:05,974 FASCINATING CELL TYPES WHICH 4832 03:09:05,974 --> 03:09:09,344 SEEMS TO BE A KEY REGULATOR FOR 4833 03:09:09,344 --> 03:09:10,512 HOMEOSTASIS IF YOU KNOCK IT OUT 4834 03:09:10,512 --> 03:09:12,214 AND THEN WHEN YOU OVEREXPRESS 4835 03:09:12,214 --> 03:09:15,584 IT, WE CAN USE ITS PLATFORM FOR 4836 03:09:15,584 --> 03:09:16,651 PLATFORM INFECTION AND T-CELL 4837 03:09:16,651 --> 03:09:18,053 DISEASE EPITHELIAL RESPONSE TO 4838 03:09:18,053 --> 03:09:19,187 PATHOGENSAs WELL AS RESPONSE 4839 03:09:19,187 --> 03:09:19,588 TO DRUGS. 4840 03:09:19,588 --> 03:09:20,889 AND TO SAY THAT AGAIN, THE 4841 03:09:20,889 --> 03:09:23,191 FUTURE DIRECTION IS TO EXPAND 4842 03:09:23,191 --> 03:09:25,594 THIS PLATFORM BEYOND 4843 03:09:25,594 --> 03:09:26,328 CYSTIC FIBROSIS AS WELL. 4844 03:09:26,328 --> 03:09:27,829 SO THE LAST FEW SLIDES, I WOULD 4845 03:09:27,829 --> 03:09:30,865 LIKE TO TALK ABOUT GAPS. 4846 03:09:30,865 --> 03:09:33,301 NEXT PLEASE, AND IN TERMS OF 4847 03:09:33,301 --> 03:09:35,403 BOTH IONOCYTES BIOLOGY AND 4848 03:09:35,403 --> 03:09:37,038 IPSCSYSTEMS, IN TERMS OF 4849 03:09:37,038 --> 03:09:38,640 IONOCYTES WE STILL NEED TO 4850 03:09:38,640 --> 03:09:41,810 UNDERSTAND THE DIFFERENT 4851 03:09:41,810 --> 03:09:43,178 SUBTYPES, JUST IONOCYTES INTO 4852 03:09:43,178 --> 03:09:44,579 OTHER TISSUES HAVE DISTRIBUTION, 4853 03:09:44,579 --> 03:09:45,880 LOCALIZATION, AND THE FUNCTIONS 4854 03:09:45,880 --> 03:09:46,281 MAY BE DIFFERENT. 4855 03:09:46,281 --> 03:09:48,350 NEED TO KNOW A SIGNALING PATHWAY 4856 03:09:48,350 --> 03:09:50,619 THAT LEAD TO DIFREBTIATION, 4857 03:09:50,619 --> 03:09:53,455 STUDY THEIR ROW IN AIRWAY 4858 03:09:53,455 --> 03:09:55,257 HOMEOSTASIS AND ALSO TON IF 4859 03:09:55,257 --> 03:09:59,027 THEIR FUNCTION DIFFERS IN 4860 03:09:59,027 --> 03:10:00,061 DIFFERENT AIRWAY DISEASES THAT 4861 03:10:00,061 --> 03:10:02,464 HAVE DIFFERENT AREAS OF 4862 03:10:02,464 --> 03:10:03,632 INFLAMMATION AND HOW OUR 4863 03:10:03,632 --> 03:10:04,566 ENVIRONMENT INFLUENCES THAT 4864 03:10:04,566 --> 03:10:05,400 FUNCTION. 4865 03:10:05,400 --> 03:10:08,203 AND AN INTRIGUING QUESTION IS 4866 03:10:08,203 --> 03:10:12,941 WHETHER OR NOT ION SO -- 4867 03:10:12,941 --> 03:10:15,577 IONOCYTES CAN BE TARGETED FOR 4868 03:10:15,577 --> 03:10:15,910 GENE THERAPY. 4869 03:10:15,910 --> 03:10:17,245 ACTUALLY CAN YOU GO TO THE NEXT 4870 03:10:17,245 --> 03:10:17,912 SLIDE. 4871 03:10:17,912 --> 03:10:20,482 OKAY, IN TERMS OF IPSCSYSTEMS, 4872 03:10:20,482 --> 03:10:22,250 TO THE BEST OF MY OWN KNOWLEDGE, 4873 03:10:22,250 --> 03:10:24,452 THE GAPS IS THAT IPSC TISSUES 4874 03:10:24,452 --> 03:10:27,956 FOR THE MOST PART ARE STILL MORE 4875 03:10:27,956 --> 03:10:29,557 IMMATURE, AND WE REALLY DO NEED 4876 03:10:29,557 --> 03:10:34,129 TO TAKE AN ACCOUNT THE MATRIX, 4877 03:10:34,129 --> 03:10:34,929 MECHANICAL PROPERTIES IMMUNE 4878 03:10:34,929 --> 03:10:35,897 CELLS AND VASCULAR CELLS. 4879 03:10:35,897 --> 03:10:38,700 WE NEED TO STUDY HOW RESPONSE TO 4880 03:10:38,700 --> 03:10:39,734 STRESSORS AND SCALABILITY, I 4881 03:10:39,734 --> 03:10:42,304 THINK IS A BIG DIESEL, IT'S 4882 03:10:42,304 --> 03:10:43,238 EXPENSIVE AND LABORIOUS AND THE 4883 03:10:43,238 --> 03:10:47,175 METHOD NEEDS TO BE MORE 4884 03:10:47,175 --> 03:10:49,311 STANDARDIZED. 4885 03:10:49,311 --> 03:10:51,946 AND SO, NEXT, I THINK THIS IS MY 4886 03:10:51,946 --> 03:10:53,214 LAST SLIDE, SO THE KEY RESEARCH 4887 03:10:53,214 --> 03:10:54,516 QUESTIONS IS THE OPTIMAL 4888 03:10:54,516 --> 03:10:55,583 CONDITIONS TO GET THE SPECIFIC 4889 03:10:55,583 --> 03:10:58,653 LUNG TYPES AND HOW DO EACH 4890 03:10:58,653 --> 03:10:59,888 GENETIC VARIATIONS EFFECT IPSC 4891 03:10:59,888 --> 03:11:02,957 LUNG CELLS AND THEN, CAN WE 4892 03:11:02,957 --> 03:11:05,827 MODEL THE DIFFERENT DISEASES AND 4893 03:11:05,827 --> 03:11:06,895 ALSO RESPONSE TO ENVIRONMENT AND 4894 03:11:06,895 --> 03:11:10,498 HOW THE CELL TYPE RESPONDS TO 4895 03:11:10,498 --> 03:11:12,233 ENVIRONMENT WITH THAT I LAST 4896 03:11:12,233 --> 03:11:13,435 SLIDE IS TO ACKNOWLEDGE THE 4897 03:11:13,435 --> 03:11:14,903 WONDERFUL PEOPLE I GET TO WORK 4898 03:11:14,903 --> 03:11:17,072 WITH EVERY DAY AND VERY NEW 4899 03:11:17,072 --> 03:11:18,239 WOBDERFUL LAB MEMBERS AND 4900 03:11:18,239 --> 03:11:19,874 AMAZING COMMUNITY WHO I GET TO 4901 03:11:19,874 --> 03:11:20,642 COLLABORATE WITH. 4902 03:11:20,642 --> 03:11:22,544 THANK YOU VERY MUCH. 4903 03:11:22,544 --> 03:11:24,746 THIS, THANK YOU SO MUCH 4904 03:11:24,746 --> 03:11:25,580 DR. WANG. 4905 03:11:25,580 --> 03:11:29,718 OUR NEXT SPEAKER IS DR. JOHN ENG 4906 03:11:29,718 --> 03:11:30,919 ELHARDT, WITH THE PROFESSOR OF 4907 03:11:30,919 --> 03:11:33,321 DEPARTMENT OF ANATOMY AND CELL 4908 03:11:33,321 --> 03:11:35,724 BIOLOGY, ROY J. CARVER CHAIR OF 4909 03:11:35,724 --> 03:11:37,225 MOLECULAR MEDICINE DIRECTOR 4910 03:11:37,225 --> 03:11:39,160 CENTER FOR GENE THERAPY CARVER 4911 03:11:39,160 --> 03:11:40,228 COLLEGE OF MEDICINE, UNIVERSITY 4912 03:11:40,228 --> 03:11:42,297 OF IOWA, HE STUDIES VECTORS TO 4913 03:11:42,297 --> 03:11:43,598 MODEL SYSTEMS AND TODAY ME WILL 4914 03:11:43,598 --> 03:11:45,467 SPEAK TO US ABOUT ASSESSING LUNG 4915 03:11:45,467 --> 03:11:48,803 INJURY AND REPAIR USING 4916 03:11:48,803 --> 03:11:49,504 TRANSIMENNIC FERRET MODELS. 4917 03:11:49,504 --> 03:11:51,473 THE FLOOR IS YOURS. 4918 03:11:51,473 --> 03:11:55,343 NTHANK YOU. 4919 03:11:55,343 --> 03:11:57,112 NEXT SLIDE. 4920 03:11:57,112 --> 03:11:59,914 THIS IS A VERY WE'VE HAD SOME 4921 03:11:59,914 --> 03:12:00,615 WONDERFUL PRESENTATIONS EARLIER 4922 03:12:00,615 --> 03:12:02,016 TODAY ABOUT DIFFERENCES IN,A NAT 4923 03:12:02,016 --> 03:12:05,453 ME AND CELL BIOLOGY BETWEEN 4924 03:12:05,453 --> 03:12:11,726 HUMANS AND RODENTS IN THE LUNG 4925 03:12:11,726 --> 03:12:12,293 AND AIR WAY. 4926 03:12:12,293 --> 03:12:14,262 AND THIS IS A VERY SUPERFICIAL 4927 03:12:14,262 --> 03:12:15,630 VIEW OF THE DIFFERENCES I WILL 4928 03:12:15,630 --> 03:12:16,698 TALK ABOUT TODAY. 4929 03:12:16,698 --> 03:12:17,866 ONE INCLUDES THE ABUNDANCE OF 4930 03:12:17,866 --> 03:12:19,434 GLANDS IF YOU LOOK ON THE LEFT 4931 03:12:19,434 --> 03:12:21,836 IN LARGER SPECIES IN HUMANS AND 4932 03:12:21,836 --> 03:12:24,372 BASAL CELLS ARE DISTRIBUTED 4933 03:12:24,372 --> 03:12:27,375 THROUGH CARTILAGE NOWS AIRWAYS 4934 03:12:27,375 --> 03:12:30,445 AND THE TYPE OF SECRETORY CELLS 4935 03:12:30,445 --> 03:12:32,113 ARE DIFFERENT THAN THAT OF 4936 03:12:32,113 --> 03:12:32,914 RODENTS AS WELL. 4937 03:12:32,914 --> 03:12:37,919 THESE ARE REASONS, NEXT, THAT 4938 03:12:37,919 --> 03:12:38,653 CYSTIC FIBROSIS OR CFTR KNOCK 4939 03:12:38,653 --> 03:12:41,623 OUT IN PIGS AND FERRETS DEVELOP 4940 03:12:41,623 --> 03:12:42,657 OBSTRUCTIVE LUNG DISEASE, MICE 4941 03:12:42,657 --> 03:12:43,992 DON'T AND THERE'S HEAVY GLAND 4942 03:12:43,992 --> 03:12:50,732 INVOLVEMENT IN THAT GENETIC 4943 03:12:50,732 --> 03:12:51,399 DISEASE. 4944 03:12:51,399 --> 03:12:51,599 NEXT. 4945 03:12:51,599 --> 03:12:53,368 AS SHOWNOT PREVIOUS SLIDES, 4946 03:12:53,368 --> 03:12:55,470 THERE WERE DISTAL AIRWAYS, THE 4947 03:12:55,470 --> 03:12:56,704 BRONCHIALES THAT DISOANT EXIST 4948 03:12:56,704 --> 03:12:58,940 WITHIN MICE BUT EXIST WITHIN 4949 03:12:58,940 --> 03:13:00,642 FERRETS AND HUMANS THAT HAS 4950 03:13:00,642 --> 03:13:01,943 NEXT, SPECIALIZED STEM CELL 4951 03:13:01,943 --> 03:13:05,980 POPULATIONS THAT WE'VE HEARD 4952 03:13:05,980 --> 03:13:06,314 ABOUT. 4953 03:13:06,314 --> 03:13:06,548 NEXT. 4954 03:13:06,548 --> 03:13:08,983 THAT WE'VE HEARD ABOUT 4955 03:13:08,983 --> 03:13:13,455 PREVIOUSLY INCLUDING RAS, 4956 03:13:13,455 --> 03:13:14,789 TERMINAL RESPIRATORY AND 4957 03:13:14,789 --> 03:13:16,090 AT-CELLS. 4958 03:13:16,090 --> 03:13:16,324 NEXT. 4959 03:13:16,324 --> 03:13:18,393 SO FOR QUITE A WHILE, I'VE 4960 03:13:18,393 --> 03:13:21,596 STUDIED THE STEM CELL BIOLOGY OF 4961 03:13:21,596 --> 03:13:23,698 SUBMUCOSAL GLANDS IN THE CONTEXT 4962 03:13:23,698 --> 03:13:24,999 OF CYSTIC FIBROSIS, WE DEMON 4963 03:13:24,999 --> 03:13:29,270 TRAITED USING MICE IN THE 2 CRE 4964 03:13:29,270 --> 03:13:31,873 DRIVERS MARKED HERE THAT THE 4965 03:13:31,873 --> 03:13:34,142 STEM CELL POPULATION IS RESERVE 4966 03:13:34,142 --> 03:13:36,344 STEM CELL THAT CAN REPOPULATE 4967 03:13:36,344 --> 03:13:38,947 STEM CELLS WITHIN THE GLAND DUCT 4968 03:13:38,947 --> 03:13:42,083 OR SURFACE AIR AIRWAY EPITHELIUM 4969 03:13:42,083 --> 03:13:45,620 ALONG WITH TATAWHO SAW SIMILAR 4970 03:13:45,620 --> 03:13:46,087 RESULTS. 4971 03:13:46,087 --> 03:13:46,421 NEXT SLIDE. 4972 03:13:46,421 --> 03:13:50,191 SO WE GENERATED THE SAME TYPE OF 4973 03:13:50,191 --> 03:13:52,160 LINEAGE TRACING FERRETS, AS WE 4974 03:13:52,160 --> 03:13:53,528 HAD STUDIED IN MICE AND WHAT YOU 4975 03:13:53,528 --> 03:13:57,465 CAN SEE HERE IS THIS IS USING AN 4976 03:13:57,465 --> 03:14:00,168 IREZ INSERTION OF THE ACTED 2 4977 03:14:00,168 --> 03:14:00,735 GENE. 4978 03:14:00,735 --> 03:14:04,706 AND AT HOMEOSTASIS, WHEN THESE 4979 03:14:04,706 --> 03:14:07,075 ANIMALS ARE TRACE WIDE TAMOXIFEN 4980 03:14:07,075 --> 03:14:10,078 ON THE LEFT AND SMOOTH MUSCLE ON 4981 03:14:10,078 --> 03:14:13,715 THE INTERMULL MONITORARY ON THE 4982 03:14:13,715 --> 03:14:14,048 AIRWAYS. 4983 03:14:14,048 --> 03:14:14,716 NEXT SLIDE. 4984 03:14:14,716 --> 03:14:19,354 AND INDEED IF WE 0 THESE DOUBLE 4985 03:14:19,354 --> 03:14:23,691 TRANSGENIC FERRETS THAT HAVE M 4986 03:14:23,691 --> 03:14:24,259 TMG REPORTER WITH TISSUE AND 4987 03:14:24,259 --> 03:14:26,461 MACROPHAGES OX FEN 4 WEEKS LATER 4988 03:14:26,461 --> 03:14:28,463 OR WE LABELED WITH TISSUE AND 4989 03:14:28,463 --> 03:14:30,565 MACROPHAGES OX FEN AND LABELED 4990 03:14:30,565 --> 03:14:34,602 THEM LATER, HARVEST, 1 SEES A 4991 03:14:34,602 --> 03:14:35,537 SIMILAR PATTERN OF DISTRIBUTION 4992 03:14:35,537 --> 03:14:38,940 THAT 1 WOULD SEE ONLY IN THE 4993 03:14:38,940 --> 03:14:41,643 PROXIMAL TRACHEA OF MICE IN 4994 03:14:41,643 --> 03:14:42,977 WHICH MILE EPITHELIAL CELLS 4995 03:14:42,977 --> 03:14:45,747 EMERGE FROM THE GLAND DUCTS, 4996 03:14:45,747 --> 03:14:47,248 NEXT, AND DIFFERENTIATE INTO 4997 03:14:47,248 --> 03:14:51,719 BOTH DUCTAL CELLS MARKED BY THE 4998 03:14:51,719 --> 03:14:54,255 ARROW THERE. 4999 03:14:54,255 --> 03:14:57,358 GLANDULAR TUBEULAR CELLS 5000 03:14:57,358 --> 03:14:58,293 INCLUDING SECRETORY AND SERA 5001 03:14:58,293 --> 03:15:00,528 CELLS AND ON THE AIR WAY SURFACE 5002 03:15:00,528 --> 03:15:03,498 ACCIDENT BASAL CELLS MARKED BY 5003 03:15:03,498 --> 03:15:06,634 P63 AND SECRETORY CELLS MARKED 5004 03:15:06,634 --> 03:15:08,970 BY MUC5 AC. 5005 03:15:08,970 --> 03:15:09,337 NEXT SLIDE. 5006 03:15:09,337 --> 03:15:12,407 AND WE WERE INTRIGUED BY THE 5007 03:15:12,407 --> 03:15:13,374 DISTAL AIRWAY DIFFERENCES 5008 03:15:13,374 --> 03:15:15,543 BETWEEN RODENTS AND FERRETS IN 5009 03:15:15,543 --> 03:15:16,945 THESE LINEAGE TRACING MODELS. 5010 03:15:16,945 --> 03:15:19,681 ONE CAN SEE ON THE LEFT, 5011 03:15:19,681 --> 03:15:22,183 LEFT-HAND SIDE, THE BRONCHIAL 5012 03:15:22,183 --> 03:15:23,318 ALVEOLAR JUNCTION WE JUST HEARD 5013 03:15:23,318 --> 03:15:28,423 QUITE A BIT ABOUT FROM DR. ZHOU, 5014 03:15:28,423 --> 03:15:30,191 THE SMOOTH MUSCLES EXIST AT THIS 5015 03:15:30,191 --> 03:15:31,359 TERMINAL REGION AS SPARSE 5016 03:15:31,359 --> 03:15:34,095 INDIVIDUAL CELLS AS COMPARED TO 5017 03:15:34,095 --> 03:15:39,734 THE RIGHT WITH THE RESPIRATORY 5018 03:15:39,734 --> 03:15:43,171 BRANCHIAL OR RAS, FOR THE 5019 03:15:43,171 --> 03:15:45,473 SECRETOR I SEMESTER CELLS, HAVE 5020 03:15:45,473 --> 03:15:47,008 SMOOTH MUSCLE BUNDLES JUST BELOW 5021 03:15:47,008 --> 03:15:48,376 THE SPECIALIZED CLUB CELL THAT 5022 03:15:48,376 --> 03:15:53,348 EXIST IN THE RESPIRATORY CELL. 5023 03:15:53,348 --> 03:15:58,453 NEXT SLIDE. 5024 03:15:58,453 --> 03:15:59,153 NEXT SLIDE. 5025 03:15:59,153 --> 03:16:00,888 THIS REGION IS QUITE UNIQUE, IF 5026 03:16:00,888 --> 03:16:03,825 1 LOOKS AT THE AREA MARKED BY AN 5027 03:16:03,825 --> 03:16:07,895 ARROW, 1 SEES THAT SECRETORY 5028 03:16:07,895 --> 03:16:09,964 EXPRESSING CLUB CELLS DECLINED 5029 03:16:09,964 --> 03:16:11,566 SIGNIFICANTLY WITH CILIATED 5030 03:16:11,566 --> 03:16:13,534 CELLS MARKED BY ACELLALATED TUBE 5031 03:16:13,534 --> 03:16:17,105 LYNN AND AS DR. BASIL SHAZ SHOWN 5032 03:16:17,105 --> 03:16:21,275 AND TATA'S GROUP THAT THIS 5033 03:16:21,275 --> 03:16:23,378 SPECIALIZED 3 A2 EXPRESSING CELL 5034 03:16:23,378 --> 03:16:25,580 EMERGES AND DOMINATES AND IN THE 5035 03:16:25,580 --> 03:16:26,848 TERMINAL BRONCHIAL AND SHOWN ON 5036 03:16:26,848 --> 03:16:30,084 THE LEFT, VERY LEFT, RESPIRATORY 5037 03:16:30,084 --> 03:16:32,920 BRONCHIALS, RB. 5038 03:16:32,920 --> 03:16:35,657 NEXT SLIDE EMPLOY NSO WE 5039 03:16:35,657 --> 03:16:38,860 HYPOTHESIZED THAT SPECIES 5040 03:16:38,860 --> 03:16:39,894 SPECIFIC DIFFERENCES IN THIS 5041 03:16:39,894 --> 03:16:41,863 PARTICULAR REGION AND IN ANATOMY 5042 03:16:41,863 --> 03:16:44,866 AND CELL BIOLOGY IN THIS 5043 03:16:44,866 --> 03:16:46,868 RESPIRATORY ZONE MAY CONTRIBUTE 5044 03:16:46,868 --> 03:16:48,436 TEHUMAN ASSPECS OF FIBROSIS 5045 03:16:48,436 --> 03:16:50,371 FOLLOWING ACUTE LUNG INJURY, SO 5046 03:16:50,371 --> 03:16:51,739 WE DEVELOPED AIBLY O MICEIN 5047 03:16:51,739 --> 03:16:53,608 INJURY MODEL IN THE FERRET 5048 03:16:53,608 --> 03:16:56,210 THAT'S SHOWN IN THE TOP. 5049 03:16:56,210 --> 03:16:57,712 THREE TYPES INJURED WITH 5050 03:16:57,712 --> 03:17:00,014 BLEOMYCIN, AND THEN HARVESTED 5051 03:17:00,014 --> 03:17:00,948 ANIMALS SUBSEQUENTLY OUT TO 12 5052 03:17:00,948 --> 03:17:02,450 WEEKS AND YOU CAN SEE ON THE 5053 03:17:02,450 --> 03:17:05,019 LEFT WITH BOTH THE RADIO GRAPHS, 5054 03:17:05,019 --> 03:17:09,457 CT IMAGES AS WELL AS HISTOLOGY, 5055 03:17:09,457 --> 03:17:10,625 SIGNIFICANT FIBROSIS AND 5056 03:17:10,625 --> 03:17:13,594 CONSOLIDATION WITHIN THE LUNG. 5057 03:17:13,594 --> 03:17:14,629 FUNCTIONALLY, THE CAPACITY 5058 03:17:14,629 --> 03:17:17,265 DECLINES AS SHOWING THE CENTER 5059 03:17:17,265 --> 03:17:18,099 AND THIS CORRELATES WITH THE 5060 03:17:18,099 --> 03:17:20,735 SCORE WHICH IS AN INDEX OF 5061 03:17:20,735 --> 03:17:23,504 FIBROSIS, AND YOU CAN SEE THESE 5062 03:17:23,504 --> 03:17:24,238 FIBROTIC FOCI, AND STARTING TO 5063 03:17:24,238 --> 03:17:27,709 FORM IN THE LOWER RIGHT. 5064 03:17:27,709 --> 03:17:29,510 NEXT SLIDE. 5065 03:17:29,510 --> 03:17:30,678 SO WE PERFORMED SINGLE YOU 5066 03:17:30,678 --> 03:17:34,282 THIS CLEAR SEQUENCING AND 5067 03:17:34,282 --> 03:17:35,450 COLLABORATION WITH 5068 03:17:35,450 --> 03:17:36,751 [INDISCERNIBLE] IN IMI 5069 03:17:36,751 --> 03:17:38,419 BIOSCIENCES AND ON THE LEFT-HAND 5070 03:17:38,419 --> 03:17:40,021 SIDE YOU CAN SEE THE UMAP WITH 5071 03:17:40,021 --> 03:17:43,991 THE TYPICAL CELL ASSIGNMENTS BUT 5072 03:17:43,991 --> 03:17:45,593 IMPORTANTLY INCLUSION OF BASIL 5073 03:17:45,593 --> 03:17:48,029 LIKE CELLS ON THE RIGHT, ONCE 5074 03:17:48,029 --> 03:17:49,263 THE SIGNIFICANT TRANSCRIPTIONAL 5075 03:17:49,263 --> 03:17:53,935 CHANGES IN THIS UMAP WHEN 1 5076 03:17:53,935 --> 03:18:04,445 MARKS THE SALINE, 1 SEALS THE 5077 03:18:05,113 --> 03:18:08,049 CELL TYPES THAT ARE SHOWN ON THE 5078 03:18:08,049 --> 03:18:09,817 LEFT, AGAIN, SIGNIFICANT 5079 03:18:09,817 --> 03:18:12,353 TRANSCRIPTIONAL CHANGES AND 5080 03:18:12,353 --> 03:18:15,123 NEXT, IF 1 LOOKS AT THE MAGENTA 5081 03:18:15,123 --> 03:18:16,157 ARROW HEAD SIGNIFICANT CHANGES 5082 03:18:16,157 --> 03:18:19,160 IN THE DISTRIBUTION OF A NUMBER 5083 03:18:19,160 --> 03:18:20,862 OF POPULATIONS INCLUDING 5084 03:18:20,862 --> 03:18:22,630 TRANSITIONAL AT2 CELLS IN 5085 03:18:22,630 --> 03:18:25,433 BASALOID LIKE CELLS. 5086 03:18:25,433 --> 03:18:28,636 IMPORTANTLY PHENOTYPICALLY, THIS 5087 03:18:28,636 --> 03:18:32,273 TP63 POSITIVE KRT NEGATIVE KRT 7 5088 03:18:32,273 --> 03:18:33,908 POSITIVE CELL MARKED BY THE 5089 03:18:33,908 --> 03:18:39,180 YELLOW ARROWS EXIST WITHIN THE 5090 03:18:39,180 --> 03:18:39,814 FERRET, TISSUE FOLLOWING 5091 03:18:39,814 --> 03:18:41,349 BLEOMYCIN, THIS IS A POPULATION 5092 03:18:41,349 --> 03:18:43,384 WE HEARD ABOUT THAT IS NOT FOUND 5093 03:18:43,384 --> 03:18:46,954 IN MOUSE. 5094 03:18:46,954 --> 03:18:48,322 NEXT SLIDE. 5095 03:18:48,322 --> 03:18:52,360 AND IF 1 PROJECTS THE 5096 03:18:52,360 --> 03:18:53,394 TRAJECTORIES IN PSEUDOTIME SHOWN 5097 03:18:53,394 --> 03:18:56,397 HERE JUST FOR THE AT2, AT1 LIKE 5098 03:18:56,397 --> 03:19:03,371 CELLS GROUPED TOGETHER, 1 SEES 2 5099 03:19:03,371 --> 03:19:04,839 TRAJECTORIES FROM THE RIGHT 5100 03:19:04,839 --> 03:19:08,476 PANEL THAT EMERGE THROUGH 5101 03:19:08,476 --> 03:19:10,278 THROUGH TRANSITIONAL AT2 CELLS 5102 03:19:10,278 --> 03:19:12,413 TO BASAL 1 AND AND NEXT, THESE 5103 03:19:12,413 --> 03:19:15,416 ARE JUST SPECIFIC MARKERS, 5104 03:19:15,416 --> 03:19:17,618 MARKING THESE POPULATIONS. 5105 03:19:17,618 --> 03:19:17,852 NEXT. 5106 03:19:17,852 --> 03:19:21,756 AND 1 CAN SEE, THIS BASALOID 5107 03:19:21,756 --> 03:19:25,593 POPULATION AT THE TOP OF THESE 5108 03:19:25,593 --> 03:19:27,228 KERATIN, AND ABERRANTLY KERATIN 5109 03:19:27,228 --> 03:19:32,066 EXPRESSING CELLS, UNFORT MATILY 5110 03:19:32,066 --> 03:19:33,000 KERT EXPRESSION IS NOT SHOW SO 5111 03:19:33,000 --> 03:19:35,002 WE CAN BE THE SO A UMAP OF THAT. 5112 03:19:35,002 --> 03:19:35,570 NEXT. 5113 03:19:35,570 --> 03:19:38,172 AND THERE ARE INTERESTING 5114 03:19:38,172 --> 03:19:40,341 ANATOMICAL SIMILARITIES TO 5115 03:19:40,341 --> 03:19:42,844 PROGRESSION OF FIBROSIS WITHIN 5116 03:19:42,844 --> 03:19:45,580 HUMANS AND IPF, WHERE 5117 03:19:45,580 --> 03:19:46,647 REGIONALLY, THE WORST AREAS OF 5118 03:19:46,647 --> 03:19:48,983 DISEASE ARE AT THE SURFACE, THE 5119 03:19:48,983 --> 03:19:51,018 PLURAL SURFACE OR PERIPHERY OF 5120 03:19:51,018 --> 03:19:52,653 THE LUNG, HERE WE'RE SHOWING THE 5121 03:19:52,653 --> 03:19:56,958 AREA MARKED IN A, STAINED FOR 5122 03:19:56,958 --> 03:19:59,327 KRT 7, NEXT, VERY LITTLE 5123 03:19:59,327 --> 03:20:02,964 EXPRESSION HOW THE KRTs CAN 5124 03:20:02,964 --> 03:20:04,232 PROGRESSIVELY BE AT THIS 5125 03:20:04,232 --> 03:20:07,602 POSITION MARKED B, NEXT, YOU SEE 5126 03:20:07,602 --> 03:20:11,305 INCREASING EMERGENCE OF KRT 17 5127 03:20:11,305 --> 03:20:12,073 AND 5 EXPRESSION. 5128 03:20:12,073 --> 03:20:12,306 NEXT. 5129 03:20:12,306 --> 03:20:15,209 AS 1 PROGRESSING TO THE EXTERIOR 5130 03:20:15,209 --> 03:20:17,545 OF THE LOBE, HERE MARKED BY 5131 03:20:17,545 --> 03:20:20,181 ARROWS ARE AGAIN, THIS ABERRANT 5132 03:20:20,181 --> 03:20:24,318 KRT 5 NEGATIVE KRT 7 POSITIVE, 5133 03:20:24,318 --> 03:20:27,355 KR17 POSITIVE CELL. 5134 03:20:27,355 --> 03:20:27,922 NEXT. 5135 03:20:27,922 --> 03:20:30,625 THIS IS JUST ANOTHER EXAMPLE OF 5136 03:20:30,625 --> 03:20:33,194 THE SIGNIFICANT TYPE OF 5137 03:20:33,194 --> 03:20:34,128 PROXIMALLIZATION THAT'S 5138 03:20:34,128 --> 03:20:35,730 OCCURRING WITHIN THE ALVEOLAR 5139 03:20:35,730 --> 03:20:38,900 SPACE LIKELY THROUGH NICHE 5140 03:20:38,900 --> 03:20:39,867 COMPETITION TO REGENERATE THE 5141 03:20:39,867 --> 03:20:42,036 ALVERMEN INFECTED O LIE AND THE 5142 03:20:42,036 --> 03:20:46,941 FIBROSIS THAT INDUCES EXPANSION 5143 03:20:46,941 --> 03:20:50,544 OF THE BASAL AND BASALOID 5144 03:20:50,544 --> 03:20:51,279 POPULATIONS, MARKED BY ARROWS 5145 03:20:51,279 --> 03:20:55,683 AGAIN IN THE UPPER RIGHT ARE 5146 03:20:55,683 --> 03:20:58,953 TP63, KRTR 7, KRT 5 XDAPI CELLS 5147 03:20:58,953 --> 03:21:04,859 MARKED IN GREEN THAT EXPRESS KRT 5148 03:21:04,859 --> 03:21:05,159 7. 5149 03:21:05,159 --> 03:21:05,426 NEXT. 5150 03:21:05,426 --> 03:21:09,063 IF 1 CLUSTER IS JUST THE 5151 03:21:09,063 --> 03:21:11,232 MESENCHYMAL CELL TYPES WITHIN 5152 03:21:11,232 --> 03:21:12,400 THE EPITHELIAL CHALLENGED LUNG, 5153 03:21:12,400 --> 03:21:16,203 1 SEES HERE, WE HAVE ALVEOLAR 5154 03:21:16,203 --> 03:21:18,806 FIBROBLAST TYPE 1 AND 2, VARIOUS 5155 03:21:18,806 --> 03:21:20,474 SMOOTH MUSCLE GROUPS, AND 5156 03:21:20,474 --> 03:21:21,275 PERISIGHTS, 1 SEES THE 5157 03:21:21,275 --> 03:21:22,810 EXPRESSION ON THE RIGHT AS 5158 03:21:22,810 --> 03:21:26,447 FAIRLY SIMILAR TO WHAT'S BEEN 5159 03:21:26,447 --> 03:21:27,815 PUBLISHED WITHIN HUMAN -- HUMAN 5160 03:21:27,815 --> 03:21:29,884 LUNG MAP ON THE TOP AND THAT 5161 03:21:29,884 --> 03:21:34,522 FERIT SEQUENCE ON THE BOTTOM, 5162 03:21:34,522 --> 03:21:35,523 NEXT. 5163 03:21:35,523 --> 03:21:41,228 IF 1 CLUSTERS OR 1 MAPS THE 5164 03:21:41,228 --> 03:21:43,197 SALINE VERSUS THE BLEOMYCIN 5165 03:21:43,197 --> 03:21:45,132 ANIMALS, THE TRANSCRIPTIONAL 5166 03:21:45,132 --> 03:21:47,001 CHANGES WITHIN THE SMOOTH MUSCLE 5167 03:21:47,001 --> 03:21:48,402 COMPARTMENT ON THE LOWER LEFT AS 5168 03:21:48,402 --> 03:21:51,339 WELL AS ON THE ALVEOLAR 5169 03:21:51,339 --> 03:21:54,375 FIBROBLASTS TYPE 1 COMPARING ON 5170 03:21:54,375 --> 03:21:55,509 THE RIGHT. 5171 03:21:55,509 --> 03:21:57,411 NEXT SLIDE. 5172 03:21:57,411 --> 03:22:00,381 SO WE HYPOTHESIZE THAT 5173 03:22:00,381 --> 03:22:05,553 RESPIRATORY SMOOTH MUSCLE 5174 03:22:05,553 --> 03:22:06,487 CONTRIBUTES TO THE FIBROBLASTS 5175 03:22:06,487 --> 03:22:08,255 IN MOUSE AND FERIT AND WE 5176 03:22:08,255 --> 03:22:09,657 COMPARED IT NEXT EMPLOY WHAT I'M 5177 03:22:09,657 --> 03:22:12,827 SHOWING HERE IS AN ENACTED ROSA 5178 03:22:12,827 --> 03:22:16,130 TG MOUSE THAT'S BEEN BLEOMYCIN 5179 03:22:16,130 --> 03:22:19,633 INJURED AND THEN TAMOXIFEN 5180 03:22:19,633 --> 03:22:20,301 LABELED ONCE IT'S OVER AND YOU 5181 03:22:20,301 --> 03:22:25,406 SLEEP APNEA AND OBESITYY HOW IT 5182 03:22:25,406 --> 03:22:27,274 TRACE, AND THE MY O FIBROBLAST 5183 03:22:27,274 --> 03:22:27,842 EXPANDING. 5184 03:22:27,842 --> 03:22:29,710 IF 1 LABELS PRIOR TO BLEOMYCIN 5185 03:22:29,710 --> 03:22:32,546 INJURY AND WASHES OUT 1 SEES 5186 03:22:32,546 --> 03:22:34,849 VERY LITTLE OVERLAP, OR VERY 5187 03:22:34,849 --> 03:22:36,484 LITTLE LABELING REALLY JUST THE 5188 03:22:36,484 --> 03:22:37,551 VESSELS IF 1 LOOKS IN THE TOP 5189 03:22:37,551 --> 03:22:42,189 RIGHT THAT ARE LABELING WITH TO 5190 03:22:42,189 --> 03:22:43,958 POST BLEOMYCIN INJURY. 5191 03:22:43,958 --> 03:22:44,191 NEXT. 5192 03:22:44,191 --> 03:22:47,495 THIS HAS BEEN SHOWN IN A NUMBER 5193 03:22:47,495 --> 03:22:54,135 OF PUBLICATIONS THAT ACTA 2 5194 03:22:54,135 --> 03:22:57,438 LINEAGE DO NOT CONTRIBUTE TO MY 5195 03:22:57,438 --> 03:22:59,507 O FIBROLASTS IN MICE FOLLOWING 5196 03:22:59,507 --> 03:23:00,641 BLEOMYCIN AND MOUSE. 5197 03:23:00,641 --> 03:23:01,709 NEXT SLIDE, THIS COMPARES TO 5198 03:23:01,709 --> 03:23:03,677 THIS TO FERRET HOWEVER, IT'S ARE 5199 03:23:03,677 --> 03:23:05,780 A VERY DIFFERENT OUTCOME. 5200 03:23:05,780 --> 03:23:08,916 ON THE LEFT-HAND SIDE, IS 5201 03:23:08,916 --> 03:23:11,385 LABELING AFTER BLEOMYCIN INJURY. 5202 03:23:11,385 --> 03:23:19,093 YOU WOULD EXPECT, YOU CAN SEE 5203 03:23:19,093 --> 03:23:20,461 SIGNIFICANTLY AS WELL AS 5204 03:23:20,461 --> 03:23:21,929 STAINING BUT IMPORTANTLY ON THE 5205 03:23:21,929 --> 03:23:25,399 RIGHT, IF 1 LABELING HOMEOSTASIS 5206 03:23:25,399 --> 03:23:26,367 WASHES OUT, THEN BLEOMYCIN 5207 03:23:26,367 --> 03:23:28,469 INJURIES, 1 SEES IF YOU FOCUS ON 5208 03:23:28,469 --> 03:23:30,704 THE MOST RIGHT PANELS WHICH ARE 5209 03:23:30,704 --> 03:23:33,641 ENLARGEMENTS OF THE YELLOW 5210 03:23:33,641 --> 03:23:35,776 ARROWSOT LEFT, 1 SEES 5211 03:23:35,776 --> 03:23:36,977 SIGNIFICANT OVERLAP IN THE 5212 03:23:36,977 --> 03:23:40,481 [INDISCERNIBLE] STAINING AND 5213 03:23:40,481 --> 03:23:41,315 REGIONS DISINTEGRATING 5214 03:23:41,315 --> 03:23:46,587 BRONCHIALS WITH ACTA 2 LINEAGE 5215 03:23:46,587 --> 03:23:47,288 TRACING. 5216 03:23:47,288 --> 03:23:48,956 NEXT. 5217 03:23:48,956 --> 03:23:50,291 NOW THERE'S SIGNATURES EXPANSION 5218 03:23:50,291 --> 03:23:55,362 OF KRT POSITIVE CELLS AROUND 5219 03:23:55,362 --> 03:23:56,197 LINEAGE TRACED [INDISCERNIBLE] 5220 03:23:56,197 --> 03:23:58,299 MY O FIBROBLASTS THAT ARE WITHIN 5221 03:23:58,299 --> 03:24:00,501 THE PATHWAY GIVES RESERVING MA, 5222 03:24:00,501 --> 03:24:02,336 COMPARING NEXT THIS ENLARGED 5223 03:24:02,336 --> 03:24:05,172 REGION RIGHT HERE, THAT THE 5224 03:24:05,172 --> 03:24:07,775 SIGNIFICANT AMOUNT OF OVERLAP 5225 03:24:07,775 --> 03:24:10,611 BETWEEN THE ACTA 2 AND TRACE AND 5226 03:24:10,611 --> 03:24:11,245 ALPHA [INDISCERNIBLE] 5227 03:24:11,245 --> 03:24:13,047 EXPRESSION, THESE ANIMALS WERE 5228 03:24:13,047 --> 03:24:13,647 LABELED WITH TISSUE AND 5229 03:24:13,647 --> 03:24:15,549 MACROPHAGES OX FEN FIRST AND 5230 03:24:15,549 --> 03:24:19,920 THEN CHASED AND INJURED WITH 5231 03:24:19,920 --> 03:24:22,923 BLEOMYCIN AND IN THE YELLOW 5232 03:24:22,923 --> 03:24:27,027 DOTTED BOX REGION, 1 CAN SEE THE 5233 03:24:27,027 --> 03:24:28,996 CLUSTERS AROUND THESE MY O 5234 03:24:28,996 --> 03:24:30,498 FIBROBLASTS THAT HAVE EMERGED 5235 03:24:30,498 --> 03:24:31,999 LIKELY FROM THE BRONCHIALS BUT 5236 03:24:31,999 --> 03:24:34,735 WE CAN'T RULE OUT THE VASCULAR 5237 03:24:34,735 --> 03:24:36,036 SMOOTH MUSCLE AT THIS POINT, THE 5238 03:24:36,036 --> 03:24:37,271 OTHER INTERESTING THING IS, 5239 03:24:37,271 --> 03:24:41,609 NEXT, IF 1 LOOKS AT THE RESIDUAL 5240 03:24:41,609 --> 03:24:42,776 SMOOTH MUSCLE OR THE SMOOTH 5241 03:24:42,776 --> 03:24:45,579 MUSCLE AROUND THE TERMINAL 5242 03:24:45,579 --> 03:24:48,716 BRANCHIALS ALOS ANGELES AS 5243 03:24:48,716 --> 03:24:49,416 RESPIRATORY WRONKIALS, 1 SEES 5244 03:24:49,416 --> 03:24:53,787 THAT THE TRACE IS LOST, BUT ACTA 5245 03:24:53,787 --> 03:24:56,857 2 EXPRESSION IS RETAINED 5246 03:24:56,857 --> 03:24:58,225 SUGGESTING THAT SOMETHING THAT 5247 03:24:58,225 --> 03:24:59,894 THE SMOOTH MUSCLES AROUND THAT 5248 03:24:59,894 --> 03:25:02,530 REGION OF THE AIRWAY ARE BEING 5249 03:25:02,530 --> 03:25:05,166 REPLACED BY SOME OTHER 5250 03:25:05,166 --> 03:25:06,967 PROGENITOR THAT DOESN'T EXPRESS 5251 03:25:06,967 --> 03:25:07,201 ACTA 2. 5252 03:25:07,201 --> 03:25:08,002 NEXT SLIDE. 5253 03:25:08,002 --> 03:25:10,337 SO IN CONCLUSION, WE FEEL THERE 5254 03:25:10,337 --> 03:25:12,640 ARE UNIQUE ASPECTS OF HUMAN LUNG 5255 03:25:12,640 --> 03:25:14,842 ANATOMY AND CELL BIOLOGY AND THE 5256 03:25:14,842 --> 03:25:16,477 RESPIRATORY ZONE THAT COULD BE 5257 03:25:16,477 --> 03:25:17,878 BETTER MODELED WITH WITHIN THE 5258 03:25:17,878 --> 03:25:19,880 FERRET AND WE'RE EXCITED TO 5259 03:25:19,880 --> 03:25:21,415 APPLY THE TRANSGENIC FERRETS AND 5260 03:25:21,415 --> 03:25:22,716 TECHNOLOGIES TO GENERATE THESE 5261 03:25:22,716 --> 03:25:26,887 ANIMALS, TO TACKET THESE 5262 03:25:26,887 --> 03:25:27,154 QUESTIONS. 5263 03:25:27,154 --> 03:25:27,488 AND NEXT. 5264 03:25:27,488 --> 03:25:29,957 AND MOVING ON SOME OF THE 5265 03:25:29,957 --> 03:25:34,562 EXCELLENT WORK OF DR. BIN ZHOU, 5266 03:25:34,562 --> 03:25:36,063 WE GENERATED AN INTERSECTIONAL 5267 03:25:36,063 --> 03:25:40,067 REPORTER FERRET AND WORKING ON 5268 03:25:40,067 --> 03:25:41,235 THE CRE-DRIVER FERRETS TO ANSWER 5269 03:25:41,235 --> 03:25:43,571 THE DIFFICULT QUESTIONS ABOUT 5270 03:25:43,571 --> 03:25:44,939 THE MESENCHYMAL ORIGINS OF MIGHT 5271 03:25:44,939 --> 03:25:46,473 BE O FIBROBLASTS AND WHAT 5272 03:25:46,473 --> 03:25:48,776 THEY'RE DOING, ARE SOME OF THEM 5273 03:25:48,776 --> 03:25:51,078 BENEFICIAL, SOME DETRIMENTAL TO 5274 03:25:51,078 --> 03:25:53,581 THE FIBROTIC RESPONSE? 5275 03:25:53,581 --> 03:25:54,782 NEXT. 5276 03:25:54,782 --> 03:25:57,318 AND LASTLY, TRANSGENIC OR FERRET 5277 03:25:57,318 --> 03:26:02,489 TRANSGENIC FETE MAPPING MODELS 5278 03:26:02,489 --> 03:26:04,558 COUPLED WITH CONDITIONAL GENETIC 5279 03:26:04,558 --> 03:26:05,893 APPROACHES MAY ENHANCE 5280 03:26:05,893 --> 03:26:07,061 TRANSLATABLE OF BASIC RESEARCH 5281 03:26:07,061 --> 03:26:08,862 AND THUS THERAPIES TO HUMANS. 5282 03:26:08,862 --> 03:26:09,530 NEXT SLIDE. 5283 03:26:09,530 --> 03:26:11,498 I WOULD LIKE TO THANK THOSE IN 5284 03:26:11,498 --> 03:26:13,734 MY GROUP, WORKING WITH FERITS 5285 03:26:13,734 --> 03:26:14,668 AND TRANSGENIC FERRETS. 5286 03:26:14,668 --> 03:26:15,369 IT'S A MAJOR EFFORT. 5287 03:26:15,369 --> 03:26:20,574 THERE ARE MAJOR COLLABORATORS 5288 03:26:20,574 --> 03:26:22,643 INCLUDING VISHWARAJ, THE 5289 03:26:22,643 --> 03:26:23,844 MORESESY LAB, TATA'S LAB AND 5290 03:26:23,844 --> 03:26:33,120 OTHERS LISTED HERE . 5291 03:26:33,120 --> 03:26:35,689 THANK YOU. 5292 03:26:35,689 --> 03:26:39,260 >> THANK YOU DR. ENG ELHARDT, 5293 03:26:39,260 --> 03:26:41,729 NOW WE CAN CAN BEGIN THE 5294 03:26:41,729 --> 03:26:42,296 DISCUSSION. 5295 03:26:42,296 --> 03:26:43,063 SOME POINTS OF DISCUSSION, WE 5296 03:26:43,063 --> 03:26:44,665 ARE HERE TO TALK ABOUT WHAT THAT 5297 03:26:44,665 --> 03:26:50,571 WE CAN DO WITH THIS TECHNOLOGY 5298 03:26:50,571 --> 03:26:52,306 WHAT ARE THE LIMITATIONS AND HOW 5299 03:26:52,306 --> 03:26:57,811 WE CAN IMPROVE ON THEM. 5300 03:26:57,811 --> 03:27:08,055 NEXT, PLEASE. 5301 03:27:20,834 --> 03:27:22,803 NEXT, PLEASE. 5302 03:27:22,803 --> 03:27:24,905 NTO START WITH, YOU SHOWED THESE 5303 03:27:24,905 --> 03:27:26,173 BEAUTIFUL, THE EMBRYO ALZHEIMER 5304 03:27:26,173 --> 03:27:27,975 BEHAVES SO WELL INVITRO. 5305 03:27:27,975 --> 03:27:31,812 AND THE ADULT IS ALWAYS 5306 03:27:31,812 --> 03:27:33,113 CHALLENGING EMPLOY AND MY 5307 03:27:33,113 --> 03:27:36,283 QUESTION, I HAVE 2 LEVELS OF 5308 03:27:36,283 --> 03:27:38,652 QUESTION 1 AND TATA SUPPOSE 5309 03:27:38,652 --> 03:27:41,322 ABOUT THIS ALSO BUT CAN WE GET 5310 03:27:41,322 --> 03:27:42,723 SOME SELF-ORGANIZATION OUT OF 5311 03:27:42,723 --> 03:27:44,525 ADULT STRUCTURES OR DO WOE HAVE 5312 03:27:44,525 --> 03:27:49,596 TO LIKE POSITION THEM PERFECTLY? 5313 03:27:49,596 --> 03:27:51,365 AND THEN SECOND COMPONENT OF 5314 03:27:51,365 --> 03:27:52,533 THAT IS, WE OFTEN THINK ABOUT, 5315 03:27:52,533 --> 03:27:57,271 YOU KNOW THE BABY AND THE ADULT 5316 03:27:57,271 --> 03:28:00,374 BUT THERE'S AN INTERMEDIATE 5317 03:28:00,374 --> 03:28:01,775 STAGE IN PEDIATRICS LIKE THE 5318 03:28:01,775 --> 03:28:02,710 TEENAGER AND IS THERE A TIME 5319 03:28:02,710 --> 03:28:06,046 WHEN YOU THINK THERE'S STILL 5320 03:28:06,046 --> 03:28:06,647 SELF-ORGANIZATIONAL PROPERTIES 5321 03:28:06,647 --> 03:28:10,651 IN 3 ADULT LUNGS THAT YOU COULD 5322 03:28:10,651 --> 03:28:11,352 EXPLOIT INVITRO? 5323 03:28:11,352 --> 03:28:13,587 >> YEAH, THANKS SO MUCH FOR 5324 03:28:13,587 --> 03:28:17,591 THOSE WONDERFUL QUESTIONS. 5325 03:28:17,591 --> 03:28:22,496 I THINK ORGANOID OR IPSC DERIVED 5326 03:28:22,496 --> 03:28:26,300 [INDISCERNIBLE] BOTTLENECK FOR 5327 03:28:26,300 --> 03:28:28,335 THE ENTIRE FIELD. 5328 03:28:28,335 --> 03:28:30,504 AS YOU MENTIONED WITH A CURRENT 5329 03:28:30,504 --> 03:28:32,272 MODEL IT'S BETTER TO STUDY 5330 03:28:32,272 --> 03:28:34,208 DEVELOPMENTAL PROCESS, BUT 5331 03:28:34,208 --> 03:28:35,676 NONAPOPTOTIC MODEL THE 5332 03:28:35,676 --> 03:28:40,381 COMPLEXITY AND ADOPT LUNGS 5333 03:28:40,381 --> 03:28:43,350 ESPECIALLY FOR SCALE UP, OUR 5334 03:28:43,350 --> 03:28:45,386 CURRENT TEENY TINY SYSTEM, IT 5335 03:28:45,386 --> 03:28:48,422 WILL REQUIRE A LOT OF EFFORT, 5336 03:28:48,422 --> 03:28:50,057 BECAUSE YOU KNOW THAT LUNG IS SO 5337 03:28:50,057 --> 03:28:53,894 MANY YEARS OF HUMAN DEVELOPMENT 5338 03:28:53,894 --> 03:28:56,029 WHEREAS OUR CURRENT SYSTEM IS 5339 03:28:56,029 --> 03:28:59,433 BASICALLY AT MOST 3 MONTHS OF 5340 03:28:59,433 --> 03:29:00,134 DIFFERENTIATION. 5341 03:29:00,134 --> 03:29:04,471 SO I THINK 1 EASY METHOD TO 5342 03:29:04,471 --> 03:29:05,839 UNDERSTAND SOME QUESTIONS, IN 5343 03:29:05,839 --> 03:29:08,842 THAT LUNG PHYSIOLOGY OR 5344 03:29:08,842 --> 03:29:10,844 PATHOPHYSIOLOGY AND TO LEVERAGE 5345 03:29:10,844 --> 03:29:11,412 ENGINEER KAFENDAR--ALEXANDER 5346 03:29:11,412 --> 03:29:14,081 OLD, SO WHAT WE COULD DO IS TO 5347 03:29:14,081 --> 03:29:15,649 DEFERENTIATE THOSE CELLS AND 5348 03:29:15,649 --> 03:29:19,720 THEN WE SEE THEM ON THE RIGHT 5349 03:29:19,720 --> 03:29:21,422 STRUCTURE TO STUDY SOME 5350 03:29:21,422 --> 03:29:27,795 INTERACTIONS, IN A REDUCED 5351 03:29:27,795 --> 03:29:28,629 DIMENSION. 5352 03:29:28,629 --> 03:29:30,664 THAT'S OUR CURRENT WAY OF USING 5353 03:29:30,664 --> 03:29:31,732 THESE ORGANOIDS TO UNDERSTAND, 5354 03:29:31,732 --> 03:29:34,802 YOU KNOW SOME OF THE ADULT HUMAN 5355 03:29:34,802 --> 03:29:36,303 LUNG QUESTIONS. 5356 03:29:36,303 --> 03:29:38,605 AND FOR PEDIATRIC LUNGS, I THINK 5357 03:29:38,605 --> 03:29:42,910 IT FALLS IN THE SAME, I GUESS 5358 03:29:42,910 --> 03:29:45,779 AREA OF DISCUSSION, HOW FAR WE 5359 03:29:45,779 --> 03:29:48,682 CAN JUST PUSH THE CURRENT SYSTEM 5360 03:29:48,682 --> 03:29:53,520 BUT I THINK SOME OF THE LUNG 5361 03:29:53,520 --> 03:29:55,489 RESPONSES TO INJURY RECAPITULATE 5362 03:29:55,489 --> 03:29:57,224 THE DEVELOPMENTAL PROCESS, SO IN 5363 03:29:57,224 --> 03:29:59,726 THAT REGARDS WE MIGHT BE ABLE TO 5364 03:29:59,726 --> 03:30:01,929 USE THIS PRENATAL SYSTEM TO 5365 03:30:01,929 --> 03:30:03,297 UNDERSTAND LONG REGENERATION AND 5366 03:30:03,297 --> 03:30:08,669 REPAIR IN RESPONSE TO INJURY,. 5367 03:30:08,669 --> 03:30:10,170 >> YOU KNOW, AREN'T YOU 5368 03:30:10,170 --> 03:30:11,705 BUILDING, AREN'T YOU ADDING MORE 5369 03:30:11,705 --> 03:30:13,874 ALVERMEN INFECTED O LIE WHEN 5370 03:30:13,874 --> 03:30:16,477 YOU'RE 2 YEARS OLD AND 4 5371 03:30:16,477 --> 03:30:19,313 YEAR-OLDS, AND ISN'T THERE SOME 5372 03:30:19,313 --> 03:30:20,380 NASCENT CAPACITY FOR 5373 03:30:20,380 --> 03:30:22,749 SELF-ORGANIZATION THAT YOU COULD 5374 03:30:22,749 --> 03:30:24,885 HARVEST AT THOSE STAGES? 5375 03:30:24,885 --> 03:30:25,652 >> I THINK SO. 5376 03:30:25,652 --> 03:30:28,889 I THINK SO, THE ALVEOLAR 5377 03:30:28,889 --> 03:30:29,590 DEVELOPINGY POSTINATEALLY. 5378 03:30:29,590 --> 03:30:30,691 >> SO MAYBE THOSE ARE GOOD 5379 03:30:30,691 --> 03:30:31,758 ENOUGH TO STUDY ADULT DISEASE. 5380 03:30:31,758 --> 03:30:33,193 MAYBE YOU DON'T HAVE TO START 5381 03:30:33,193 --> 03:30:37,030 WITH ADULT CELLS IF THAT'S 5382 03:30:37,030 --> 03:30:37,798 DOABLE. 5383 03:30:37,798 --> 03:30:38,432 >> YEAH, ABSOLUTELY. 5384 03:30:38,432 --> 03:30:40,100 THOSE ARE THE QUESTIONS 5385 03:30:40,100 --> 03:30:42,035 ADDRESSABLE USING THE IS. 5386 03:30:42,035 --> 03:30:44,638 YEAH, QUITE DEPENDENT ON WHAT 5387 03:30:44,638 --> 03:30:46,607 OUR LIST OF QUESTIONS WE'RE 5388 03:30:46,607 --> 03:30:48,342 ASKING USING THIS ORGANOIDS AND 5389 03:30:48,342 --> 03:30:52,312 THEY'RE SERVING AS A 5390 03:30:52,312 --> 03:30:54,314 COMPLIMENTARY PLATFORM TO FERIT 5391 03:30:54,314 --> 03:31:04,157 OR MOUSE OR EVEN LARGER ANIMALS. 5392 03:31:04,157 --> 03:31:06,093 >> I THINK [INDISCERNIBLE] HAD A 5393 03:31:06,093 --> 03:31:06,460 QUESTION. 5394 03:31:06,460 --> 03:31:08,262 >> I DO HAVE A QUESTION, I DON'T 5395 03:31:08,262 --> 03:31:11,932 KNOW WHETHER MY HAND OR -- CAN 5396 03:31:11,932 --> 03:31:12,833 YOU HEAR ME? 5397 03:31:12,833 --> 03:31:13,133 >> YEAH. 5398 03:31:13,133 --> 03:31:18,005 WE CAN HEAR YOU, YOU CAN BRING 5399 03:31:18,005 --> 03:31:18,639 UP YOUR QUESTION. 5400 03:31:18,639 --> 03:31:20,173 >> THANK YOU VERY MUCH. 5401 03:31:20,173 --> 03:31:24,344 I WONDERED DR. ZHOU, VERY -- ALL 5402 03:31:24,344 --> 03:31:26,847 PRESENTATIONS WERE VERY 5403 03:31:26,847 --> 03:31:27,915 WONDERFUL, DR. ZHOU, I HAVE IA 5404 03:31:27,915 --> 03:31:29,216 QUESTION FOR YOU, IT LOOKS LIKE 5405 03:31:29,216 --> 03:31:32,486 HAVING THE CLUB CELLS, HAVING 5406 03:31:32,486 --> 03:31:34,354 THE CAPABILITY OF BECOMING 5407 03:31:34,354 --> 03:31:36,957 ESSENTIALLY TYPE 2 CELLS AND 5408 03:31:36,957 --> 03:31:40,160 TYPE 1 CELLS AND LIKE THE OTHER 5409 03:31:40,160 --> 03:31:45,299 CELLS AS WELL, BECOMES SO 5410 03:31:45,299 --> 03:31:47,034 FLEXIBLE IN PLASTICITY TO 5411 03:31:47,034 --> 03:31:49,336 DIFFERENTIATE IN CELL TYPES, IS 5412 03:31:49,336 --> 03:31:51,605 IT POSSIBLE THAT DEPENDING ON 5413 03:31:51,605 --> 03:31:54,575 INJURY SAY FOR EXAMPLE, YOU DID 5414 03:31:54,575 --> 03:31:57,411 BLEOMYCIN, SAY IF YOU HAD 5415 03:31:57,411 --> 03:31:59,880 ANOTHER INJURY, LET'S SAY OR 5416 03:31:59,880 --> 03:32:03,617 OTHER TYPES OF CHRONIC INJURY 5417 03:32:03,617 --> 03:32:07,521 MODELS, WOULD YOU EXPECT OTHER 5418 03:32:07,521 --> 03:32:11,992 CELL TYPES THAT DOMINATE THE 5419 03:32:11,992 --> 03:32:13,026 DIFFERENTIATION PATHWAY GOING 5420 03:32:13,026 --> 03:32:14,695 INTO -- DEPENDING ON WHAT TYPE 5421 03:32:14,695 --> 03:32:16,196 OF INJURY AND HOW THE CELL 5422 03:32:16,196 --> 03:32:22,736 RESPONDS TO THE INJURY, THAT 5423 03:32:22,736 --> 03:32:27,140 PLASTICITY IS IT SOMETHING THAT 5424 03:32:27,140 --> 03:32:31,878 COULD BE-SOMETHING TO LOOK INTO? 5425 03:32:31,878 --> 03:32:32,512 >> YEAH. 5426 03:32:32,512 --> 03:32:34,815 THANK YOU FOR YOUR QUESTION. 5427 03:32:34,815 --> 03:32:37,317 YEAH, IT'S POSSIBLE THAT IF YOU 5428 03:32:37,317 --> 03:32:45,726 GIVE A DIFFERENT INJURY, OTHER 5429 03:32:45,726 --> 03:32:48,095 RESIDUE REMAINING PROGENITORS 5430 03:32:48,095 --> 03:32:50,030 CAN RESPOND CAN COMPENSATE FOR 5431 03:32:50,030 --> 03:32:51,898 THE LOSS OF THE EPITHELIAL CELLS 5432 03:32:51,898 --> 03:32:54,768 THAT ARE INJURED BY THE SPECIAL 5433 03:32:54,768 --> 03:32:59,740 CONDITIONS SO IN OUR CASES, WE 5434 03:32:59,740 --> 03:33:02,309 INDUCE AN ARTIFICIAL MODEL FOR 5435 03:33:02,309 --> 03:33:05,812 SEVERE INJURY ON THE ALVEOLAR 5436 03:33:05,812 --> 03:33:07,881 AT2 CELLS. 5437 03:33:07,881 --> 03:33:13,820 WE USE P21 OR WE CAN ALSO USE 5438 03:33:13,820 --> 03:33:16,823 DTR SYSTEM TO ABLATE A LARGE 5439 03:33:16,823 --> 03:33:21,328 PORTION OF AT2 CELLS SO THAT 5440 03:33:21,328 --> 03:33:25,232 OVEREXPRESSION OF P21 IMPAIRED 5441 03:33:25,232 --> 03:33:25,866 THEIR PROLIFERATION POTENTIAL, 5442 03:33:25,866 --> 03:33:29,569 SO IN THIS CASE, SPECIAL CASE, 5443 03:33:29,569 --> 03:33:33,240 ARTIFICIAL CASE, MODEL, THE CLUB 5444 03:33:33,240 --> 03:33:35,842 CELLS PLASTICITY TO REGENERATE 5445 03:33:35,842 --> 03:33:40,714 VIRTUALLY ALL AT2 CELLS IN SUCH 5446 03:33:40,714 --> 03:33:41,048 CONDITIONS. 5447 03:33:41,048 --> 03:33:43,083 WE SHOWED THIS BECAUSE WE CAN 5448 03:33:43,083 --> 03:33:44,484 SEE IT. 5449 03:33:44,484 --> 03:33:47,821 WE CAN DISTINGUISH IT, FROM 5450 03:33:47,821 --> 03:33:52,292 BASCs, CLUB CELLS AND AT2 5451 03:33:52,292 --> 03:33:54,561 CELLS, USING FEWER RECOMBIN ACES 5452 03:33:54,561 --> 03:33:58,298 THAT WE CAN TRACE 3 POPULATIONS 5453 03:33:58,298 --> 03:34:00,233 SIMULTANEOUSLY WITH 3 DISTINCT 5454 03:34:00,233 --> 03:34:01,735 COLORS, FOR INSTANCE THE 5455 03:34:01,735 --> 03:34:06,139 REPORTERS AND WE CAN SEE IT, BY 5456 03:34:06,139 --> 03:34:06,740 THIS MODEL. 5457 03:34:06,740 --> 03:34:08,942 I AGREE WITH YOU THAT IF WE 5458 03:34:08,942 --> 03:34:13,080 ABLATE OR INJURED THE CLUB 5459 03:34:13,080 --> 03:34:14,581 CELLS, LIKE USING 5460 03:34:14,581 --> 03:34:15,515 [INDISCERNIBLE] INJURY MODEL, WE 5461 03:34:15,515 --> 03:34:20,921 IS SEE THAT AS A BASC CELLS, THE 5462 03:34:20,921 --> 03:34:26,426 BASC CELLS CAN MIGRATE INTO 5463 03:34:26,426 --> 03:34:27,594 BRONCHIALES AND REGENERATE CLUB 5464 03:34:27,594 --> 03:34:31,064 CELLS IN OUR PREVIOUS STUDIES, 5465 03:34:31,064 --> 03:34:34,401 AND USING SPECIFIC LINEAGE 5466 03:34:34,401 --> 03:34:36,169 TRACING OF BASCs SO IT LARGELY 5467 03:34:36,169 --> 03:34:44,878 DEPENDS ON WHICH MODEL, YOU USE 5468 03:34:44,878 --> 03:34:46,947 FOR STUDIES THE LUNG 5469 03:34:46,947 --> 03:34:47,280 REGENERATION. 5470 03:34:47,280 --> 03:34:52,018 THANK YOU FOR THE QUESTION. 5471 03:34:52,018 --> 03:34:52,919 >> THANK YOU. 5472 03:34:52,919 --> 03:34:53,854 NTHAT WOULD INDICATE, I MEAN 5473 03:34:53,854 --> 03:34:57,157 JUST AS A GENERAL DISCUSSION, 5474 03:34:57,157 --> 03:34:59,593 YOU KNOW, ALTHOUGH THE MODELS 5475 03:34:59,593 --> 03:35:01,461 ARE WONDERFUL, TRYING TO CAPTURE 5476 03:35:01,461 --> 03:35:03,430 THIS COMPLEXITY OF THE LUNG, IN 5477 03:35:03,430 --> 03:35:10,937 TERMS OF BEING ABLE TO BE SO, SO 5478 03:35:10,937 --> 03:35:13,473 CONDUCIVE OR SO ESSENTIALLY 5479 03:35:13,473 --> 03:35:15,642 ADJUSTABLE TO WHATEVER IT GETS 5480 03:35:15,642 --> 03:35:17,377 AS AN INJURY, THAT'S SOMETHING 5481 03:35:17,377 --> 03:35:20,714 THAT WE SHOULD PROARP -- 5482 03:35:20,714 --> 03:35:27,087 PROBABLY THINK ABOUT MORE. 5483 03:35:27,087 --> 03:35:31,258 OKAY, IS THE QUESTION FOR ME? 5484 03:35:31,258 --> 03:35:31,525 >> YEAH. 5485 03:35:31,525 --> 03:35:33,059 HI BIN, GOOD TO SEE YOU IF I MAY 5486 03:35:33,059 --> 03:35:39,232 ASK IN THE SAME LINE, SO IN SOME 5487 03:35:39,232 --> 03:35:42,135 INJURY MODELS, WE SEE THE 5488 03:35:42,135 --> 03:35:43,003 MIGRATION OF [INDISCERNIBLE] 5489 03:35:43,003 --> 03:35:45,405 CELLS IN CONTRIBUTION TO YOU 5490 03:35:45,405 --> 03:35:47,941 KNOW ALVEOLAR, THEY MOVE TO 5491 03:35:47,941 --> 03:35:49,042 ALVEOLAR DAMAGED REGIONS, RIGHT? 5492 03:35:49,042 --> 03:35:51,578 SO I WAS WONDERING DO YOU THINK 5493 03:35:51,578 --> 03:35:53,180 SIMILARLY, THE NOTCH SIGNALING 5494 03:35:53,180 --> 03:35:56,516 IS ALSO PLAYING YOUR ROLE IN 5495 03:35:56,516 --> 03:35:57,584 MODELIZATION OF THIS VERSION IN 5496 03:35:57,584 --> 03:36:00,120 THE MODEL, NOT IN A GAIN OF 5497 03:36:00,120 --> 03:36:02,289 FUNCTION MODEL BUT JUDGE UOF THE 5498 03:36:02,289 --> 03:36:04,324 IN A NONINJURY REPAIR. 5499 03:36:04,324 --> 03:36:12,032 IF YES, HOW IS THE NOTCH 5500 03:36:12,032 --> 03:36:13,900 SIGNALING ACTUALLY WORKING BY 5501 03:36:13,900 --> 03:36:14,734 NEIGHBORING CELLS INTERACTING 5502 03:36:14,734 --> 03:36:16,837 AND NOTCH LIGAND FROM 1 CELL TO 5503 03:36:16,837 --> 03:36:19,206 ACTIVATING OTHER CELL. 5504 03:36:19,206 --> 03:36:23,877 SO I'M WONDERING HOW THE -- NYOU 5505 03:36:23,877 --> 03:36:25,946 MEAN THE CLUB CONTRIBUTION TO 5506 03:36:25,946 --> 03:36:29,683 AT2 CELL REGULATION BY NOTCH IN. 5507 03:36:29,683 --> 03:36:33,153 >> THAT'S RIGHT. 5508 03:36:33,153 --> 03:36:35,989 >> YEAH, IT'S POSSIBLE THAT 5509 03:36:35,989 --> 03:36:36,790 [INDISCERNIBLE] CELLS MIGHT 5510 03:36:36,790 --> 03:36:40,060 PROVIDE THE NOTCH SIGNALING TO 5511 03:36:40,060 --> 03:36:45,599 THE CLUB CELLS, THAT PROMOTED 5512 03:36:45,599 --> 03:36:49,336 THEIR DIFFERENTIATION INTO AT2 5513 03:36:49,336 --> 03:36:51,838 CELLS AFTER THE YOUR. 5514 03:36:51,838 --> 03:36:54,507 SO WE -- 1 OF MY STUDENTS ARE 5515 03:36:54,507 --> 03:36:57,177 TRYING TO PURSUE IT HERE FOR 5516 03:36:57,177 --> 03:36:59,846 MANIPULATION OR THE NEIGHBORING 5517 03:36:59,846 --> 03:37:04,751 CELLS OR CLUB CELLS IF THEY CAN 5518 03:37:04,751 --> 03:37:08,688 HAVE AN IMPACT ON THEM. 5519 03:37:08,688 --> 03:37:11,224 DIFFERENTIATION, TO THE IT2 5520 03:37:11,224 --> 03:37:17,797 CELLS AND WORKING ON THAT, WE 5521 03:37:17,797 --> 03:37:20,066 DEVELOP SOME AND INTRACELLULAR 5522 03:37:20,066 --> 03:37:23,336 GENETIC APPROACH USING SIGNAL 5523 03:37:23,336 --> 03:37:27,407 NOTCH TO MANIPULATE THE NEIGHBOR 5524 03:37:27,407 --> 03:37:30,377 OR CELLS TARGETED CELLS TO SEE 5525 03:37:30,377 --> 03:37:32,979 IF WE'RE -- THEY HAVE SUPPORT 5526 03:37:32,979 --> 03:37:39,619 PROVIDE A NICHE OR SUPPORTIVE 5527 03:37:39,619 --> 03:37:42,255 SIGNALS TO THE SURROUNDING, 5528 03:37:42,255 --> 03:37:43,490 YEAH, CELLS, WE ARE STILL 5529 03:37:43,490 --> 03:37:44,157 WORKING ON THAT. 5530 03:37:44,157 --> 03:37:53,700 THANKS FOR THE QUESTION. 5531 03:37:53,700 --> 03:37:54,401 >> THANK YOU. 5532 03:37:54,401 --> 03:37:56,670 >> I CAN READ OUT 1 OF THE 5533 03:37:56,670 --> 03:37:59,406 QUESTIONS ASKED IN CHAT TO HALL 5534 03:37:59,406 --> 03:38:05,578 CHAPMAN TO THE BIN ZHOU, THE 5535 03:38:05,578 --> 03:38:06,880 CAPACITY FOR CLUB CELLS IN THE 5536 03:38:06,880 --> 03:38:10,951 GRAPH, HAVE YOU TRIED TO DOUBLE 5537 03:38:10,951 --> 03:38:15,355 LABEL THIS POPULATION AND IF SO, 5538 03:38:15,355 --> 03:38:19,059 WHAT EXTENT OF CC10 TRACE IS 5539 03:38:19,059 --> 03:38:20,260 [INDISCERNIBLE] TOWARDS THIS 5540 03:38:20,260 --> 03:38:24,965 NTHANKS FOR THE COMPLEMENTS AND 5541 03:38:24,965 --> 03:38:25,465 QUESTION. 5542 03:38:25,465 --> 03:38:32,238 YEAH, WE HAVEN'T DONE ANY 5543 03:38:32,238 --> 03:38:39,079 INGRAFTMENT AND TRANSPLANTATION 5544 03:38:39,079 --> 03:38:46,586 EXPERIMENTED BUT IT IS IF YOU 5545 03:38:46,586 --> 03:38:47,954 HAVE MODULATION THROUGH THE CLUB 5546 03:38:47,954 --> 03:38:50,857 CELLS WE CAN DO THIS TRACING OF 5547 03:38:50,857 --> 03:38:52,592 SUBPOPULATION OF CLUB CELLS IN 5548 03:38:52,592 --> 03:39:03,036 VIVO OR IN TRANSPLANTATION 5549 03:39:03,303 --> 03:39:03,703 ASSAY. 5550 03:39:03,703 --> 03:39:06,573 I THINK RECENTLY THEY STARTED TO 5551 03:39:06,573 --> 03:39:08,842 SHOW COLLABORATION WITH CELL, 5552 03:39:08,842 --> 03:39:11,511 WHERE HE'S DONE SOME DUAL 5553 03:39:11,511 --> 03:39:12,445 RECOMBINATION MEDIATED LINEAGE 5554 03:39:12,445 --> 03:39:17,017 TRACING TARGETING ON THE SGTP1 5555 03:39:17,017 --> 03:39:25,158 AC1 AND CGP3 A2, SUBPOPULATIONS 5556 03:39:25,158 --> 03:39:27,060 IN CLUB CELLS AND INSURING THEIR 5557 03:39:27,060 --> 03:39:33,400 CONTRIBUTION TO THE LUNG 5558 03:39:33,400 --> 03:39:34,567 REGENERATION SO I THINK IT'S 5559 03:39:34,567 --> 03:39:36,536 POSSIBLE THAT IF WE HAVE MARKERS 5560 03:39:36,536 --> 03:39:36,770 -- 5561 03:39:36,770 --> 03:39:38,204 >> I WAS THINKING OF SOMETHING 5562 03:39:38,204 --> 03:39:39,906 SIMILAR, THERE ARE NO REAL BASAL 5563 03:39:39,906 --> 03:39:41,875 CELLS IN THE DISTAL MOUSE AIRWAY 5564 03:39:41,875 --> 03:39:43,643 BUT THERE ARE SMALL POPULATIONS 5565 03:39:43,643 --> 03:39:49,049 OF P63 POSITIVE CELLS AND THOSE 5566 03:39:49,049 --> 03:39:50,517 CELLS CAN DIFFERENTIATE DOWN 5567 03:39:50,517 --> 03:39:51,217 DIFFERENT PATHS DEPEBDING ON 5568 03:39:51,217 --> 03:39:52,819 WHERE THEY FIND THEMSELVES SO 5569 03:39:52,819 --> 03:39:54,254 WONDERING IF YOU EVER TRIED TO 5570 03:39:54,254 --> 03:40:00,693 LOOK AT THE DUO BETWEEN SGBAP131 5571 03:40:00,693 --> 03:40:00,927 AND P63. 5572 03:40:00,927 --> 03:40:03,363 >> THANK YOU FOR THE QUESTION, 5573 03:40:03,363 --> 03:40:05,031 WE HAVE DONE RECENTLY A PAPER 5574 03:40:05,031 --> 03:40:06,766 SHOWING THAT CLUB CELLS WHEN 5575 03:40:06,766 --> 03:40:10,703 THEY MIGRATE OUT INTO THE 5576 03:40:10,703 --> 03:40:14,174 SURROUNDINGS ALVEOLAR REGIONS 5577 03:40:14,174 --> 03:40:15,708 THEY ARE UPREGULATION P6 A3, AND 5578 03:40:15,708 --> 03:40:22,382 THEY CONTRIBUTE TO THE AT2 5579 03:40:22,382 --> 03:40:22,582 CELLS. 5580 03:40:22,582 --> 03:40:25,985 YEAH, IT'S POSSIBLE BUT WE FIND 5581 03:40:25,985 --> 03:40:33,426 IN HOMEOSTASIS IN CONDITION, NO 5582 03:40:33,426 --> 03:40:34,727 PROXIMAL IN THE [INDISCERNIBLE] 5583 03:40:34,727 --> 03:40:37,230 REGION WE SET SUCH A P16 5584 03:40:37,230 --> 03:40:39,299 POSITIVE CLUB CELLS BUT ONLY 5585 03:40:39,299 --> 03:40:43,002 AFTER INJURY, WHEN THESE CLUB 5586 03:40:43,002 --> 03:40:43,837 CELLS INTEGRATE OUT, THEY 5587 03:40:43,837 --> 03:40:53,179 INCREASE THE LEVEL OF P6 A3. 5588 03:40:53,179 --> 03:40:53,746 YEAH. 5589 03:40:53,746 --> 03:40:56,249 >> SO MAYBE THAT ACCOUNTS FOR 5590 03:40:56,249 --> 03:40:59,052 THE CLUB CELLS POTENTIATING AND 5591 03:40:59,052 --> 03:41:01,688 DEVELOPING IN THE ALVEOLAR WHEN 5592 03:41:01,688 --> 03:41:03,957 THEY'RE ACTUALLY DEVELOPING A 5593 03:41:03,957 --> 03:41:07,861 REAM PHENOTYPE WITH P63. 5594 03:41:07,861 --> 03:41:08,695 >> YEAH. 5595 03:41:08,695 --> 03:41:10,630 >> DO HAVE YOU A QUESTION? 5596 03:41:10,630 --> 03:41:12,432 >> YEAH, JAY IS FINE. 5597 03:41:12,432 --> 03:41:15,602 >> RUBY IT'S NIGHT TO SEE THE 5598 03:41:15,602 --> 03:41:16,669 WORK COMING LIEWNG SO NICELY. 5599 03:41:16,669 --> 03:41:18,338 I HAD A QUESTION FOR YOU, IT'S A 5600 03:41:18,338 --> 03:41:22,342 GOOD THING JOHN IS HERE BECAUSE 5601 03:41:22,342 --> 03:41:24,544 YOU MENTIONED IONOCYTES 5602 03:41:24,544 --> 03:41:25,778 HETEROGENEITY AS 1 POSSIBILITY 5603 03:41:25,778 --> 03:41:27,680 BUZZ THERE IS 1 GROUP AS 5604 03:41:27,680 --> 03:41:31,050 ABNORMALITIES SOFGZ, 1 SAYING 5605 03:41:31,050 --> 03:41:32,452 SECRETION, 1 SAYING BI 5606 03:41:32,452 --> 03:41:33,653 CARBONATE, AND 1 THING I LIKED 5607 03:41:33,653 --> 03:41:36,222 ABOUT JOHN'S PAPER IS THAT IT 5608 03:41:36,222 --> 03:41:37,157 PERFORMED PROTURBATION AND 5609 03:41:37,157 --> 03:41:38,558 SHOWED THINGS CAN CHANGE. 5610 03:41:38,558 --> 03:41:39,893 SEE OIM WONDER FIGURE YOU THINK 5611 03:41:39,893 --> 03:41:41,561 A GIVEN IEE, AUDIENCEON O SIGHT 5612 03:41:41,561 --> 03:41:44,330 CAN SECRET AND ABSORB BOY MOVING 5613 03:41:44,330 --> 03:41:44,998 IT THROUGH. 5614 03:41:44,998 --> 03:41:46,733 BECAUSE THESE SAM INDUCED AND 5615 03:41:46,733 --> 03:41:49,502 STUFF LIKE, OR WHETHER THERE'S 5616 03:41:49,502 --> 03:41:50,770 LIKE FIXED HETEROGENERATED 8ITY 5617 03:41:50,770 --> 03:41:53,406 IN DIFFERENT POPULATIONS OF 5618 03:41:53,406 --> 03:41:57,377 IONOCYTES AND JOHN AFTER RUOBING 5619 03:41:57,377 --> 03:41:58,444 GIVES HER ANSWER, I WOULD LIKE 5620 03:41:58,444 --> 03:42:03,650 TO HEAR WHAT SHE HAS TO SAY. 5621 03:42:03,650 --> 03:42:04,751 >> THAT'S SUCH A GOOD QUESTION, 5622 03:42:04,751 --> 03:42:06,819 I JUST CAME BACK FROM IPSC, TO 5623 03:42:06,819 --> 03:42:08,454 WE'RE NOT SURE WHAT IT DOES BUT 5624 03:42:08,454 --> 03:42:11,291 IT DOES EVERYTHING, IT ABSORBS, 5625 03:42:11,291 --> 03:42:11,958 BIOCARBS, APPROXIMATE, H, SO I 5626 03:42:11,958 --> 03:42:14,394 THINK WOOER IN THE PROCESS OF 5627 03:42:14,394 --> 03:42:15,695 PERFORMING SINGLE CELL RNASEQ IN 5628 03:42:15,695 --> 03:42:16,763 OUR SYSTEM AND IT WILL BE NICE 5629 03:42:16,763 --> 03:42:18,932 TO SEE IF THE TYPES OF IONOCYTES 5630 03:42:18,932 --> 03:42:21,100 WERE ALSO IN THE PROCESS OF 5631 03:42:21,100 --> 03:42:27,707 GIVING OUR SYSTEM A PROTURBATION 5632 03:42:27,707 --> 03:42:28,875 IN THE DIFFERENCE IN 5633 03:42:28,875 --> 03:42:31,844 SALIVA--SALIVAINITY AND Ph AND 5634 03:42:31,844 --> 03:42:32,612 PROINFLAMMATORY PROTURBATIONS 5635 03:42:32,612 --> 03:42:33,846 AND SEE THE CHANGES. 5636 03:42:33,846 --> 03:42:35,949 SO THIS WORK IS ONGOING, YES, 5637 03:42:35,949 --> 03:42:37,584 AND SO JUST, PLEASE, YAWN, I 5638 03:42:37,584 --> 03:42:40,453 THINK YOU KNOW ABOUT THIS MORE, 5639 03:42:40,453 --> 03:42:41,721 MY UNDERSTANDING FROM THE TOP, 5640 03:42:41,721 --> 03:42:49,195 IS THAT THERE ARE THESE USE OF 5641 03:42:49,195 --> 03:42:52,765 DIFFERENT BASAL LATERAL -- I'M 5642 03:42:52,765 --> 03:42:53,633 NOT AN ELECTROPHYSIOLOGIST, I 5643 03:42:53,633 --> 03:42:57,403 WONDER IF WE DO OUR CHAMBER THE 5644 03:42:57,403 --> 03:42:59,539 SAME WAY THAT THE IOWA GROUP DID 5645 03:42:59,539 --> 03:43:02,775 IT THAT SHOWS THAT IONOCYTES 5646 03:43:02,775 --> 03:43:03,943 SECRETE, ABSORB, I WONDER WOULD 5647 03:43:03,943 --> 03:43:06,279 WE ALSO GET SIMILAR RESULTS? 5648 03:43:06,279 --> 03:43:08,047 AND I DON'T KNOW IF THAT'S A 5649 03:43:08,047 --> 03:43:09,449 GOOD ANSWER BUT I THINK IT'S -- 5650 03:43:09,449 --> 03:43:12,085 I THINK THERE ARE SUBTYPES AND I 5651 03:43:12,085 --> 03:43:13,886 THINK THEY CHANGE WITH DIFFERENT 5652 03:43:13,886 --> 03:43:15,455 PROTURBATIONS, JOHN I WOULD LOVE 5653 03:43:15,455 --> 03:43:17,857 TO HEAR YOUR ANSWER. 5654 03:43:17,857 --> 03:43:19,125 >> A SUGGESTION AND MAYBE YOU'VE 5655 03:43:19,125 --> 03:43:20,493 DONE THIS ALREADY, BUT YOU'VE 5656 03:43:20,493 --> 03:43:21,461 ALREADY DONE A PROTURBATION 5657 03:43:21,461 --> 03:43:23,663 WHICH IS THE KNOCK OUT, AND THE 5658 03:43:23,663 --> 03:43:26,299 OTHER CELLS RESPOND TO THE LOSS 5659 03:43:26,299 --> 03:43:26,899 OF IONOCYTES. 5660 03:43:26,899 --> 03:43:30,737 >> YEAH, SO I THINK WE'RE IN THE 5661 03:43:30,737 --> 03:43:34,207 MIDDLE OF -- WE'RE GETTING 5662 03:43:34,207 --> 03:43:35,375 SINGLE SRNASEQ FROM OUR KNOCK 5663 03:43:35,375 --> 03:43:36,676 OUT CULTURES AND WILD-TYPE 5664 03:43:36,676 --> 03:43:40,980 KOWLTURES AND I'M EXCITED TO SEE 5665 03:43:40,980 --> 03:43:42,815 HOW ESPECIALLY THE SECRET ATORY 5666 03:43:42,815 --> 03:43:44,350 CELLS AND GIVEN TYPES OF CELLS 5667 03:43:44,350 --> 03:43:46,452 AND SOME OF THEM ARE HIGH AND 5668 03:43:46,452 --> 03:43:48,421 SO, YES, NOT JUST HOW SUBTYPES 5669 03:43:48,421 --> 03:43:52,725 OF THIS, BUT ALSO SUBTYPES OF 5670 03:43:52,725 --> 03:43:55,895 OTHER CELLS CHANGES WITH FOX AND 5671 03:43:55,895 --> 03:43:57,764 OUR SYSTEM DOES THAT ANSWER YOUR 5672 03:43:57,764 --> 03:43:58,031 QUESTION? 5673 03:43:58,031 --> 03:44:00,400 >> YEAH, BEFORE I COMMENT ON 5674 03:44:00,400 --> 03:44:02,502 JAY'S QUESTION, RUBY DO YOU KNOW 5675 03:44:02,502 --> 03:44:04,103 IN THE ELECTROPHYSIOLOGY THAT 5676 03:44:04,103 --> 03:44:07,540 YOU SHOWED, WAS IT APICAL LO 5677 03:44:07,540 --> 03:44:08,408 CHLORIDE OR SYMMETRICAL 5678 03:44:08,408 --> 03:44:08,875 CHLORIDE. 5679 03:44:08,875 --> 03:44:11,911 >> I THINK IT WAS SYMMETRICAL. 5680 03:44:11,911 --> 03:44:14,213 WE DID IT WITH YAY AND WE DID IT 5681 03:44:14,213 --> 03:44:15,882 WITH -- YEAH, I THINK IT WAS -- 5682 03:44:15,882 --> 03:44:17,850 I'M PRETTY SURE IT WAS 5683 03:44:17,850 --> 03:44:20,153 SYMMETRICAL, AS SOON AS I SAW 5684 03:44:20,153 --> 03:44:22,121 THOSE DATA, I TALKED TO JAY AND 5685 03:44:22,121 --> 03:44:25,458 WE USED THE SYMMETRICAL FLUORIDE 5686 03:44:25,458 --> 03:44:25,858 GRADIENT. 5687 03:44:25,858 --> 03:44:26,459 >> RIGHT. 5688 03:44:26,459 --> 03:44:28,227 SO THE POSITIVE CURRENT YOU SEE 5689 03:44:28,227 --> 03:44:33,533 WOULD BE SECRETION OF CHLORIDE. 5690 03:44:33,533 --> 03:44:36,269 AND I'M SURE IF YOU VARY IN OUR 5691 03:44:36,269 --> 03:44:38,705 PAPER WE USE SYMMETRICAL 5692 03:44:38,705 --> 03:44:41,441 CHLORIDE SO THAT OUR OUR 5693 03:44:41,441 --> 03:44:42,408 IMPRESSION WE'RE PHYSIOLOGICALLY 5694 03:44:42,408 --> 03:44:43,976 RELEVANT, THERE ARE CHLORIDE 5695 03:44:43,976 --> 03:44:46,546 GRAYIENTS IN IN VIVO, BUT IF YOU 5696 03:44:46,546 --> 03:44:49,382 MANIPULATE IT AND YOU MACK THE 5697 03:44:49,382 --> 03:44:50,883 CHLORIDE, YOUR CURRENT WILL GO 5698 03:44:50,883 --> 03:44:54,187 UP AS YOU EXPECT, MAKE LOW BASAL 5699 03:44:54,187 --> 03:44:55,922 LATERAL CHLORIDE AND YOU SEE 5700 03:44:55,922 --> 03:44:58,157 FAIRLY LARGE NEGATIVE CURRENT, 5701 03:44:58,157 --> 03:44:58,725 TOO. 5702 03:44:58,725 --> 03:44:59,625 NYEAH, ABSOLUTELY, YEAH. 5703 03:44:59,625 --> 03:45:02,795 >> TO YOUR QUESTION, JAY, IT'S 5704 03:45:02,795 --> 03:45:04,063 REALLY INTERESTING. 5705 03:45:04,063 --> 03:45:06,733 I MEAN THERE ARE REGIONAL 5706 03:45:06,733 --> 03:45:07,867 ANATOMICAL DIFFERENCES TO THINK 5707 03:45:07,867 --> 03:45:10,169 ABOUT WHEN YOU THINK ABOUT 5708 03:45:10,169 --> 03:45:10,570 IONOCYTES. 5709 03:45:10,570 --> 03:45:11,571 THEY'RE ARK ROUND GLANDS SO 5710 03:45:11,571 --> 03:45:13,206 THEY'RE IN THE GLANDS IN THE 5711 03:45:13,206 --> 03:45:15,641 DUCTS AND WE NEVER KNEW THAT 5712 03:45:15,641 --> 03:45:18,945 WERE EVEN REALLY FAR DOWN IN 5713 03:45:18,945 --> 03:45:20,446 FREQUENT CELLS NEAR THE VERY 5714 03:45:20,446 --> 03:45:23,483 DISTAL END OF THE SNI, THAT THAT 5715 03:45:23,483 --> 03:45:27,053 EXPRESS FOX 1 AND LINEAGE TRACE. 5716 03:45:27,053 --> 03:45:28,654 SO THE REGIONALLITY DOES THAT 5717 03:45:28,654 --> 03:45:32,625 LEAD TO SUBTYPE OR IS IT A 5718 03:45:32,625 --> 03:45:33,059 STATE? 5719 03:45:33,059 --> 03:45:35,395 AND YOU KNOW THERE REALLY AREN'T 5720 03:45:35,395 --> 03:45:36,529 SUBTYPES BUT 3 DIFFERENT STATES 5721 03:45:36,529 --> 03:45:43,369 THAT ADJUST IS THE CELL LOCKED 5722 03:45:43,369 --> 03:45:47,039 INTO A TYPE OF PHYSIOLOGY. 5723 03:45:47,039 --> 03:45:48,875 WE DID THE HYPOTONIC AND 5724 03:45:48,875 --> 03:45:50,276 HYPERTONIC STRESSOT SITES AND IT 5725 03:45:50,276 --> 03:45:51,444 VERY MUCH CHANGES THE CHANNELS 5726 03:45:51,444 --> 03:45:52,945 THAT ARE EXPRESSED WITHIN THAT 5727 03:45:52,945 --> 03:45:57,116 THAT WOULD CONTROL SECRETION OR 5728 03:45:57,116 --> 03:45:59,519 ABSORPTION AND TO ANSWER THE 5729 03:45:59,519 --> 03:46:01,821 QUESTION, KNOCKING OUT FOXI 1, 5730 03:46:01,821 --> 03:46:02,822 AND CHANGES OTHER CELL TYPES AT 5731 03:46:02,822 --> 03:46:04,190 LEAST IN THE STUDIES WE DID, WE 5732 03:46:04,190 --> 03:46:06,959 FOUND THAT OTHER CELLS LIKE 5733 03:46:06,959 --> 03:46:08,027 SECRETORY CELLS WOULD ADOPT 5734 03:46:08,027 --> 03:46:10,563 HIGHER EXPRESSION OF CHANNELS 5735 03:46:10,563 --> 03:46:11,497 THAT WERE DIFFERENTIALLY 5736 03:46:11,497 --> 03:46:14,500 EXPRESSED AT HIGH LEVELS IN 5737 03:46:14,500 --> 03:46:14,801 IONOCYTES. 5738 03:46:14,801 --> 03:46:17,703 SO CERTAIN 3 THERE'S SOME 5739 03:46:17,703 --> 03:46:19,071 COMPENSATION BY THE EPITHELIUM 5740 03:46:19,071 --> 03:46:22,408 TO TRY ITS BEST EVEN IF IT CAN'T 5741 03:46:22,408 --> 03:46:23,476 COMPLETELY CORRECT TO MODULATE 5742 03:46:23,476 --> 03:46:26,813 OTHER CHANNEL ANDS GET BACK TO 5743 03:46:26,813 --> 03:46:27,480 HOMEIO STASES. 5744 03:46:27,480 --> 03:46:29,549 >> I'M NOT SURE HOW OR WHY 1 5745 03:46:29,549 --> 03:46:31,751 EXPECT IT TO BE THAT DIFFERENT 5746 03:46:31,751 --> 03:46:34,921 THAN THE KIDNEY. 5747 03:46:34,921 --> 03:46:36,789 THAT THEIR COMPENSATORY 5748 03:46:36,789 --> 03:46:37,457 MECHANISMS, IONOCYTES ARE 5749 03:46:37,457 --> 03:46:38,691 PLASTIC AND I WOULDN'T BE 5750 03:46:38,691 --> 03:46:40,593 SURPRISED IF THEY WEREN'T LIKE 5751 03:46:40,593 --> 03:46:42,562 ABLE TO CHANGE THEIR PHYSIOLOGY 5752 03:46:42,562 --> 03:46:45,198 AND RESPONSE TO AN ENVIRONMENTAL 5753 03:46:45,198 --> 03:46:45,665 CONSTRAIN. 5754 03:46:45,665 --> 03:46:47,300 >> YEAH, I TEND TO AGREE WITH 5755 03:46:47,300 --> 03:46:48,568 YOU BUT AT LEAST FOR OUR STUDIES 5756 03:46:48,568 --> 03:46:49,769 AND FOR DOING THAT IN FERRET 5757 03:46:49,769 --> 03:46:51,170 THERE ARE A NUMBER OF OTHER 5758 03:46:51,170 --> 03:47:01,681 DRIVERS WE HAVE TO MAKE AND I 5759 03:47:04,517 --> 03:47:05,985 WILL ADDRESS THAT. 5760 03:47:05,985 --> 03:47:08,955 >> WHILE WE WAIT FOR QUESTIONS, 5761 03:47:08,955 --> 03:47:10,523 WILL WE TALK ABOUT USING 5762 03:47:10,523 --> 03:47:11,891 MULTIPILL MODELS AND 5763 03:47:11,891 --> 03:47:14,861 TECHNOLOGIES, HOW DO WE TACKLE 5764 03:47:14,861 --> 03:47:16,596 MODEL SPECISKS THAT ARE MAY NOT 5765 03:47:16,596 --> 03:47:17,563 TRANSLATE INTO THE BIOLOGY. 5766 03:47:17,563 --> 03:47:18,731 WHERE DO WE START WITH THAT? 5767 03:47:18,731 --> 03:47:22,034 I WILL DRAW THE LINE OF WHAT 5768 03:47:22,034 --> 03:47:29,842 WE'VE SEEN AND WHAT STILL STANDS 5769 03:47:29,842 --> 03:47:32,879 OUT IN 5770 03:47:32,879 --> 03:47:34,280 >> THE SIMPLE ANSWER FOR OUR 5771 03:47:34,280 --> 03:47:36,215 ENGINEERED AIR WAY, I ALWAYS 5772 03:47:36,215 --> 03:47:38,751 VALIDATED WITH A PRIMARY AIR WAY 5773 03:47:38,751 --> 03:47:40,286 AND ALSO MODEL SYSTEM AND ONCE I 5774 03:47:40,286 --> 03:47:42,522 SEE THE PHENOTYPES IN A PRIMARY 5775 03:47:42,522 --> 03:47:43,923 ANIMAL SYSTEM, AT LEAST FOR THIS 5776 03:47:43,923 --> 03:47:45,191 VERY NEW PROTOCOL, THAT'S WHERE 5777 03:47:45,191 --> 03:47:46,526 I FEEL A LITTLE BIT MORE 5778 03:47:46,526 --> 03:47:50,196 CONFIDENCE AND MAYBE WHAT I'M 5779 03:47:50,196 --> 03:47:51,564 SEEING IS BIOLOGICAL BUT EVEN 5780 03:47:51,564 --> 03:47:54,066 THEN, I THINK IT'S RIGHT, I 5781 03:47:54,066 --> 03:47:56,402 THINK IT'S HARD TO INTERPRET AND 5782 03:47:56,402 --> 03:47:58,237 ESPECIALLY SORT OF GIVEN WHAT 5783 03:47:58,237 --> 03:48:02,008 QUESTION YOU ARE ASKING, I HOPE 5784 03:48:02,008 --> 03:48:08,180 THAT ANSWERS, TOO, TO SOME 5785 03:48:08,180 --> 03:48:08,581 DEGREE. 5786 03:48:08,581 --> 03:48:09,515 >> NO MODEL'S PERFECT. 5787 03:48:09,515 --> 03:48:10,783 AND MICE, OBVIOUSLY, YOU KNOW 5788 03:48:10,783 --> 03:48:13,686 YOU CAN GET, YOU CAN ADDRESS 5789 03:48:13,686 --> 03:48:15,288 DEEPER AND DEEPER MECHANISM THAN 5790 03:48:15,288 --> 03:48:17,023 YOU EVER COULD IN A FERRET. 5791 03:48:17,023 --> 03:48:18,858 AND WHEN THERE ARE DIFFERENCES 5792 03:48:18,858 --> 03:48:21,060 I'VE ALWAYS BEEN AN ADVOCATE OF 5793 03:48:21,060 --> 03:48:22,361 LEARNING THAT BIOLOGY BECAUSE I 5794 03:48:22,361 --> 03:48:23,763 THINK IT'S TELLING YOU SOMETHING 5795 03:48:23,763 --> 03:48:26,732 AND IT'S POTENTIALLY LIKE IN THE 5796 03:48:26,732 --> 03:48:28,568 CASE OF CYSTIC FIBROSIS, 5797 03:48:28,568 --> 03:48:30,970 PROVIDING OPPORTUNITIES TO 5798 03:48:30,970 --> 03:48:32,905 APPROACH THERAPIES FROM A NEW 5799 03:48:32,905 --> 03:48:36,208 ANGLE BECAUSE YOU UNDERSTAND WHY 5800 03:48:36,208 --> 03:48:37,343 MICE DON'T GET CYSTIC FIBROSIS 5801 03:48:37,343 --> 03:48:41,781 LUNG DISEASE WHEN YOU TAKE OUT 5802 03:48:41,781 --> 03:48:43,516 CFTR, YOU WILL NEVER GET AROUND 5803 03:48:43,516 --> 03:48:45,818 SOME OF THE ANATOMICAL CELL 5804 03:48:45,818 --> 03:48:47,486 BIOLOGY DIFFERENCES BUT EMBEDDED 5805 03:48:47,486 --> 03:48:54,360 THEY ARE REALLY INFORMATIVE 5806 03:48:54,360 --> 03:48:55,494 LESSONS, I THINK. 5807 03:48:55,494 --> 03:48:57,096 >> YEAH, I AGREE WITH JOHN. 5808 03:48:57,096 --> 03:49:00,533 TODAY I SEE THE FERRET MODELS 5809 03:49:00,533 --> 03:49:06,238 THAT HAVE LIKE TERMINAL 5810 03:49:06,238 --> 03:49:07,940 RESPIRATORY FROM DIFFERENT 5811 03:49:07,940 --> 03:49:10,476 MOUSE, I THINK MAYBE IN THE 5812 03:49:10,476 --> 03:49:13,746 FUTURE, WE CAN ALSO TRY TO 5813 03:49:13,746 --> 03:49:17,316 DEVELOP SOME MUSEUM MODELS ON 5814 03:49:17,316 --> 03:49:19,619 THIS NEW GENETIC MODELS ON THIS 5815 03:49:19,619 --> 03:49:21,320 ROAD WHICH IS REALLY PROMISING 5816 03:49:21,320 --> 03:49:25,057 AND MORE CLOSE TO HUMAN DISEASES 5817 03:49:25,057 --> 03:49:35,534 WHICH I LEARNED FROM TODAY'S 5818 03:49:39,739 --> 03:49:40,106 COMMUNICATION. 5819 03:49:40,106 --> 03:49:41,273 WE'RE MODELING OFF YOUR 5820 03:49:41,273 --> 03:49:41,641 EXCELLENT WORK. 5821 03:49:41,641 --> 03:49:44,644 >> I WANT TO MAKE 1 MORE COMMENT 5822 03:49:44,644 --> 03:49:47,480 ABOUT ORGANOID MODELS, I THINK 5823 03:49:47,480 --> 03:49:49,382 TO, ALSO GOING BACK TO 1 OF 5824 03:49:49,382 --> 03:49:53,185 JAY'S EARLIER COMMENTS ABOUT THE 5825 03:49:53,185 --> 03:49:56,188 STAGE OF THE ORGANOIDS, I THINK 5826 03:49:56,188 --> 03:50:00,693 RIDE NOW, THERE'S STILL MISSING 5827 03:50:00,693 --> 03:50:03,663 PIECES TO FURTHER RECAPITULATE, 5828 03:50:03,663 --> 03:50:05,765 THAT EARLY POSTNATAL PERIOD, 5829 03:50:05,765 --> 03:50:08,334 THERE'S A LACK OF OXYGEN 5830 03:50:08,334 --> 03:50:11,504 EXPOSURE, AND THERE'S ALSO A 5831 03:50:11,504 --> 03:50:12,538 LACK OF MECHANICAL STRETCH 5832 03:50:12,538 --> 03:50:14,740 BECAUSE AFTER BIRTH, RIGHT, 5833 03:50:14,740 --> 03:50:15,775 BABIES START TAKING THE FIRST 5834 03:50:15,775 --> 03:50:17,943 BREATH AND A LOT OF THINGS 5835 03:50:17,943 --> 03:50:21,981 ACTUALLY CHANGE ON THAT DAY IN 5836 03:50:21,981 --> 03:50:25,051 THE ALVERMEN INFECTED O LIAISON 5837 03:50:25,051 --> 03:50:27,253 THAT WILL KEEP DEVELOPING IN 5838 03:50:27,253 --> 03:50:28,487 RESPONSE TO THE 5839 03:50:28,487 --> 03:50:28,888 MICROENVIRONMENT. 5840 03:50:28,888 --> 03:50:30,456 THAT'S SOMETHING WE'RE TRYING TO 5841 03:50:30,456 --> 03:50:34,193 INCORPORATE INTO OUR CURRENT 5842 03:50:34,193 --> 03:50:36,495 SYSTEM, THE OXYGEN GRADIENT AND 5843 03:50:36,495 --> 03:50:37,830 USE A STRETCHABLE MEMBRANE TO 5844 03:50:37,830 --> 03:50:39,832 STUDY SOME OF THE MECHAN O 5845 03:50:39,832 --> 03:50:43,569 TRANSDUCTION IN THE ORGANOID 5846 03:50:43,569 --> 03:50:45,271 SYSTEM, POSSIBLY AND ALSO, YOU 5847 03:50:45,271 --> 03:50:47,339 KNOW THE STARTING OF THE 5848 03:50:47,339 --> 03:50:49,809 PULMONARY CIRCULATION, IS ALSO 5849 03:50:49,809 --> 03:50:51,644 SOMETHING WE THINK WOULD BE 5850 03:50:51,644 --> 03:50:54,847 IMPORTANT TO ADD INTO THE SYSTEM 5851 03:50:54,847 --> 03:51:02,421 TO BETTER RECAPITULATE IN HUMAN 5852 03:51:02,421 --> 03:51:02,722 PHYSIOLOGY. 5853 03:51:02,722 --> 03:51:08,394 >> I HAD A QUESTION ABOUT 5854 03:51:08,394 --> 03:51:09,495 ORGANOID, IT WAS REALLY 5855 03:51:09,495 --> 03:51:10,763 FASCINATING SINCE THE 5856 03:51:10,763 --> 03:51:12,698 VASCULATURE IS CAPABLE OF FLOW 5857 03:51:12,698 --> 03:51:14,166 THROUGH, DO YOU THINK YOU CAN 5858 03:51:14,166 --> 03:51:16,235 USE THAT TO STUDY IMMUNE 5859 03:51:16,235 --> 03:51:18,070 MOLLULATION, CAN YOU STUDY 5860 03:51:18,070 --> 03:51:19,438 IMMUNE INTERACTIONS HAVE YOU 5861 03:51:19,438 --> 03:51:21,207 TRIED THAT. 5862 03:51:21,207 --> 03:51:22,374 YEAH, ABSOLUTELY THAT'S AN AREA 5863 03:51:22,374 --> 03:51:23,375 WE'RE INTERESTED IN PURSUING, 5864 03:51:23,375 --> 03:51:25,211 FOR THE TIME BEING, WE'RE 5865 03:51:25,211 --> 03:51:27,079 BASICALLY TRYING TO OPTIMIZE THE 5866 03:51:27,079 --> 03:51:28,881 BARRIER FUNCTION OF THE 5867 03:51:28,881 --> 03:51:29,815 VASCULATURE WITHIN THE ORGANOIDS 5868 03:51:29,815 --> 03:51:34,320 AND AFTER WE, YOU KNOW DEVELOP A 5869 03:51:34,320 --> 03:51:38,157 BETTER JUNCTION, AND THAT'S 5870 03:51:38,157 --> 03:51:39,125 DEFINITELY SOMETHING WE CAN 5871 03:51:39,125 --> 03:51:42,061 FURTHER DEVELOP WHICH REQUIRES A 5872 03:51:42,061 --> 03:51:42,995 CONNECTION WITH A 5873 03:51:42,995 --> 03:51:44,330 [INDISCERNIBLE] DEVICE AND/OR 5874 03:51:44,330 --> 03:51:47,633 CURRENT THOUGHT IS TO YOU KNOW 5875 03:51:47,633 --> 03:51:48,801 CULTURE SOME MORE ROBUST VASC 5876 03:51:48,801 --> 03:51:50,436 DATURE ON THE CHIP AND THEN 5877 03:51:50,436 --> 03:51:56,041 CONNECT WITH THE VESSELS WITHIN 5878 03:51:56,041 --> 03:51:57,576 THE ORGANOIDS AND THAT WAY WE 5879 03:51:57,576 --> 03:51:59,078 HAVE AN INLET AND OUTLET AND 5880 03:51:59,078 --> 03:52:00,246 INTO THE SYSTEM AND HELP US 5881 03:52:00,246 --> 03:52:02,815 ADDRESS A LOT OF QUESTIONS. 5882 03:52:02,815 --> 03:52:06,886 AND MODEL A LOT OF SYSTEMS, 5883 03:52:06,886 --> 03:52:12,758 YEAH. 5884 03:52:12,758 --> 03:52:13,092 CONDITIONS. 5885 03:52:13,092 --> 03:52:21,367 >> I HAVE A QUESTION, ARE THESE 5886 03:52:21,367 --> 03:52:21,967 POSSIBLE? 5887 03:52:21,967 --> 03:52:22,635 [INDISCERNIBLE], YOUR SYSTEM IS 5888 03:52:22,635 --> 03:52:24,537 FASCINATING AND I WANTED TO ASK 5889 03:52:24,537 --> 03:52:26,772 A QUESTION REGARDING TO THE 5890 03:52:26,772 --> 03:52:29,742 MODEL THAT YOU ARE PROPOSING AT 5891 03:52:29,742 --> 03:52:34,046 THE END IN WHICH BY DISRUPTING 5892 03:52:34,046 --> 03:52:35,948 NOTCH SIGNALING WHAT YOU HAVE A 5893 03:52:35,948 --> 03:52:36,549 CONTRIBUTION THAT GOES 5894 03:52:36,549 --> 03:52:40,085 SPECIFICALLY TO THE TYPE 2 CELLS 5895 03:52:40,085 --> 03:52:44,590 OF THE BASCs, RIGHT, AND AS 5896 03:52:44,590 --> 03:52:47,660 OPPOSE TO THE TYPE 2 CELL, THE 5897 03:52:47,660 --> 03:52:49,862 CLUB CELL, GOING INTO ALVEOLAR 5898 03:52:49,862 --> 03:52:54,533 CELL ITSELF, THE TYPE 2 CELL, SO 5899 03:52:54,533 --> 03:52:55,668 THE ISSUE, THE NONAPOPTOTIC THE 5900 03:52:55,668 --> 03:52:58,604 ISSUE BUT THE OBSERVATION IS 5901 03:52:58,604 --> 03:53:02,074 THAT IN THE ADULT WHEN YOU 5902 03:53:02,074 --> 03:53:02,975 DISRUPT NOTCH SIGNALING, YOU 5903 03:53:02,975 --> 03:53:04,376 ACTUALLY DO HAVE A 5904 03:53:04,376 --> 03:53:05,778 TRANSFORMATION OF THE CLUB CELLS 5905 03:53:05,778 --> 03:53:07,213 BO THE CILIATED CELLS WHICH I 5906 03:53:07,213 --> 03:53:08,380 WOULD BE SURPRISED BECAUSE IN 5907 03:53:08,380 --> 03:53:11,116 SOME WAYS IT SHOULD ACTUALLY 5908 03:53:11,116 --> 03:53:12,852 HAPPEN FROM THE PROIENITTOR 5909 03:53:12,852 --> 03:53:14,820 ITSELF, NOT NECESSARILY FROM THE 5910 03:53:14,820 --> 03:53:15,421 ALREADY DIFFERENTIATED CELL, 5911 03:53:15,421 --> 03:53:16,589 UNLESS THERE IS SOME OTHER 5912 03:53:16,589 --> 03:53:17,990 MECHANISM I'M NOT SURE ABOUT, 5913 03:53:17,990 --> 03:53:19,158 BUT IF THAT'S THE CASE, THEN 5914 03:53:19,158 --> 03:53:21,327 WHAT YOU SEE IS THE 5915 03:53:21,327 --> 03:53:22,728 DISASSOCIATION BETWEEN THEZ 5916 03:53:22,728 --> 03:53:25,698 MECHANISM OF REGENERATION THAT 5917 03:53:25,698 --> 03:53:27,433 IS ORIGINALLY FROM THE TYPE 2 5918 03:53:27,433 --> 03:53:29,468 CELLS AND THE 1 THAT IS THE 5919 03:53:29,468 --> 03:53:32,738 CONTRIBUTION OF THE AIRWAY 5920 03:53:32,738 --> 03:53:34,773 ITSELF, GIVEN THAT YOU ARE NOT 5921 03:53:34,773 --> 03:53:37,309 SUPPOSED TO HAVE THEN CLUB 5922 03:53:37,309 --> 03:53:38,844 CELLS, TO GIVE RISE TO THE TYPE 5923 03:53:38,844 --> 03:53:41,814 2 CELLS, BUT THEN, IT IS THEN 5924 03:53:41,814 --> 03:53:45,017 THE BASC, THAT WE TAKE THE TYPE 5925 03:53:45,017 --> 03:53:46,285 2 CELL COMPONENT THAT IT HAS 5926 03:53:46,285 --> 03:53:50,222 THAT IT HAS THE SBC, SEON TO 5927 03:53:50,222 --> 03:53:52,057 REGENERATE THE ALVEOLAR TYPE 2 5928 03:53:52,057 --> 03:53:52,291 CELL. 5929 03:53:52,291 --> 03:53:54,927 I WONDER IF THIS IS CLEAR OR IF 5930 03:53:54,927 --> 03:54:04,370 I NEED TO EXPLAIN MORE? 5931 03:54:04,370 --> 03:54:06,138 YOU MEAN THE CLUB CELL 5932 03:54:06,138 --> 03:54:07,740 DIFFERENTIATING THROUGH THE BASC 5933 03:54:07,740 --> 03:54:09,241 CELL GOING THROUGH THE PHASE 2 5934 03:54:09,241 --> 03:54:09,675 STATE? 5935 03:54:09,675 --> 03:54:10,976 AM I UNDERSTANDING RIGHT IN. 5936 03:54:10,976 --> 03:54:12,811 >> GIVEN THAT YOU DO NOT HAVE 5937 03:54:12,811 --> 03:54:15,781 CLUB CELL OR YOU HAVE EITHER 5938 03:54:15,781 --> 03:54:16,949 DEFECTIVE CLUB CELL OR SO, IT 5939 03:54:16,949 --> 03:54:19,885 WOULD NOT BE ABLE TO OR GIVE 5940 03:54:19,885 --> 03:54:23,923 PRIZE TO A TYPE 2 CELL ITSELF 5941 03:54:23,923 --> 03:54:25,758 AND THAT IT IS WHAT IT IS 5942 03:54:25,758 --> 03:54:28,360 BLOCKED BY THE KNOCK OUT OF THE 5943 03:54:28,360 --> 03:54:28,694 NOTCH. 5944 03:54:28,694 --> 03:54:31,563 AND THE ONLY THING THAT WOULD 5945 03:54:31,563 --> 03:54:34,199 REMAIN WOULD BE THE BASC CELL 5946 03:54:34,199 --> 03:54:39,071 GIVING RISE THEN TO THE TYPE 2 5947 03:54:39,071 --> 03:54:41,540 CELL, YEAH, BECAUSE IT DOESN'T 5948 03:54:41,540 --> 03:54:42,841 HAVE THE COMPONENT OF THE CLUB 5949 03:54:42,841 --> 03:54:45,844 CELL THAT THE BASC WOULD HAVE 5950 03:54:45,844 --> 03:54:49,214 THAT IT IS [INDISCERNIBLE]. 5951 03:54:49,214 --> 03:54:52,618 >> OKAY, YEAH, SO, IF WE KNOCK 5952 03:54:52,618 --> 03:54:55,220 OUT NOTCH, IN THE CLUB CELLS SO 5953 03:54:55,220 --> 03:54:59,625 THEIR CONTRIBUTION TO AT2 IS 5954 03:54:59,625 --> 03:55:00,693 SIGNIFICANTLY REDUCED SO IT'S 5955 03:55:00,693 --> 03:55:05,798 POSSIBLE THAT THE BASCs FOR NO 5956 03:55:05,798 --> 03:55:07,499 REASON, SENSE THIS DEFECT AND 5957 03:55:07,499 --> 03:55:08,801 THE COMPENSATED CONTRIBUTE MORE 5958 03:55:08,801 --> 03:55:13,439 TO AT2. 5959 03:55:13,439 --> 03:55:14,673 >> EXACTLY. 5960 03:55:14,673 --> 03:55:15,007 >> EXACTLY. 5961 03:55:15,007 --> 03:55:15,607 >> THERE'S DISASSOCIATION 5962 03:55:15,607 --> 03:55:17,609 BETWEEN THE 2 COMPONENTS, THE 5963 03:55:17,609 --> 03:55:18,544 COMPONENT THAT IT IS, WHAT YOU 5964 03:55:18,544 --> 03:55:20,646 HAVE IN MY VIEW, WHAT HAVE YOU 5965 03:55:20,646 --> 03:55:22,281 DESCRIBED VERY BEAUTIFULLY IS, A 5966 03:55:22,281 --> 03:55:24,049 COMPONENT THAT BELONGS TO THE 5967 03:55:24,049 --> 03:55:25,784 AIR WAY, AND IT ANOTHER 1 THAT 5968 03:55:25,784 --> 03:55:29,521 BELONGS TO THE BASC. 5969 03:55:29,521 --> 03:55:32,925 AND THAT CLEARLY, THE NOTCH IS 5970 03:55:32,925 --> 03:55:34,526 DOING THE SELECTION BETWEEN THE 5971 03:55:34,526 --> 03:55:39,598 2 COMPONENTS OF WHEN YOU HAVE 5972 03:55:39,598 --> 03:55:40,566 THE BLEOMYCIN REGENERATION, 5973 03:55:40,566 --> 03:55:42,267 REGENERATION AFTER THE 5974 03:55:42,267 --> 03:55:44,570 BLEOMYCIN. 5975 03:55:44,570 --> 03:55:46,839 >> YEAH, I THINK THIS TOO 5976 03:55:46,839 --> 03:55:47,873 POPULATION ARE FUNCTIONALLY 5977 03:55:47,873 --> 03:55:53,012 DIFFERENT IN THEIR RESPONSE TO 5978 03:55:53,012 --> 03:55:54,980 BLEOMYCIN INJURY BECAUSE IF THEY 5979 03:55:54,980 --> 03:55:57,683 RESPOND SIMILARLY, THEY SHOULD 5980 03:55:57,683 --> 03:55:59,385 BE DIFFERENT APPROXIMATE BASC 5981 03:55:59,385 --> 03:56:01,920 PART OF CLUB POPULATION, 5982 03:56:01,920 --> 03:56:04,423 SUBPOPULATION, THEY SHOULD 5983 03:56:04,423 --> 03:56:06,458 DECREASE THAT THEY ARE 5984 03:56:06,458 --> 03:56:09,395 DIFFERENTIATION INTO AT2 CELLS 5985 03:56:09,395 --> 03:56:11,430 WHEN NOTCH IS KNOCK OUT AFTER 5986 03:56:11,430 --> 03:56:11,764 BLEOMYCIN. 5987 03:56:11,764 --> 03:56:16,068 BUT WHAT WE SEE, BASICALLY IS 5988 03:56:16,068 --> 03:56:19,238 NOT CHANGE THEM, OR INSTEAD 5989 03:56:19,238 --> 03:56:21,073 INCREASE THEM, THE REASON FOR 5990 03:56:21,073 --> 03:56:24,176 INCREASE COULD BE AS A RESPONSE 5991 03:56:24,176 --> 03:56:26,578 TO REDUCE THE CLUB SALE 5992 03:56:26,578 --> 03:56:28,047 DIFFERENTIATION TO AT2, BUT IT 5993 03:56:28,047 --> 03:56:31,350 COULD ALSO BE TO THEY ARE 5994 03:56:31,350 --> 03:56:34,153 DIFFERENT POPULATION, THEY 5995 03:56:34,153 --> 03:56:35,621 FUNCTION DEFINITE BUT, WE THINK 5996 03:56:35,621 --> 03:56:38,991 THEY ARE NOT SAME POPULATION, 5997 03:56:38,991 --> 03:56:42,961 NOT ONLY FROM MOLECULAR 5998 03:56:42,961 --> 03:56:48,033 SIGNATURES BUT ALSO FROM 5999 03:56:48,033 --> 03:56:48,967 DISTINCT FUNCTIONAL DISTIRCHGHT 6000 03:56:48,967 --> 03:56:50,869 POPULATION FOR FUNCTION AS THEY 6001 03:56:50,869 --> 03:56:51,937 RESPOND DIFFERENTLY. 6002 03:56:51,937 --> 03:56:56,008 THIS IS WHAT WE CAN 6003 03:56:56,008 --> 03:56:57,176 [INDISCERNIBLE] FROM THIS DATA. 6004 03:56:57,176 --> 03:56:59,711 BUT AS YOU POINT OUT, I AGREE 6005 03:56:59,711 --> 03:57:04,216 WITH YOU, THAT IT'S ALSO 6006 03:57:04,216 --> 03:57:07,252 POSSIBLE THAT BASC INCREASE THE 6007 03:57:07,252 --> 03:57:07,986 BASC TO THE INTERNATIONAL 6008 03:57:07,986 --> 03:57:09,922 CLASSIFICATION IMRAIGZ TO AT2 6009 03:57:09,922 --> 03:57:20,432 CAN BE A SECONDARY TO REDUCED 6010 03:57:23,068 --> 03:57:27,272 [INDISCERNIBLE] CLUB AT2 6011 03:57:27,272 --> 03:57:27,606 REGENERATION. 6012 03:57:27,606 --> 03:57:29,007 THANKS OF. 6013 03:57:29,007 --> 03:57:33,479 >> SEUNG HYE HAS A QUESTION. 6014 03:57:33,479 --> 03:57:39,318 >> I HAVE A QUESTION FOR PANELS, 6015 03:57:39,318 --> 03:57:41,954 THAT IE. THINKING MORE LIKE 6016 03:57:41,954 --> 03:57:44,590 ALVEOLAR CELLS ACTUALLY BUT HOW 6017 03:57:44,590 --> 03:57:49,528 SIMILAR, THE INVITRO 3D SYSTEM, 6018 03:57:49,528 --> 03:57:51,163 CELL IS ACTUALLY -- HOW SIMILAR 6019 03:57:51,163 --> 03:57:54,066 TO THE INVITRO SETTING, SO IT 6020 03:57:54,066 --> 03:57:55,934 HAS VERY DIFFERENT METABOLIC 6021 03:57:55,934 --> 03:57:58,570 SETTING, COMPARED TO IN VIVO. 6022 03:57:58,570 --> 03:58:03,675 SO LIKE FOR EXAMPLE, IF WE LIKE 6023 03:58:03,675 --> 03:58:05,010 INDUCE DIFFERENTIATION, MY 6024 03:58:05,010 --> 03:58:06,945 LIMITED EXPERIENCE IS THAT THE 6025 03:58:06,945 --> 03:58:09,448 CELLS DOES NOT FULLY 6026 03:58:09,448 --> 03:58:11,416 DIFFERENTIATE INTO -- BECAUSE IT 6027 03:58:11,416 --> 03:58:14,386 LOOKED LIKE AT1 LIKE CELLS BUT 6028 03:58:14,386 --> 03:58:16,722 IT DOESN'T REALLY AT1 CELLS LIKE 6029 03:58:16,722 --> 03:58:20,659 IN VIVO, BUT IT CLEARLY, I HAVE 6030 03:58:20,659 --> 03:58:21,693 VERY LIMITED EXPERIENCE, SO I 6031 03:58:21,693 --> 03:58:24,396 JUST WANT TO ASK THE EXPERIENCE 6032 03:58:24,396 --> 03:58:25,831 IN PANELS, AND ALSO THE REASON 6033 03:58:25,831 --> 03:58:27,933 I'M ASKING IS THAT AT THE END, I 6034 03:58:27,933 --> 03:58:30,369 THINK IN TERPS OF THE RELATED TO 6035 03:58:30,369 --> 03:58:32,004 RESILIENCE IN OUR WORKSHOP, I 6036 03:58:32,004 --> 03:58:35,507 THINK AT THE END WE WANT TO KNOW 6037 03:58:35,507 --> 03:58:36,675 ONCE IT'S INITIATE THE 6038 03:58:36,675 --> 03:58:37,976 DIFFERENTIATION, WE WANT TO KNOW 6039 03:58:37,976 --> 03:58:41,713 WHAT ARE FACTORS TO MAKE THE 6040 03:58:41,713 --> 03:58:44,449 CELLS INVOLVING TERMINAL 6041 03:58:44,449 --> 03:58:45,284 DIFFERENTIATION, FULLY MATURE, 6042 03:58:45,284 --> 03:58:46,118 INTO FUNCTIONAL CELLS AND I 6043 03:58:46,118 --> 03:58:49,922 THINK THAT IF WE INVITRO SYSTEMS 6044 03:58:49,922 --> 03:58:51,790 CAN CAPTURE THAT PART, IT COULD 6045 03:58:51,790 --> 03:58:55,327 BE LIMITED IN DATA ASPECT, SO I 6046 03:58:55,327 --> 03:58:57,062 JUST WANTED TO ASK PANEL'S 6047 03:58:57,062 --> 03:59:02,100 EXPERIENCE OR OPINION ON THAT. 6048 03:59:02,100 --> 03:59:04,503 >> ALL RIGHT, I GUESS I CAN 6049 03:59:04,503 --> 03:59:06,338 START, FOR CURRENT ORGANOID, OF 6050 03:59:06,338 --> 03:59:08,073 COURSE DID BEPENDS HOW LONG WE 6051 03:59:08,073 --> 03:59:10,709 KEEP THEM IN CULTURE. 6052 03:59:10,709 --> 03:59:14,213 THE LONGEST WE TRIED IS ABOUT 6053 03:59:14,213 --> 03:59:16,882 ALMOST 4 MONTHS BUT THAT'S NOT 6054 03:59:16,882 --> 03:59:19,418 COMPLETELY INVITRO, WE TRAN 6055 03:59:19,418 --> 03:59:22,888 PLANTED THOSE ORGANOIDS AND THE 6056 03:59:22,888 --> 03:59:24,523 CAPSULE IN SKID MICE SO THEY CAN 6057 03:59:24,523 --> 03:59:28,460 FURTHER GROW AND CONNECT WITH 6058 03:59:28,460 --> 03:59:38,503 THE HOSTS CIRCULATION AND 6059 03:59:38,503 --> 03:59:40,606 MATURE, AND FOR THOSE ORGANIES 6060 03:59:40,606 --> 03:59:42,874 WE ARE DOING THEM TO UNDERSTAND 6061 03:59:42,874 --> 03:59:44,276 THE MATURATION OF THE CELLS ON 6062 03:59:44,276 --> 03:59:49,248 BUT IF THEY'RE TERMINALLILY 6063 03:59:49,248 --> 03:59:51,483 DIFFERENTIATIONS, IF THEY'RE 6064 03:59:51,483 --> 03:59:52,084 DIFFERENTIATED FROM IPSCs, 1 6065 03:59:52,084 --> 04:00:02,628 THING WE DID WAS TO COMPARE THE 6066 04:00:04,463 --> 04:00:07,366 TRANSI 6067 04:00:07,366 --> 04:00:11,937 TRAN SCRIPT OHM TO THE SYSTEM, 6068 04:00:11,937 --> 04:00:15,173 AND WE CAN TRANSFER IN VIVO FROM 6069 04:00:15,173 --> 04:00:17,909 GUESTATIONAL AGE A COUPLE WEEKS, 6070 04:00:17,909 --> 04:00:20,412 WEEK 4 OR 6, ALL THE WAY TO YOU 6071 04:00:20,412 --> 04:00:24,216 KNOW A THIRD TRIMESTER, HUMAN 6072 04:00:24,216 --> 04:00:27,319 FETAL LUNG, AND BASED ON 6073 04:00:27,319 --> 04:00:28,553 TRANSCRIPTOMIC ANALYSIS, IT'S 6074 04:00:28,553 --> 04:00:33,325 EQUIVALENT OR MORE SIMILAR TO 6075 04:00:33,325 --> 04:00:36,161 HUMAN FETAL LUNG AT ABOUT 80 6076 04:00:36,161 --> 04:00:39,131 DAYS OR SOMETHING LIKE THAT. 6077 04:00:39,131 --> 04:00:44,636 SO, OF COURSE, THIS IS STILL 6078 04:00:44,636 --> 04:00:46,938 VERY PREMATURE. 6079 04:00:46,938 --> 04:00:49,141 AND FOR USING THE MODEL TO 6080 04:00:49,141 --> 04:00:51,576 STUDY, YOU KNOW BIOLOGICAL 6081 04:00:51,576 --> 04:00:53,278 QUESTIONS, I THINK 1 POTENTIAL 6082 04:00:53,278 --> 04:00:54,446 ADVANTAGE OF THE SYSTEM, 6083 04:00:54,446 --> 04:00:57,883 ALTHOUGH IS NOW MATURE OR 6084 04:00:57,883 --> 04:00:59,484 TERMINAL DIFFERENTIATED, IT'S A 6085 04:00:59,484 --> 04:01:01,620 REDUCE DIMENSION SYSTEM, SO IT 6086 04:01:01,620 --> 04:01:05,290 AVOIDS COMPLEXITY OF THE IN VIVO 6087 04:01:05,290 --> 04:01:08,126 ENVIRONMENT, SO IF YOU WANT TO 6088 04:01:08,126 --> 04:01:12,431 UNDERSTAND SOME CELL AUTONOMOUS, 6089 04:01:12,431 --> 04:01:15,067 MECHANISM, IT MIGHT BE A 6090 04:01:15,067 --> 04:01:17,002 SIMPLER, PLATFORM, TO LOOK AT 6091 04:01:17,002 --> 04:01:18,904 FOR EXAMPLE, JUST ENDOTHELIAL, 6092 04:01:18,904 --> 04:01:20,605 EPITHELIAL CROSS TALK, SO YOU 6093 04:01:20,605 --> 04:01:22,240 DON'T HAVE, OTHER CELL TYPES, 6094 04:01:22,240 --> 04:01:24,543 INVOLVED IN THE SYSTEM, BECAUSE 6095 04:01:24,543 --> 04:01:26,878 WE KNOW, YOU KNOW ALL THE 6096 04:01:26,878 --> 04:01:28,680 PROGENITOR STEM CELLS IN THE 6097 04:01:28,680 --> 04:01:31,450 LUNG, THEY ARE PLASTIC AND THEY 6098 04:01:31,450 --> 04:01:33,085 CAN BE TRANSDIFFERENTIATED INTO 6099 04:01:33,085 --> 04:01:34,619 OTHER CELL TYPES WHICH INTRODUCE 6100 04:01:34,619 --> 04:01:37,255 A LOT OF COMPLEXITY, FOR 6101 04:01:37,255 --> 04:01:39,591 UNDERSTANDING A PARTICULAR 6102 04:01:39,591 --> 04:01:39,858 QUESTION. 6103 04:01:39,858 --> 04:01:43,729 SO IN MY VIEW, THESE IPS 6104 04:01:43,729 --> 04:01:50,669 DERIVATIVES ARE SERVING AS 6105 04:01:50,669 --> 04:01:52,971 SIMPLIFIED SYSTEM TO UNDERSTAND 6106 04:01:52,971 --> 04:01:53,372 AUTONOMOUS EFFECT. 6107 04:01:53,372 --> 04:01:55,540 >> YEAH, I HAVE TO SAY I 6108 04:01:55,540 --> 04:01:57,242 COMPLETELY AGREE WITH EVERYTHING 6109 04:01:57,242 --> 04:01:59,411 YOU JUST SAID I KNOW YOU'RE 6110 04:01:59,411 --> 04:02:02,614 QUESTIONS ARE FOR FOR THE 6111 04:02:02,614 --> 04:02:06,351 ALVEOLAR, BUT WHEN YOU COMPARE 6112 04:02:06,351 --> 04:02:07,919 AIRWAY TO UNCULTURED, FRESH 6113 04:02:07,919 --> 04:02:10,822 LUNG, AS WELL AS CULTURE TO 6114 04:02:10,822 --> 04:02:12,624 HUMAN BRONCHIAL EPITHELIAL 6115 04:02:12,624 --> 04:02:14,693 CELLS, THEY'RE SIMILAR WITH THAT 6116 04:02:14,693 --> 04:02:15,861 CORRECTION OF THE SINGLE CELL 6117 04:02:15,861 --> 04:02:17,396 DATA AND SO THEN ALSO WHEN WE 6118 04:02:17,396 --> 04:02:19,464 GIVE IT A PATHOGEN RESPONSE, WE 6119 04:02:19,464 --> 04:02:21,099 ALWAYS -- AT LEAST OUR LAB 6120 04:02:21,099 --> 04:02:22,401 ALWAYS COMPARED TO A PRIMARY 6121 04:02:22,401 --> 04:02:25,570 RESPONSE TO MAKE SURE IT'S NOT 6122 04:02:25,570 --> 04:02:26,171 AN IPSC PHENOMENON. 6123 04:02:26,171 --> 04:02:29,741 AND NOT FROM MY LAB BUT THE LAB 6124 04:02:29,741 --> 04:02:34,112 I TRAINED IN AT BU, TRANSPLANTED 6125 04:02:34,112 --> 04:02:34,746 IPSC DERIVED BASAL CELLS IN THE 6126 04:02:34,746 --> 04:02:37,349 MOUSE AND THEY WERE ABLE TO 6127 04:02:37,349 --> 04:02:42,053 DIFFERENTIATE INTO SOME OF THOSE 6128 04:02:42,053 --> 04:02:43,221 CELL TYPES IN VIVO. 6129 04:02:43,221 --> 04:02:44,189 SO YEAH. 6130 04:02:44,189 --> 04:02:47,392 I COMPLETELY AGREE WITH WHAT YOU 6131 04:02:47,392 --> 04:02:49,494 SAID MING XIA, ITIVE GOES A VERY 6132 04:02:49,494 --> 04:02:51,596 CLEAN WAY IF YOU COMPARE WITH 6133 04:02:51,596 --> 04:02:53,198 GENE EDITING IT'S A REDUCTIONIST 6134 04:02:53,198 --> 04:02:57,803 WAY TO ANSWER LIKE A ANSWER 6135 04:02:57,803 --> 04:02:59,204 SPECIFIC QUESTION. 6136 04:02:59,204 --> 04:03:01,139 >> YEAH, I GUESS OUR ALTERNATIVE 6137 04:03:01,139 --> 04:03:04,910 STRATEGY IS TO USE PRECISION CUT 6138 04:03:04,910 --> 04:03:06,645 LUNG SLICE, YOU CAN GET THOSE IN 6139 04:03:06,645 --> 04:03:08,380 CULTURE AND WITH AN ADULT LUNG 6140 04:03:08,380 --> 04:03:12,050 AS WELL AS AN INVITRO MODELING 6141 04:03:12,050 --> 04:03:12,384 SYSTEM. 6142 04:03:12,384 --> 04:03:19,624 >> I DON'T DENY THAT THIS SYSTM 6143 04:03:19,624 --> 04:03:21,092 IS HELPFUL TOOL TO ASK CERTAIN 6144 04:03:21,092 --> 04:03:22,594 QUESTIONS AND THEN UNDERSTAND 6145 04:03:22,594 --> 04:03:24,262 THE BIOLOGY, PATHOLOGY AND 6146 04:03:24,262 --> 04:03:27,232 POETICIENTIALLY USE IT AS A DRUG 6147 04:03:27,232 --> 04:03:29,301 SCREENING TOOL OR SOME 6148 04:03:29,301 --> 04:03:32,003 THERAPEUTIC TARGET BUT I CLEARLY 6149 04:03:32,003 --> 04:03:35,707 ALSO THERE ARE LIMITATIONS IN 6150 04:03:35,707 --> 04:03:38,677 TERMS OF HOW MUCH WE CAN MIMIC 6151 04:03:38,677 --> 04:03:40,545 IN VIVO SYSTEM, SO I JUST WANTED 6152 04:03:40,545 --> 04:03:42,514 TO DISCUSS ABOUT THAT. 6153 04:03:42,514 --> 04:03:44,716 I GUESS TATA HAS A COMMENT ON 6154 04:03:44,716 --> 04:03:45,317 THAT. 6155 04:03:45,317 --> 04:03:46,651 I ASKED HIM. 6156 04:03:46,651 --> 04:03:47,853 >> YEAH, IT'S NOT A QUESTION, 6157 04:03:47,853 --> 04:03:49,688 IT'S JUST A THOUGHT. 6158 04:03:49,688 --> 04:03:51,556 I WAS WONDERING WITH RESPECT TO 6159 04:03:51,556 --> 04:03:53,158 THE MATURITY, IS THERE SOMETHING 6160 04:03:53,158 --> 04:03:58,230 WE ARE MISSING, RIGHT IN 1 6161 04:03:58,230 --> 04:03:59,998 ASPECT IS YOU KNOW DURING 6162 04:03:59,998 --> 04:04:00,866 DEVELOPMENT AND DEVELOPMENT 6163 04:04:00,866 --> 04:04:03,902 PARTICULARLY, SO WE HAVE THIS 6164 04:04:03,902 --> 04:04:05,737 SELF-VERSUS NONSELF, WITH ALL OF 6165 04:04:05,737 --> 04:04:09,341 THIS IMMUNE TOLERANCE, RIGHT? 6166 04:04:09,341 --> 04:04:11,076 SO IS THAT COMPETENT BECAUSE I 6167 04:04:11,076 --> 04:04:12,711 REMEMBER SEEING SOME OF LAB 6168 04:04:12,711 --> 04:04:13,678 PAPERS WHERE I THINK THEY 6169 04:04:13,678 --> 04:04:17,282 POINTEDDA THE SOME OF THOSE LIKE 6170 04:04:17,282 --> 04:04:20,886 THEY DON'T EXPRESS, MHC PROFILE 6171 04:04:20,886 --> 04:04:23,622 IS DIFFERENT, ACTUALLY. 6172 04:04:23,622 --> 04:04:25,290 BUT IPSC DERIVED 2 AT2 CELLS, 6173 04:04:25,290 --> 04:04:29,060 BASAL CELLS THEY DON'T HAVE 6174 04:04:29,060 --> 04:04:30,128 THEEZ IMMHC PROFILES SO IF THAT 6175 04:04:30,128 --> 04:04:32,230 IS A WAY TO INDUCE AND IF THAT 6176 04:04:32,230 --> 04:04:42,774 IS ACTUALLY INDUCING SOME TYPE 6177 04:04:43,308 --> 04:04:44,843 OF MATURITY. 6178 04:04:44,843 --> 04:04:45,777 >> IME WONDERING ABOUT 6179 04:04:45,777 --> 04:04:48,580 COMPONENTS FROM THE IMMUNE 6180 04:04:48,580 --> 04:04:52,150 SYSTEM MOSTLY OR FOR A MATURE 6181 04:04:52,150 --> 04:04:52,517 SYSTEM? 6182 04:04:52,517 --> 04:04:54,452 >> YEAH, MHC COMPETENCE, RIGHT? 6183 04:04:54,452 --> 04:05:00,091 THAT'S HOW WE DEVELOP, DURING 6184 04:05:00,091 --> 04:05:03,061 DEVELOPMENT THIS SELF, VERSUS 6185 04:05:03,061 --> 04:05:06,398 NONSELF, I WONDER IF THAT AS A 6186 04:05:06,398 --> 04:05:07,265 ROLE IN MATURITY? 6187 04:05:07,265 --> 04:05:11,903 BECAUSE I REMEMBER LIKE EVEN A 6188 04:05:11,903 --> 04:05:12,971 TRANSPLANTATION STUDIES, FROM 6189 04:05:12,971 --> 04:05:17,175 DARYL'S GROUP, THE MORE 6190 04:05:17,175 --> 04:05:18,643 TRANSPLANTED, IBCs, 6191 04:05:18,643 --> 04:05:20,412 TRANSPLANTED INTO MICE, SHOWED 6192 04:05:20,412 --> 04:05:27,752 CHARACTERISTICS MORE CLOSE TO 6193 04:05:27,752 --> 04:05:28,486 THE ADULT. 6194 04:05:28,486 --> 04:05:30,121 NWELL, THANK YOU SO MUCH FOR 6195 04:05:30,121 --> 04:05:31,923 THIS, I THINK WE WILL CARRY THE 6196 04:05:31,923 --> 04:05:32,991 DISCUSSION OVER THE CHAT BECAUSE 6197 04:05:32,991 --> 04:05:34,859 WE HAVE TO GO TO THE SESSION 3, 6198 04:05:34,859 --> 04:05:37,963 BUT I THANK ALL THE PRESENTERS 6199 04:05:37,963 --> 04:05:40,165 IN A LIVELY DISCUSSION, THANK 6200 04:05:40,165 --> 04:05:42,267 YOU SO MUCH. 6201 04:05:42,267 --> 04:05:52,677 >> THANK YOU EVERYONE. 6202 04:05:55,046 --> 04:05:57,215 >> YEAH, WE WILL START SESSION 6203 04:05:57,215 --> 04:05:57,682 3. 6204 04:05:57,682 --> 04:06:02,220 THIS WILL BE ON PROGENITOR BASED 6205 04:06:02,220 --> 04:06:03,655 MARKERS PREDICTING EARLY CHRONIC 6206 04:06:03,655 --> 04:06:04,456 LUNG DISEASES. 6207 04:06:04,456 --> 04:06:07,626 IF WE GO TO THE NEXT SLIDE. 6208 04:06:07,626 --> 04:06:10,729 SO THIS SESSION WILL BE FOCUSED 6209 04:06:10,729 --> 04:06:13,098 ON LOOKING INTO PROGENITOR BASED 6210 04:06:13,098 --> 04:06:15,166 MARKERS THAT COULD PREDICT EARLY 6211 04:06:15,166 --> 04:06:23,208 ONSET OF CHRONIC DEC. 6212 04:06:23,208 --> 04:06:24,843 INITIALLY OF COURSE WE WILL HAVE 6213 04:06:24,843 --> 04:06:27,879 TO BE TALKING ABOUT RESEARCH 6214 04:06:27,879 --> 04:06:33,385 GAPS LATER ON BUT NEXT SLIDE, 6215 04:06:33,385 --> 04:06:33,652 PLEASE. 6216 04:06:33,652 --> 04:06:39,090 NEXT SLIDE. 6217 04:06:39,090 --> 04:06:41,192 NEXT. 6218 04:06:41,192 --> 04:06:41,459 NEXT. 6219 04:06:41,459 --> 04:06:42,661 SO THE FIRST PRESENTATION WILL 6220 04:06:42,661 --> 04:06:45,363 BE FOCUSED ON LOOKING AT AGAIN, 6221 04:06:45,363 --> 04:06:47,599 THE MARKERS OF PROIENITTOR BASED 6222 04:06:47,599 --> 04:06:49,668 MARKERS, THAT ACCOUNTED BE USED 6223 04:06:49,668 --> 04:06:51,670 FOR CHRONIC LUNG DEC, AND THE 6224 04:06:51,670 --> 04:06:54,406 SECOND PRESENTATIONS GOING TO BE 6225 04:06:54,406 --> 04:06:56,441 FOCUSED ON LOOKING INTO WHETHER 6226 04:06:56,441 --> 04:06:59,444 WE CAN USE BRONCHIAL RAVAGE 6227 04:06:59,444 --> 04:07:01,046 FLUID, PLASMA SAMPLES, THAT 6228 04:07:01,046 --> 04:07:03,314 WOULD PREDICT OR SHOW SOME 6229 04:07:03,314 --> 04:07:06,117 PATHOLOGICAL SOUTH STATES THAT 6230 04:07:06,117 --> 04:07:08,319 ARE FOULING THE LUNG AND WE WILL 6231 04:07:08,319 --> 04:07:09,387 HEAR ABOUT THESE 2 6232 04:07:09,387 --> 04:07:10,522 PRESENTATIONS, MAYBE YOU SHOULD 6233 04:07:10,522 --> 04:07:16,661 GO TO THE PRESENTATIONS 6234 04:07:16,661 --> 04:07:16,928 DIRECTLY. 6235 04:07:16,928 --> 04:07:20,565 THE FIRST PRESENTATION WILL BE 6236 04:07:20,565 --> 04:07:24,135 BY DR. MOUMITA GHOSH, ASSOCIATE 6237 04:07:24,135 --> 04:07:26,638 PROFESSOR OF MEDICINE AND IN THE 6238 04:07:26,638 --> 04:07:28,006 MEL MONEY SCIENCES AND CRITICAL 6239 04:07:28,006 --> 04:07:28,973 CARE UNIVERSITY OF COLORADO AND 6240 04:07:28,973 --> 04:07:36,381 SHE WILL TALK ABOUT DYSFUNCTION 6241 04:07:36,381 --> 04:07:38,249 OF AIRWAY BASAL PROGENITOR CELLS 6242 04:07:38,249 --> 04:07:40,985 IN YOUNGER SMOKERS WHETHER THAT 6243 04:07:40,985 --> 04:07:44,522 IS ASSOCIATED WITH AFFAIRS TEAM 6244 04:07:44,522 --> 04:07:45,090 LEADERRERRED BIOENERGETICS. 6245 04:07:45,090 --> 04:07:46,091 PLEASE GO,A HEAD. 6246 04:07:46,091 --> 04:07:46,458 >> THANK YOU. 6247 04:07:46,458 --> 04:07:47,358 THANK YOU FOR THE INTRODUCTION 6248 04:07:47,358 --> 04:07:49,728 AND I WOULD LIKE TO THANK THE 6249 04:07:49,728 --> 04:07:50,762 ORGANIZERS FOR THIS OPPORTUNITY. 6250 04:07:50,762 --> 04:07:54,866 SO I WILL TALK ABOUT DYSFUNCTION 6251 04:07:54,866 --> 04:07:57,135 AND, OPPORTUNITY, BASAL 6252 04:07:57,135 --> 04:07:58,670 PROGENITOR, AND ASSOCIATION WITH 6253 04:07:58,670 --> 04:08:01,840 BIOGENETICS AND I WILL ALSO LIKE 6254 04:08:01,840 --> 04:08:04,342 TO SHARE SOME NEW DATA TO SHOW 6255 04:08:04,342 --> 04:08:08,580 THAT HOW THIS COULD BE RELEVANT 6256 04:08:08,580 --> 04:08:11,116 FOR THE PATHOGENICITY OF EARLY 6257 04:08:11,116 --> 04:08:11,316 COPD. 6258 04:08:11,316 --> 04:08:13,885 SO AS WE ALL KNOW COPD, 6259 04:08:13,885 --> 04:08:16,788 CIGARETTE SMOKE IS THE MAJOR -- 6260 04:08:16,788 --> 04:08:18,690 IDIO LOGIC FACTOR FOR COPD, 6261 04:08:18,690 --> 04:08:20,492 OTHER FACTORS CAN DEFINITELY 6262 04:08:20,492 --> 04:08:29,234 CONTRIBUTE TO THE DEC 6263 04:08:29,234 --> 04:08:30,268 PATHOGENESIS, IT INVOLVES 2 6264 04:08:30,268 --> 04:08:33,972 PATHWAYS TO THE LUNGS, AIRWAY 6265 04:08:33,972 --> 04:08:38,710 AND ALVEOLAR, COPD IS DONE BY 6266 04:08:38,710 --> 04:08:39,277 SPIRITUAL STRUGGLESOMETRIC 6267 04:08:39,277 --> 04:08:40,111 MEASUREMENT SO IT'S IMPORTANT TO 6268 04:08:40,111 --> 04:08:42,413 VEE WHERE THIS THE AREA IT IS, 6269 04:08:42,413 --> 04:08:45,316 SPIROMICS ROUGH ATOM METIC LUNG 6270 04:08:45,316 --> 04:08:46,985 FUNCTION DECLINE THAT DEFINES 6271 04:08:46,985 --> 04:08:48,386 COPD IS COMING FROM, SO ON THE 6272 04:08:48,386 --> 04:08:50,188 LEFT WE'RE LOOKING AT THE 6273 04:08:50,188 --> 04:08:53,525 DIFFERENT GENERATION OF THE 6274 04:08:53,525 --> 04:08:56,795 AIRWAY, SO FEV1 DECLINE WHICH WE 6275 04:08:56,795 --> 04:09:00,565 SEE IN THE COPD, THAT'S COMING 6276 04:09:00,565 --> 04:09:01,833 FROM 5 TO 6 GENE GENERATION OF 6277 04:09:01,833 --> 04:09:08,006 THE AIR WAY IN THE TERMINAL 6278 04:09:08,006 --> 04:09:09,174 BRONCHIAL AND THEN, THE 6279 04:09:09,174 --> 04:09:11,910 DIFFUSION ISSUE THAT HAPPENS IN 6280 04:09:11,910 --> 04:09:14,312 THE ALVEOLAR IN THE PARRINK MA 6281 04:09:14,312 --> 04:09:20,985 THAT LEADS TO LOSS OF DLCO, IN 6282 04:09:20,985 --> 04:09:24,989 SPITE OF [INDISCERNIBLE], YOU 6283 04:09:24,989 --> 04:09:26,491 ARE LOOKING AT [INDISCERNIBLE] 6284 04:09:26,491 --> 04:09:28,827 VOLUME AND IN THE COPD WE SEE 6285 04:09:28,827 --> 04:09:31,462 THAT THESE VERY CHARACTERISTICS 6286 04:09:31,462 --> 04:09:32,497 SCOOPED FEAT AND YOU ARE THAT 6287 04:09:32,497 --> 04:09:34,499 RELATES TO THE BASICALLY SAYS 6288 04:09:34,499 --> 04:09:37,769 THAT FIXED OBSTRUCTION THAT WE 6289 04:09:37,769 --> 04:09:39,838 SEE IN COPD AND WITH THAT IT'S 6290 04:09:39,838 --> 04:09:42,907 BASICALLY THIS RATIO OF FEV 1 6291 04:09:42,907 --> 04:09:45,376 AND IF WE SEE LESS THAN 70% THAT 6292 04:09:45,376 --> 04:09:47,045 IS THE DIAGNOSTIC FEATURE OF 6293 04:09:47,045 --> 04:09:48,980 COPD, I WILL JUST COMBACK TO 6294 04:09:48,980 --> 04:09:51,182 THIS, WHY THIS IS SO IMPORTANT 6295 04:09:51,182 --> 04:09:52,584 TO UNDERSTAND THAT WHERE IT'S 6296 04:09:52,584 --> 04:09:53,351 COMING FROM. 6297 04:09:53,351 --> 04:10:00,325 MOVING ON, NEXT SLIDE, PLEASE. 6298 04:10:00,325 --> 04:10:05,196 SO, WE HEARD A LOT ABOUT THE 6299 04:10:05,196 --> 04:10:05,930 BASAL PROGENITOR CELL, SO THIS 6300 04:10:05,930 --> 04:10:07,432 IS 1 OF THE MOST CRITICAL CELLS 6301 04:10:07,432 --> 04:10:09,801 IN THE AREA BECAUSE THEY ARE 6302 04:10:09,801 --> 04:10:10,902 INVOLVED BOTH IN THE MAINTENANCE 6303 04:10:10,902 --> 04:10:13,538 AND FOR THE REPAIR OF THE 6304 04:10:13,538 --> 04:10:14,939 ALVEOLAR AFTER AN INJURY, AND 6305 04:10:14,939 --> 04:10:17,308 THESE CELLS DO THEIR FUNCTION BY 6306 04:10:17,308 --> 04:10:22,614 2 WAYS, 1 THEY ARE HIGHLY 6307 04:10:22,614 --> 04:10:23,648 SELF-RENEWING, THEY CAN MAKE A 6308 04:10:23,648 --> 04:10:26,050 COPY OF THEMSELVES AND THEY'RE 6309 04:10:26,050 --> 04:10:27,318 ALL MULTIPOTENT SO THEY CAN GIVE 6310 04:10:27,318 --> 04:10:28,987 RISE TO ALL THE DIFFERENT CELL 6311 04:10:28,987 --> 04:10:33,491 TYPES PRESENT IN THE AIR WAY. 6312 04:10:33,491 --> 04:10:34,192 NEXT SLIDE, PLEASE. 6313 04:10:34,192 --> 04:10:36,761 SO A FEW YEARS AGO, WE STARTED 6314 04:10:36,761 --> 04:10:38,296 DOING A PROJECT WHERE OUR 6315 04:10:38,296 --> 04:10:40,765 HYPOTHESIS WAS TO SEE, BECAUSE, 6316 04:10:40,765 --> 04:10:43,968 THESE CELLS ARE SO IMPORTANT FOR 6317 04:10:43,968 --> 04:10:45,370 AIRWAY, REPAIR, THAT WHETHER 6318 04:10:45,370 --> 04:10:47,305 DYSFUNCTION OF THIS BASAL 6319 04:10:47,305 --> 04:10:49,807 PROGENITORS ARE PART OF THE 6320 04:10:49,807 --> 04:10:50,875 PATHOGENICITYS OF COPD, SO FOR 6321 04:10:50,875 --> 04:10:55,613 THIS STUDY, WE TOOK ADVANTAGE OF 6322 04:10:55,613 --> 04:10:56,748 BRONCO SCOPEY STUDY THAT GOING 6323 04:10:56,748 --> 04:10:58,950 ON IN COLORADO WHERE PEOPLE WHO 6324 04:10:58,950 --> 04:11:00,885 AREAT RISK FOR LUNG CANCER, ARE 6325 04:11:00,885 --> 04:11:07,025 UNDERGOING IN THE ENDOBRONCHIAL 6326 04:11:07,025 --> 04:11:09,127 BIOPSIES TO GET TISSUES FOR 6327 04:11:09,127 --> 04:11:09,627 BIOPSIES. 6328 04:11:09,627 --> 04:11:11,663 SO WE COLLECTED THEM AND LOOK 6329 04:11:11,663 --> 04:11:13,064 FOR PROGENITOR FUNCTION AND 6330 04:11:13,064 --> 04:11:17,835 THESE ARE THE 3 THINGS WE ARE 6331 04:11:17,835 --> 04:11:18,603 LOOKING FOR. 6332 04:11:18,603 --> 04:11:20,004 HOW MUCH PRESENTED IN THE BIOPSY 6333 04:11:20,004 --> 04:11:21,539 AND THE ABILITY TO SELF-RENEW 6334 04:11:21,539 --> 04:11:24,542 AND THEN LOOKEDDA THE ABILITY TO 6335 04:11:24,542 --> 04:11:25,410 DIFFERENTIATE TO ALL DIFFERENT 6336 04:11:25,410 --> 04:11:27,578 CELL TYPES AND ON THE TOP, YOU 6337 04:11:27,578 --> 04:11:28,613 ARE LOOKING AT THE TIME FRAME 6338 04:11:28,613 --> 04:11:31,049 THAT EACH OF THESE THINGS TAKES 6339 04:11:31,049 --> 04:11:33,718 AND IN THE CULTURE FROM THE TIME 6340 04:11:33,718 --> 04:11:37,355 OF DRONKIAL COPY EMPLOY SO NEXT 6341 04:11:37,355 --> 04:11:38,056 SLIDE, PLEASE. 6342 04:11:38,056 --> 04:11:40,692 SO WHEN IT'S COMPARED, SO THESE 6343 04:11:40,692 --> 04:11:42,226 PEOPLE, WHO HAVE SO NOW WE ARE 6344 04:11:42,226 --> 04:11:47,098 LOOKING AT THESE PEOPLE WHO HAVE 6345 04:11:47,098 --> 04:11:57,442 COPD, BI SPIROMETRY. 6346 04:12:02,714 --> 04:12:04,983 -- THEY ALL WERE SEVERELY 6347 04:12:04,983 --> 04:12:07,085 IMPAIRED IN COPD COMPARED TO 6348 04:12:07,085 --> 04:12:10,021 NONCOPD. 6349 04:12:10,021 --> 04:12:10,822 NEXT SLIDE, PLEASE. 6350 04:12:10,822 --> 04:12:12,523 NOT ONLY THAT, THE OTHER 6351 04:12:12,523 --> 04:12:15,460 INTERESTING THING THAT WE FOUND 6352 04:12:15,460 --> 04:12:18,162 THAT THE PROGENITOR COUNT WHICH 6353 04:12:18,162 --> 04:12:19,998 WAS THE VERY FIRST MEASURE WE 6354 04:12:19,998 --> 04:12:22,767 DID FOR PROGENITOR FOR HOW MANY 6355 04:12:22,767 --> 04:12:24,369 PROGENITOR PRESENT, WE FOUND 6356 04:12:24,369 --> 04:12:28,339 THAT PROGENITOR COUNT IS REALLY 6357 04:12:28,339 --> 04:12:29,474 HIGHLY ASSOCIATED WITH LUNG 6358 04:12:29,474 --> 04:12:30,775 FUNCTION DECLINE AND EACH WAY WE 6359 04:12:30,775 --> 04:12:33,177 COULD LOOK AT IF WE VIEW ON 6360 04:12:33,177 --> 04:12:35,546 RATIO, AND THE MOST INTERESTING 6361 04:12:35,546 --> 04:12:40,051 THING IS THAT THESE BIOPSIES 6362 04:12:40,051 --> 04:12:42,020 WERE TAKEN FROM [INDISCERNIBLE] 6363 04:12:42,020 --> 04:12:43,788 GENERATION OF THE AIRWAY, 6364 04:12:43,788 --> 04:12:45,189 WHEREAS THE LUNG FUNCTION 6365 04:12:45,189 --> 04:12:47,658 DECLINED WHAT WE ARE LOOKING AT 6366 04:12:47,658 --> 04:12:48,693 HERE, PARTICULARLY DIFFUSION, 6367 04:12:48,693 --> 04:12:50,928 THAT'S UPON HAING MUCH MORE 6368 04:12:50,928 --> 04:12:53,598 DISTAL TO THE LUNG SO WHAT WE 6369 04:12:53,598 --> 04:12:56,100 FOUND IS THAT LARGER PROGENITOR 6370 04:12:56,100 --> 04:12:57,735 RELATES TO THE PHYSIOLOGY THAT'S 6371 04:12:57,735 --> 04:13:00,238 HAPPENING MUCH DEEPER IN THE 6372 04:13:00,238 --> 04:13:03,174 LUNG. 6373 04:13:03,174 --> 04:13:04,042 NEXT SLIDE, PLEASE. 6374 04:13:04,042 --> 04:13:05,943 ONE MORE INTERESTING FEATURE 6375 04:13:05,943 --> 04:13:08,980 FROM THIS STUDY THAT WE FOUND 6376 04:13:08,980 --> 04:13:13,918 THAT WHILE ALL THE COPD, AIR WAY 6377 04:13:13,918 --> 04:13:16,854 BIOPSIES GAVE US VERY LITTLE 6378 04:13:16,854 --> 04:13:18,256 PROGENITORS, NONCOPD HAD A MUCH 6379 04:13:18,256 --> 04:13:19,657 HIGHER SPREAD, AND SO SOME OF 6380 04:13:19,657 --> 04:13:21,926 THEM, LIKE A GROUP, WE FOUND 6381 04:13:21,926 --> 04:13:24,495 THAT THEY ARE PROGENITOR COUNT 6382 04:13:24,495 --> 04:13:26,597 SIMILAR TO COPD, SO WE WANTED TO 6383 04:13:26,597 --> 04:13:30,401 KNOW, IF WE DIVIDE THIS GROUP 6384 04:13:30,401 --> 04:13:34,172 INTO NONCOPD HIGH PROGENITOR AND 6385 04:13:34,172 --> 04:13:35,540 NONCOPD LOW PROGENITOR AND HOW 6386 04:13:35,540 --> 04:13:36,474 THAT RELATES TO THEIR LUNG 6387 04:13:36,474 --> 04:13:37,675 FUNCTION AND HOW YOU SEE THE 6388 04:13:37,675 --> 04:13:39,744 RIGHT SIDE AND BASICALLY FOUND 6389 04:13:39,744 --> 04:13:41,913 THE PEOPLE WHO HAVE BIOPSIES 6390 04:13:41,913 --> 04:13:44,315 THAT HAD LOW PROGENITORS AND 6391 04:13:44,315 --> 04:13:45,583 THEY HAVE INTERMEDIATE LUNG 6392 04:13:45,583 --> 04:13:47,652 FUNCTION AND I'M SHOWING YOU HER 6393 04:13:47,652 --> 04:13:49,153 2 DIFFERENT FEATURES AND WE 6394 04:13:49,153 --> 04:13:50,555 LOOKED AT ALL DIFFERENT 6395 04:13:50,555 --> 04:13:51,722 MEASUREMENT OF LUNG PHYSIOLOGIC 6396 04:13:51,722 --> 04:13:56,828 AND EACH CARE WE FOUND THIS, LO 6397 04:13:56,828 --> 04:13:57,795 PROGENITOR BIOPSY, THEY HAVE -- 6398 04:13:57,795 --> 04:14:00,331 THEY ARE COMING FROM THIS 6399 04:14:00,331 --> 04:14:01,132 INTERMEDIATE LUNG FUNCTION. 6400 04:14:01,132 --> 04:14:04,102 SO THAT GIVES US KIND OF AN IDEA 6401 04:14:04,102 --> 04:14:06,604 THAT THESE PEOPLE, MAYBE THAT 6402 04:14:06,604 --> 04:14:10,108 THEY ARE AT-RISK TO DEVELOP THE 6403 04:14:10,108 --> 04:14:10,441 DISEASE. 6404 04:14:10,441 --> 04:14:11,943 WE ALSO, THE NEXT THING WE DID 6405 04:14:11,943 --> 04:14:15,913 WAS WE WANTED TO UNDERSTAND WHAT 6406 04:14:15,913 --> 04:14:17,081 WAS THE MOLECULAR DIFFERENCE 6407 04:14:17,081 --> 04:14:19,016 BETWEEN THESE GROUPS OF 6408 04:14:19,016 --> 04:14:21,419 PROGENITOR CELLS. 6409 04:14:21,419 --> 04:14:22,153 NEXT SLIDE, PLEASE. 6410 04:14:22,153 --> 04:14:23,187 SO THE FIRST THING I WOULD LIKE 6411 04:14:23,187 --> 04:14:24,522 TO GET YOUR ATTENTIONOT LEFT 6412 04:14:24,522 --> 04:14:27,325 PART OF THE SLIDE, SO, HERE WE 6413 04:14:27,325 --> 04:14:30,061 ARE USING A BULK APPROACH TO 6414 04:14:30,061 --> 04:14:36,968 LOOK AT THE DIFFERENCE BETWEEN 6415 04:14:36,968 --> 04:14:38,503 NONCOPD HIGH AND PROGENITORS TO 6416 04:14:38,503 --> 04:14:41,372 SEE IF THERE ARE SOME KIND OF 6417 04:14:41,372 --> 04:14:42,607 LIKE A STABILIZED CHANGE IN THE 6418 04:14:42,607 --> 04:14:44,542 EXPRESSION OF DIFFERENT GENES IN 6419 04:14:44,542 --> 04:14:47,011 THESE 3 GROUPS AND WE FOUND THAT 6420 04:14:47,011 --> 04:14:49,747 THERE ARE 47 YEENS ONLY THAT ARE 6421 04:14:49,747 --> 04:14:50,815 SIGNIFICANTLY DIFFERENT BETWEEN 6422 04:14:50,815 --> 04:14:52,416 2 AND 3 GROUPS AND WHEN WE LOOK 6423 04:14:52,416 --> 04:14:54,252 AT THE PATHWAYS OR CELLULAR 6424 04:14:54,252 --> 04:14:58,723 FUNCTION THAT ARE IMPLICATED AND 6425 04:14:58,723 --> 04:15:00,358 REALLY WHAT CAN TURN OUT TO BE 6426 04:15:00,358 --> 04:15:02,627 MORE IMPORTANT IS THAT SIMILAR 6427 04:15:02,627 --> 04:15:03,227 GENERATEDET INCREASE IN BODYS 6428 04:15:03,227 --> 04:15:05,062 SEEM TO BE SOMETHING THAT'S KIND 6429 04:15:05,062 --> 04:15:08,533 OF CHANGING AS WE GO FROM LEFT 6430 04:15:08,533 --> 04:15:09,167 TO RIGHT. 6431 04:15:09,167 --> 04:15:11,202 SO PROMO AND INTEREST TO 6432 04:15:11,202 --> 04:15:12,803 ACTUALLY UNDERSTAND THE 6433 04:15:12,803 --> 04:15:14,672 DIFFERENCE IN BETWEEN NONCOPD 6434 04:15:14,672 --> 04:15:17,542 HIGH AND LOW PROGENITORS, WE 6435 04:15:17,542 --> 04:15:20,144 MIXED IT LIKE A TOY AN SIS 6436 04:15:20,144 --> 04:15:21,312 BETWEEN THIS GROUP WHICH IS IN 6437 04:15:21,312 --> 04:15:23,381 THE RIGHT AND NOW WE ARE SEEING 6438 04:15:23,381 --> 04:15:24,916 THAT ABOUT A HUNDRED AND 10 6439 04:15:24,916 --> 04:15:26,884 YEARS, WHICH ARE SIGNIFICANTLY 6440 04:15:26,884 --> 04:15:27,518 DIFFERENT BETWEEN THESE GROUPS 6441 04:15:27,518 --> 04:15:30,454 AND WHEN YOU LOOK AT THE 6442 04:15:30,454 --> 04:15:32,190 PATHWAYS, IT'S REALLY BECOME 6443 04:15:32,190 --> 04:15:34,392 OBVIOUS, THE DIFFERENCE BETWEEN 6444 04:15:34,392 --> 04:15:37,528 THESE 2 PROGENITORS SO THEY'RE 6445 04:15:37,528 --> 04:15:40,631 FUNCTIONALLY VERY DIFFERENT, 6446 04:15:40,631 --> 04:15:44,535 THEY ARE BIOGENETICS 6447 04:15:44,535 --> 04:15:45,369 PARTICULARLYOXIDATIVE 6448 04:15:45,369 --> 04:15:45,970 PHOSPHORYLATION, MITOCHONDRIA 6449 04:15:45,970 --> 04:15:46,637 MORPHOLOGY, SO EVERYTHING I 6450 04:15:46,637 --> 04:15:48,472 SHOWED YOU SO FAR, THEY'RE ALL 6451 04:15:48,472 --> 04:15:51,242 DONE IN A RELATEDLY OLDER 6452 04:15:51,242 --> 04:15:53,544 SMOKERS SO THEY ARE MEDIAN AGE 6453 04:15:53,544 --> 04:15:54,111 WAS ABOUT 60. 6454 04:15:54,111 --> 04:15:57,415 SO NEXT WE WANTED TO UNDERSTAND 6455 04:15:57,415 --> 04:16:00,484 WHETHER THE SAME MECHANISMS ARE 6456 04:16:00,484 --> 04:16:05,556 IN PLAY IN PEOPLE WITH 6457 04:16:05,556 --> 04:16:06,424 [INDISCERNIBLE] COPD. 6458 04:16:06,424 --> 04:16:06,891 NEXT SLIDE, PLEASE. 6459 04:16:06,891 --> 04:16:08,559 SO BEFORE I IMET TO THE DATA, I 6460 04:16:08,559 --> 04:16:12,863 WANTED TO KIND OF LIKE TALK 6461 04:16:12,863 --> 04:16:15,199 ABOUT WHO IS EARLY COPD, IT'S 6462 04:16:15,199 --> 04:16:17,702 REALLY A CONCEPT, THAT IT'S THE 6463 04:16:17,702 --> 04:16:19,470 CRITICAL TIME PERIOD WHEN 6464 04:16:19,470 --> 04:16:21,072 PATHOLOGIC MECHANISM ANDS THE 6465 04:16:21,072 --> 04:16:23,274 STRUCTURAL CHANGES ALL ARE 6466 04:16:23,274 --> 04:16:25,610 INITIATED AND THAT EVENTUALLY 6467 04:16:25,610 --> 04:16:26,510 DEVELOP INTO COPD. 6468 04:16:26,510 --> 04:16:28,512 SO THESE ARE REALLY CRITICAL 6469 04:16:28,512 --> 04:16:31,148 TIME, AND IF WE CAN UNDERSTAND 6470 04:16:31,148 --> 04:16:33,985 WHAT ARE THE PATHWAYS, MECHANISM 6471 04:16:33,985 --> 04:16:36,153 THAT ARE INVOLVED, NOW WE CAN 6472 04:16:36,153 --> 04:16:38,956 INTERCEPT THOSE, AND THEN 6473 04:16:38,956 --> 04:16:39,890 ACTUALLY DO SOMETHING OTHER THAN 6474 04:16:39,890 --> 04:16:41,259 AFTER THE DISEASE DIAGNOSIS, 6475 04:16:41,259 --> 04:16:44,395 WHEN ALL WE CAN DO IS TREAT THE 6476 04:16:44,395 --> 04:16:44,662 SYMPTOMS. 6477 04:16:44,662 --> 04:16:46,264 SO BECAUSE WE DO NOT HAVE A 6478 04:16:46,264 --> 04:16:49,033 DEFINITION, WE DO HAVE AN 6479 04:16:49,033 --> 04:16:51,068 OPERATIONAL DEFINITION, PUT 6480 04:16:51,068 --> 04:16:53,137 FORTH BY -- IN THIS PAPER, SO 6481 04:16:53,137 --> 04:16:54,171 THE VERY IMPORTANT THING IS 6482 04:16:54,171 --> 04:16:55,740 THESE ARE YOUNGER PEOPLE, SO 6483 04:16:55,740 --> 04:16:59,076 LESS THAN 50 YEARS OLD. 6484 04:16:59,076 --> 04:17:01,212 THEY HAVE 10 PACK CAREER SMOKING 6485 04:17:01,212 --> 04:17:02,613 HISTORY, AND THEY NEED TO HAVE 1 6486 04:17:02,613 --> 04:17:05,683 OF THE FOLLOWING FEATURES, POST 6487 04:17:05,683 --> 04:17:07,618 BRORCHGIAL DILATOR IS LESS THAN 6488 04:17:07,618 --> 04:17:09,520 OR LIMITED THAN NORMAL. 6489 04:17:09,520 --> 04:17:10,454 THAT'S REALLY LESS, WE DON'T 6490 04:17:10,454 --> 04:17:12,923 KNOW WHAT THE LOW LIMIT OF 6491 04:17:12,923 --> 04:17:13,958 NORMAL IS. 6492 04:17:13,958 --> 04:17:16,827 WE NEED TO HAVE RADIO LOGIC 6493 04:17:16,827 --> 04:17:18,796 ABILITIES AND REALLY TO FIND 6494 04:17:18,796 --> 04:17:26,370 EARLY COPD WE NEED TO DO A 6495 04:17:26,370 --> 04:17:29,607 LONGITUDINAL TO SEE IF THEY HAVE 6496 04:17:29,607 --> 04:17:30,675 RAPID DECLINE IN LUNG FUNCTION. 6497 04:17:30,675 --> 04:17:31,976 NOW TO GET THAT AND THE 6498 04:17:31,976 --> 04:17:34,812 KNOWLEDGE WE GAINED FROM THE 6499 04:17:34,812 --> 04:17:35,780 OLDER PEOPLE, OR SIMILAR THINGS 6500 04:17:35,780 --> 04:17:40,751 HAPPENING IN THE YOUNGER PEOPLE. 6501 04:17:40,751 --> 04:17:44,255 SO WE TOOK ADVANTAGE WITH THE 6502 04:17:44,255 --> 04:17:46,524 [INDISCERNIBLE] AND WE GOT CELLS 6503 04:17:46,524 --> 04:17:49,560 FROM OUR LOCAL [INDISCERNIBLE] 6504 04:17:49,560 --> 04:17:50,461 FROM BIOREPOSITORY WHERE THE 6505 04:17:50,461 --> 04:17:53,497 BIGGEST THING THAT TO LOOK AT 6506 04:17:53,497 --> 04:17:55,666 HERE THAT THE AGE GROUP OF THESE 6507 04:17:55,666 --> 04:17:58,436 PEOPLE ARE THEY'RE ALL BELOW 50 6508 04:17:58,436 --> 04:18:00,137 AND WE ONLY KNOW THAT THEY DID 6509 04:18:00,137 --> 04:18:02,206 NOT HAVE ANY KNOWN LUNG DISEASE. 6510 04:18:02,206 --> 04:18:04,108 SO FIRST WE GROW BASAL 6511 04:18:04,108 --> 04:18:04,909 PROGENITOR CLONED FROM THEM AND 6512 04:18:04,909 --> 04:18:09,080 THEN NEXT THING WE LOOKED AT IS 6513 04:18:09,080 --> 04:18:10,981 THE DIFFERENCE IN SELF-RENEWAL. 6514 04:18:10,981 --> 04:18:13,284 THE FIRST WHAT WE SAW THAT 6515 04:18:13,284 --> 04:18:15,619 NONSMOKER HAS MUCH HIGHER 6516 04:18:15,619 --> 04:18:17,588 SELF-RENEWAL, SIGNIFICANTLY 6517 04:18:17,588 --> 04:18:19,857 HIGHER SELF-RENEWAL, THAN 6518 04:18:19,857 --> 04:18:21,325 SMOKERS, BUT MORE IMPORTANT PART 6519 04:18:21,325 --> 04:18:24,295 WAS THAT WE FOUND JUST LIKE OUR 6520 04:18:24,295 --> 04:18:26,831 OLDER COHORT, THAT IN SMOKER HAS 6521 04:18:26,831 --> 04:18:28,999 A MUCH BIGGER SPREAD IN THEIR 6522 04:18:28,999 --> 04:18:29,400 SELF-RENEWAL. 6523 04:18:29,400 --> 04:18:31,736 SO WE WANTED TO DIVIDE THIS 6524 04:18:31,736 --> 04:18:38,275 GROUP INTO 2 GROUPS AND THAT 6525 04:18:38,275 --> 04:18:39,377 YOUNGER SMOKERS WITH LOW 6526 04:18:39,377 --> 04:18:41,412 SELF-RENEWAL AND WHEN YOU LOOK 6527 04:18:41,412 --> 04:18:42,613 AT THE DIFFERENTIATION IN THE 6528 04:18:42,613 --> 04:18:45,616 CULTURE WE FOUND THAT THE 6529 04:18:45,616 --> 04:18:47,651 DIFFERENTIATE THE FIND, THEY 6530 04:18:47,651 --> 04:18:50,054 MAKE A NORMAL MUCUS EPITHELIUM, 6531 04:18:50,054 --> 04:18:52,289 IN CONTRAST ISSUES THE LOW GROUP 6532 04:18:52,289 --> 04:18:55,559 MAKES A FLAT SCORE EPITHELIUM 6533 04:18:55,559 --> 04:18:56,827 AND THE EXPRESS [INDISCERNIBLE] 6534 04:18:56,827 --> 04:19:00,464 AND THEY BASICALLY FELL TO FULLY 6535 04:19:00,464 --> 04:19:01,532 DIFFERENTIATE BUT THEY DON'T 6536 04:19:01,532 --> 04:19:02,600 CRASH OR BURN, THEY JUST 6537 04:19:02,600 --> 04:19:03,934 BASICALLY AT A THERE. 6538 04:19:03,934 --> 04:19:05,970 THEY JUST FORGOT HOW TO 6539 04:19:05,970 --> 04:19:13,043 DIFFERENTIATE. 6540 04:19:13,043 --> 04:19:13,711 NEXT SLIDE, PLEASE. 6541 04:19:13,711 --> 04:19:15,479 SO TO GO BACK TO THE MECHANISM 6542 04:19:15,479 --> 04:19:16,680 WE SAW THE PROGENITORS SO WE 6543 04:19:16,680 --> 04:19:18,883 WANT TO LEARN THAT THERE IS A 6544 04:19:18,883 --> 04:19:25,623 BIG DIFFERENCE IN METABOLISM 6545 04:19:25,623 --> 04:19:28,359 FROM NONCOPD, SO WE DIVIDE THEM 6546 04:19:28,359 --> 04:19:30,294 INTO HIGHER, LOW, AND I GIVE 6547 04:19:30,294 --> 04:19:31,495 THOSE STUDIES PATIENT ID NUMBERS 6548 04:19:31,495 --> 04:19:33,130 HERE, SO JUST TO MAKE SURE, LIKE 6549 04:19:33,130 --> 04:19:42,573 SO TO MAKE IT CLEAR HOW 6550 04:19:42,573 --> 04:19:44,775 DIFFERENT THEY ARE, SO TO CREATE 6551 04:19:44,775 --> 04:19:46,243 A MORE RELATABLE SITUATION, WE 6552 04:19:46,243 --> 04:19:52,850 ALSO TREAT THESE CELLS WITH AIR 6553 04:19:52,850 --> 04:19:54,385 OR THE TRACT, THE MOST IMPORTANT 6554 04:19:54,385 --> 04:19:57,755 THING WE FOUND IN THE PRINCIPAL 6555 04:19:57,755 --> 04:20:00,491 ANALYSIS WAS WE FOWBD THAT THE 6556 04:20:00,491 --> 04:20:02,326 PROGENITORS BETWEEN 6557 04:20:02,326 --> 04:20:03,127 SELF-RENEWALS ARE BIOLOGICALLY 6558 04:20:03,127 --> 04:20:06,297 MORE DIFFERENT THAN CIGARETTE 6559 04:20:06,297 --> 04:20:08,532 SMOKE EXTRACT TREATMENT. 6560 04:20:08,532 --> 04:20:10,601 WE EXPECT IT DIFFERENT BUT IF 6561 04:20:10,601 --> 04:20:12,303 YOU LOOK AT THEY'RE ACTUALLY A 6562 04:20:12,303 --> 04:20:14,438 GROUPING BASED ON SELF-RENEWAL 6563 04:20:14,438 --> 04:20:15,573 RATHER THAN CIGARETTE SMOKE 6564 04:20:15,573 --> 04:20:16,040 EXTRACT TREATMENT. 6565 04:20:16,040 --> 04:20:17,708 AND WHEN YOU LOOK AT THESE IN 6566 04:20:17,708 --> 04:20:21,378 THE RIGHT MOST PANEL, WE'RE 6567 04:20:21,378 --> 04:20:25,082 LOOKING THE 15 MOST 6568 04:20:25,082 --> 04:20:25,583 SIGNIFICANTLY DIFFERENT 6569 04:20:25,583 --> 04:20:27,952 METABOLITES THAT ARE -- IF WE 6570 04:20:27,952 --> 04:20:29,153 LOOK AT, THIS WAS REALLY 6571 04:20:29,153 --> 04:20:33,057 SURPRISING THAT WE FOUND THAT 6572 04:20:33,057 --> 04:20:35,726 PROGENITOR WITH COMPOUND, ALL 6573 04:20:35,726 --> 04:20:37,094 HIGH METABOLITES, UTP, THEY ARE 6574 04:20:37,094 --> 04:20:40,030 EVERYTHING THAT GOES WITH HIGH 6575 04:20:40,030 --> 04:20:42,833 ENERGY THEY ARE PRESENT IN THE 6576 04:20:42,833 --> 04:20:45,069 LOW SELF-RENEW, RATHER THAN HIGH 6577 04:20:45,069 --> 04:20:47,338 SELF-RENEWAL GROUP EMPLOY SO 6578 04:20:47,338 --> 04:20:48,472 METABOLOMICS GIVE US THAT 6579 04:20:48,472 --> 04:20:49,540 [INDISCERNIBLE] WHAT IS 6580 04:20:49,540 --> 04:20:50,841 PRESENTING THE CELLS, SO WE 6581 04:20:50,841 --> 04:20:55,012 WANTED TO DO A MORE OF A KINETIC 6582 04:20:55,012 --> 04:20:57,915 ANALYSIS, NEXT, SLIDE, PLEASE. 6583 04:20:57,915 --> 04:21:01,085 SO WE USE THIS PROGENITOR CELLS 6584 04:21:01,085 --> 04:21:02,953 AND SEA HORSE STUDY, AND JUST AT 6585 04:21:02,953 --> 04:21:06,257 THE LEFT, YOU ARE LOOKING AT 6586 04:21:06,257 --> 04:21:08,359 JUST OVERALL, YOU KNOW 6587 04:21:08,359 --> 04:21:12,496 REPRESENTATIVE PICTURE OF HOW 6588 04:21:12,496 --> 04:21:13,230 THE RESPIRATION LOOKS LIKE AND 6589 04:21:13,230 --> 04:21:17,968 AS YOU CAN SEE THERE IS A 6590 04:21:17,968 --> 04:21:20,170 SIGNIFICANTLY HIGHER MAXIMAL 6591 04:21:20,170 --> 04:21:21,472 INSPIRATION AND THE LOW 6592 04:21:21,472 --> 04:21:22,306 SELF-GROUP COMPARED TO HIGH. 6593 04:21:22,306 --> 04:21:28,612 WHEN YOU LOOK AT EXTRA CELLULAR 6594 04:21:28,612 --> 04:21:30,748 [INDISCERNIBLE] HE FOUND THE 6595 04:21:30,748 --> 04:21:32,616 SAME THING SO THESE CELLS ARE 6596 04:21:32,616 --> 04:21:34,318 FIRING IN THE ALL DIRECTION TO 6597 04:21:34,318 --> 04:21:35,753 MAKE MORE AND MORE ENERGY AND WE 6598 04:21:35,753 --> 04:21:39,089 ALSO FOUND THAT SELF-RENEWAL IS 6599 04:21:39,089 --> 04:21:42,726 NEGATIVELY CORRELATED WITH BOTH 6600 04:21:42,726 --> 04:21:49,099 OXYGEN COMSUMPTION OR FOR DPLIK 6601 04:21:49,099 --> 04:21:51,302 O LYTIC FLUX. 6602 04:21:51,302 --> 04:21:53,137 SO THE OTHER THING IS THE 6603 04:21:53,137 --> 04:22:02,846 MORPHOLOGY, SO WE USE DIFFERENT 6604 04:22:02,846 --> 04:22:06,016 KINDINGS BOGHT ARE SIGNIFICANTLY 6605 04:22:06,016 --> 04:22:07,751 HIGHER IN LOW SELF-RENEWING 6606 04:22:07,751 --> 04:22:09,587 GROUP COMPARED TO HIGH 6607 04:22:09,587 --> 04:22:13,891 SELF-RENEWING GROUP. 6608 04:22:13,891 --> 04:22:14,792 NEXT SLIDE, PLEASE. 6609 04:22:14,792 --> 04:22:16,760 WE ALSO DID ELECTRON MICROSCOPY 6610 04:22:16,760 --> 04:22:18,429 TO BED THAT LIKE IN A REALLY 6611 04:22:18,429 --> 04:22:20,130 GETTING TO THE STRUCTURE OF 6612 04:22:20,130 --> 04:22:23,133 MITOCHONDRIA, AND WE FOUND THAT 6613 04:22:23,133 --> 04:22:25,235 LOW SELF-RENEWAL -- RENEWAL 6614 04:22:25,235 --> 04:22:27,204 PROGENITORS HAS THIS ELONGATED 6615 04:22:27,204 --> 04:22:29,907 FEATURE WHICH GOES WITH THEIR 6616 04:22:29,907 --> 04:22:31,542 FUSION, SO BASICALLY THESE MIOF 6617 04:22:31,542 --> 04:22:32,710 THE ARE FUSING WITH EACH OTHER 6618 04:22:32,710 --> 04:22:36,113 AND MAKING THIS LONG ELONGATED 6619 04:22:36,113 --> 04:22:38,949 STRUCTURE. 6620 04:22:38,949 --> 04:22:39,950 NEXT SLIDE, PLEASE. 6621 04:22:39,950 --> 04:22:40,784 SO BASICALLY TO SUMMARIZE WHAT 6622 04:22:40,784 --> 04:22:42,620 WE FOUND IS THAT PROGENITOR 6623 04:22:42,620 --> 04:22:45,122 DISCUSSION HAPPENS IN A SUBSET 6624 04:22:45,122 --> 04:22:46,423 OF YOUNGER SMOKERS AND 6625 04:22:46,423 --> 04:22:52,296 SURPRISINGLY, THIS LOW 6626 04:22:52,296 --> 04:22:52,830 SELF-RENEWING PROGENITORS 6627 04:22:52,830 --> 04:22:58,435 REQUIRE MORE ENERGY AND IT LEAS 6628 04:22:58,435 --> 04:23:04,141 TO ELONGATED STRUCTURE WHICH IS 6629 04:23:04,141 --> 04:23:06,677 PROBABLY CLEARS FOR THE ENERGY 6630 04:23:06,677 --> 04:23:07,211 REQUIREMENT. 6631 04:23:07,211 --> 04:23:07,578 NEXT SLIDE. 6632 04:23:07,578 --> 04:23:08,779 SO THE GAP HERE IS TO TRY TO 6633 04:23:08,779 --> 04:23:10,047 UNDERSTAND WHAT ARE THE 6634 04:23:10,047 --> 04:23:15,386 MECHANISM THAT DRIVING THIS? 6635 04:23:15,386 --> 04:23:16,687 AND MORE IMPORTANTLY HOW ARE 6636 04:23:16,687 --> 04:23:23,293 THAT I RELATED TO COPD 6637 04:23:23,293 --> 04:23:23,794 PATHOGENESIS. 6638 04:23:23,794 --> 04:23:26,296 THAT LEADS TO OUR ONGOING STUDY 6639 04:23:26,296 --> 04:23:28,799 WHERE OUR TARGETED GROUP IS 6640 04:23:28,799 --> 04:23:30,801 30-50 YEARS AND WHERE WE ARE 6641 04:23:30,801 --> 04:23:32,069 ENROLLING SMOKERS WITHOUT ANY 6642 04:23:32,069 --> 04:23:35,105 KNOWN LUNG DISEASE AND THEN 6643 04:23:35,105 --> 04:23:37,207 HAVING CONTROL NEVER SMOKERS AND 6644 04:23:37,207 --> 04:23:40,744 COPD SMOKERS, WE ARE COLLECTING 6645 04:23:40,744 --> 04:23:42,780 THEIR ENDOBRONCHIAL BIOPSY AND 6646 04:23:42,780 --> 04:23:44,815 NAISAL BRUSHINGS TO MAKE IT MORE 6647 04:23:44,815 --> 04:23:46,016 REAL LIFE SITUATION SO WE DON'T 6648 04:23:46,016 --> 04:23:47,618 HAVE TO BRONCH EVERYONE AND THIS 6649 04:23:47,618 --> 04:23:49,753 YEAR WE ARE LOOKING AT 6650 04:23:49,753 --> 04:23:52,189 PROGENITOR AND MEASURES FOR 6651 04:23:52,189 --> 04:23:52,656 COUNT, SELF-RENEWAL 6652 04:23:52,656 --> 04:23:53,490 IVRENTIATION, THIS WE ARE ALSO 6653 04:23:53,490 --> 04:23:58,128 THE PEOPLE ARE GOING THROUGH A 6654 04:23:58,128 --> 04:24:04,234 VERY COMPREHENSIVE OF CLINICAL 6655 04:24:04,234 --> 04:24:05,502 VISION, LUNG FUNCTION, AND THEN 6656 04:24:05,502 --> 04:24:07,104 THESE PEOPLE ARE GOING TO COME 6657 04:24:07,104 --> 04:24:08,505 BACK IN EACH YEAR, AND THEN 6658 04:24:08,505 --> 04:24:13,911 WHERE WE ARE GOING TO DO THEIR 6659 04:24:13,911 --> 04:24:15,379 BRONCHIAL, PULMONARY FUNCTION 6660 04:24:15,379 --> 04:24:17,448 AND ALSO COLLECT NAISAL 6661 04:24:17,448 --> 04:24:20,451 BRUSHINGS, AND WE WILL ONLY DO 6662 04:24:20,451 --> 04:24:22,753 BRONCHOSCOPY IF THERE IS AN 6663 04:24:22,753 --> 04:24:23,587 UNEXPECTED DECLINE OF LUNG 6664 04:24:23,587 --> 04:24:23,921 FUNCTION. 6665 04:24:23,921 --> 04:24:25,889 SO THIS STUDY IS ALREADY 6666 04:24:25,889 --> 04:24:27,391 RECRUITING PATIENTS AND THEN 6667 04:24:27,391 --> 04:24:28,892 HOPEFULLY WE WILL UNDERSTAND THE 6668 04:24:28,892 --> 04:24:30,394 IMPORTANCE OF THE BIOLOGY THAT 6669 04:24:30,394 --> 04:24:32,596 WE LEARN FROM OLDER COHORT, HOW 6670 04:24:32,596 --> 04:24:37,301 THAT IS RELATED TO EARLY COPD. 6671 04:24:37,301 --> 04:24:38,001 NEXT SLIDE, PLEASE. 6672 04:24:38,001 --> 04:24:42,005 AND I WOULD JUST RIKE -- LIKE O 6673 04:24:42,005 --> 04:24:44,742 THANK THE PEOPLE WHO PARTICIPATE 6674 04:24:44,742 --> 04:24:46,410 INDEED THE WORK, MY COLLABORATOR 6675 04:24:46,410 --> 04:24:46,744 ANDS FUNDING. 6676 04:24:46,744 --> 04:24:49,446 THANK YOU IF ARE YOUR ATTENTION. 6677 04:24:49,446 --> 04:24:50,681 THANK YOU MOUMITA FOR A 6678 04:24:50,681 --> 04:24:51,782 WONDERFUL TALK. 6679 04:24:51,782 --> 04:24:54,084 SO LARGE AIRWAYS BEING AFFECTED 6680 04:24:54,084 --> 04:24:57,321 SOMEHOW BY WHAT'S HAPPENING AT 6681 04:24:57,321 --> 04:24:58,589 THE LOWER AIRWAY, WITH 6682 04:24:58,589 --> 04:25:01,225 SIGNATURESIET SMOKE, THE LOWER 6683 04:25:01,225 --> 04:25:01,825 AIRWAY DISCIPLINARY STROID 6684 04:25:01,825 --> 04:25:03,293 SOMEHOW EMPLOY SO THANK YOU. 6685 04:25:03,293 --> 04:25:09,433 THE NEXT TALK WILL BE BY 6686 04:25:09,433 --> 04:25:14,938 DR. HERBERT SCHILLER, DIRECTOR 6687 04:25:14,938 --> 04:25:18,108 PRECISION REGENERATIVE MEDICINE 6688 04:25:18,108 --> 04:25:20,844 IN MUNICH AS WELL, HERBERT GO 6689 04:25:20,844 --> 04:25:23,981 ASHES HEAD. 6690 04:25:23,981 --> 04:25:24,348 >> THANK YOU. 6691 04:25:24,348 --> 04:25:26,750 FIRST OF ALL THANKS A LOT FOR 6692 04:25:26,750 --> 04:25:37,294 INVITATION THIS HAS BEEN REALLY 6693 04:26:01,652 --> 04:26:02,753 -- IT'S REGULATED. 6694 04:26:02,753 --> 04:26:04,454 SO RESILIENCE COULD BE DEFINED 6695 04:26:04,454 --> 04:26:06,523 AS THE ABILITY TO GO BACK AND 6696 04:26:06,523 --> 04:26:07,658 FORTH BETWEEN THESE INJURYITATES 6697 04:26:07,658 --> 04:26:18,202 HERE AND THE HEALTHY AND MY LAB 6698 04:26:20,871 --> 04:26:22,673 TRIES TO USE SINGLE SEARCH 6699 04:26:22,673 --> 04:26:27,411 ECONOMICS TO DISSECT THE 6700 04:26:27,411 --> 04:26:28,579 CELLULAR CIRCUITS THAT DEFINE 6701 04:26:28,579 --> 04:26:32,249 SIGNALS PATHWAYS AND MECHANISMS 6702 04:26:32,249 --> 04:26:33,817 THAT DEFINE THESE BARRIERS 6703 04:26:33,817 --> 04:26:34,852 BETWEEN DIFFERENT TISSUE SPACE, 6704 04:26:34,852 --> 04:26:42,659 SO HOW CAN WE GET LOCKED INTO AN 6705 04:26:42,659 --> 04:26:43,594 IRREVERSIBLE CONFIGURURATION HOW 6706 04:26:43,594 --> 04:26:45,095 CAN WE REPROGRAM THAT AND ALSO 6707 04:26:45,095 --> 04:26:46,496 FOR PURPOSES OF THIS TALK, I 6708 04:26:46,496 --> 04:26:47,898 WANT TO STRESS IT'S IMPORTANT IF 6709 04:26:47,898 --> 04:26:53,070 YOU COULD GO NEXT, PLEASE, THAT 6710 04:26:53,070 --> 04:26:55,439 IT'S VERY IMPORTANT CLINICALLY 6711 04:26:55,439 --> 04:26:58,342 TO READ OUT THESE TISSUE STATES 6712 04:26:58,342 --> 04:27:01,612 IDEALLY PERIPHERY FROM THE 6713 04:27:01,612 --> 04:27:02,279 BLOOD. 6714 04:27:02,279 --> 04:27:02,746 NEXT. 6715 04:27:02,746 --> 04:27:04,248 SO HOW CAN WE UNDERSTAND HOW 6716 04:27:04,248 --> 04:27:08,185 DIFFERENT TISSUE STATES ARE 6717 04:27:08,185 --> 04:27:11,588 REPRESENTED IN THIS SECRETED 6718 04:27:11,588 --> 04:27:13,056 PROTEINS FOR INSTANCE, IN 6719 04:27:13,056 --> 04:27:15,926 GENERAL MY LAB TRIES TO SCALE 6720 04:27:15,926 --> 04:27:16,927 EXPERIMENTAL PROTURBATIONS 6721 04:27:16,927 --> 04:27:18,762 MOSTLY IN PRESUGZ CUT LUNG 6722 04:27:18,762 --> 04:27:20,063 SLICES TO SIGNIFY SECTIONAL 6723 04:27:20,063 --> 04:27:21,598 ANALYSIS MECHANISMS USING SINGLE 6724 04:27:21,598 --> 04:27:22,199 SEGENOME MODEL CITIZENNICS TO 6725 04:27:22,199 --> 04:27:23,400 READ OUT THE TRANSCRIPTIONAL 6726 04:27:23,400 --> 04:27:29,907 STATES BUT WE CAN ALSO CORRELATE 6727 04:27:29,907 --> 04:27:34,978 SUPERINATENT [INDISCERNIBLE] PCS 6728 04:27:34,978 --> 04:27:35,545 AND SECRET OMICS. 6729 04:27:35,545 --> 04:27:39,917 SO WHAT WE STARTED TO DO WAS 6730 04:27:39,917 --> 04:27:41,985 TAKE DIFFERENT TISSUES CAPTURE 6731 04:27:41,985 --> 04:27:45,389 THEM EXVIVO AND DO ALL TYPE OF 6732 04:27:45,389 --> 04:27:46,757 GENETIC AND PUSH TURB EGGS AND 6733 04:27:46,757 --> 04:27:48,425 AS I SAID WE COULD LEARN 6734 04:27:48,425 --> 04:27:50,527 SOMETHING ABOUT THE BIOMARKERS 6735 04:27:50,527 --> 04:27:52,930 AND DIVISION WE HOPE TO USE THE 6736 04:27:52,930 --> 04:27:58,435 MODELS SO THAT THE NEXT PHASE OF 6737 04:27:58,435 --> 04:28:02,906 HUMAN CELL ATLAS IS PROBABLY 6738 04:28:02,906 --> 04:28:04,007 BASED ON ALL THESE DATA SETS 6739 04:28:04,007 --> 04:28:05,876 THAT CAN BE USED TO TRAIN 6740 04:28:05,876 --> 04:28:07,144 FOUNDATIONAL MODELS AND LEARN 6741 04:28:07,144 --> 04:28:11,648 ABOUT CAUSAL CELL AND TISSUE 6742 04:28:11,648 --> 04:28:13,951 BIOLOGY SO WE WANT TO PREDICT 6743 04:28:13,951 --> 04:28:15,018 DIFFERENT COMBINATIONS OF 6744 04:28:15,018 --> 04:28:16,653 PROTURBATIONS THAT CAN INDUCE 6745 04:28:16,653 --> 04:28:22,993 CERTAIN TISSUE STATES. 6746 04:28:22,993 --> 04:28:23,193 NEXT. 6747 04:28:23,193 --> 04:28:26,697 AND OF COURSE THIS IS AN ICS 6748 04:28:26,697 --> 04:28:27,431 VIVO MODEL, EXPERIMENTAL MODEL 6749 04:28:27,431 --> 04:28:30,133 SO WE LOOK AT THE PATIENT AND WE 6750 04:28:30,133 --> 04:28:32,302 TRY TO UNDERSTAND INSITU IN 6751 04:28:32,302 --> 04:28:33,136 PATIENT TISSUES WHAT WHAT 6752 04:28:33,136 --> 04:28:34,271 HAPPENS IN THE EARLY STAGE OF 6753 04:28:34,271 --> 04:28:36,673 THE DISEASE AND EVENTUALLY WE 6754 04:28:36,673 --> 04:28:39,977 NEED TO DESIGN BETTER STUDIES 6755 04:28:39,977 --> 04:28:44,881 WHERE WE CAN MAYBE FOLLOW 6756 04:28:44,881 --> 04:28:45,816 LONGITUDINALLY AND FOLLOW 6757 04:28:45,816 --> 04:28:49,686 THERAPEUTIC TREMES TO SEE HOW 6758 04:28:49,686 --> 04:28:50,354 THESE CELLULAR SECOND QUARTER 6759 04:28:50,354 --> 04:28:58,161 UTRS IN THE LUNG ARE RESPONDING. 6760 04:28:58,161 --> 04:28:58,528 NEXT. 6761 04:28:58,528 --> 04:29:00,731 SO 1 OF THE APPROACHES WE USE IN 6762 04:29:00,731 --> 04:29:04,534 COLLABORATION WITH THE 6763 04:29:04,534 --> 04:29:06,703 [INDISCERNIBLE] IN BELGIUM AND 6764 04:29:06,703 --> 04:29:07,771 [INDISCERNIBLE] DID A POST DOC 6765 04:29:07,771 --> 04:29:09,740 IN MY LAB WHERE THEY ARE REAL 6766 04:29:09,740 --> 04:29:12,509 SPECIALISTS IN DOING THE 6767 04:29:12,509 --> 04:29:13,443 MICROSTAGING ON IPS LUNG PLANTS 6768 04:29:13,443 --> 04:29:16,079 SO YOU CAN SEE THESE CORES THAT 6769 04:29:16,079 --> 04:29:17,280 WERE DRILLED FROM THESE FROZEN 6770 04:29:17,280 --> 04:29:20,150 LUNGS THAT WERE AIR INFLATED 6771 04:29:20,150 --> 04:29:23,086 OVER LIQUID NITROGEN AND THEN 6772 04:29:23,086 --> 04:29:28,325 THE MICRO CT SCAN CAN GOVERN A 6773 04:29:28,325 --> 04:29:29,459 VERY PRECISE QUANTIFICATION OF 6774 04:29:29,459 --> 04:29:30,961 THE TISSUE MODELING SO NEXT, SO 6775 04:29:30,961 --> 04:29:35,032 IT TOOK THE LUNGS AND 6 COURSE 6776 04:29:35,032 --> 04:29:36,633 PER LUNGS AND CONTROL LUNGS WITH 6777 04:29:36,633 --> 04:29:39,836 SEVERAL COURSE PER LUNG, SO THAT 6778 04:29:39,836 --> 04:29:42,973 WE ANALYZE A TOTAL OF 164 OF 6779 04:29:42,973 --> 04:29:48,211 THESE CORES. 6780 04:29:48,211 --> 04:29:48,445 NEXT. 6781 04:29:48,445 --> 04:29:51,081 AND SO WE DO THIS PROGRESSION, 6782 04:29:51,081 --> 04:29:52,516 SO WHAT I WANT TO EMPHASIZE HERE 6783 04:29:52,516 --> 04:29:55,685 IS YOU CAN APPRECIATE IN THE 6784 04:29:55,685 --> 04:29:57,554 GRAPHOT LEFT, THE SURFACE 6785 04:29:57,554 --> 04:30:00,924 DENSITY VERSUS THE TISSUE 6786 04:30:00,924 --> 04:30:05,962 PERCENTAGE, SO, BASICALLY THE 6787 04:30:05,962 --> 04:30:08,131 ALVEOLAR SURFACE AREA IS GOING 6788 04:30:08,131 --> 04:30:09,633 DOWN WITH DISEASE PROGRESSION 6789 04:30:09,633 --> 04:30:11,001 WHILE THE PERCENTAGE OF TISSUE 6790 04:30:11,001 --> 04:30:14,304 MASS IS GOING UP AND YOU SEE 6791 04:30:14,304 --> 04:30:16,606 THIS GRADUAL CONTINUATION OF THE 6792 04:30:16,606 --> 04:30:18,809 TISSUE REMODELING THAT -- AND 6793 04:30:18,809 --> 04:30:22,345 ALL THESE SAMPLES WERE SEQUENCED 6794 04:30:22,345 --> 04:30:29,186 BY THE NUCLEI R, INA SEQUENCING 6795 04:30:29,186 --> 04:30:29,719 EMPLOY NEXT. 6796 04:30:29,719 --> 04:30:31,488 OKAY SO THAT'S ALL THE CELL 6797 04:30:31,488 --> 04:30:31,788 TYPES, NEXT. 6798 04:30:31,788 --> 04:30:34,057 AND AS AN EXAMPLE WE CAN GO INTO 6799 04:30:34,057 --> 04:30:37,461 THE EPITHELIAL CELL TYPES, YOU 6800 04:30:37,461 --> 04:30:39,563 CAN SEE THE AT2 CELLS IN ORANGE 6801 04:30:39,563 --> 04:30:42,399 AND 1, AND THE 1S IN BLUE HERE 6802 04:30:42,399 --> 04:30:42,766 AND NEXT. 6803 04:30:42,766 --> 04:30:46,603 WHAT WE CAN DO IS WE CAN 6804 04:30:46,603 --> 04:30:48,338 SUBCLUSTER INTO DIFFERENT 6805 04:30:48,338 --> 04:30:50,140 TRANSCRIPTIONAL SUBSTATES OF 6806 04:30:50,140 --> 04:30:52,409 THESE CELL TYPE IDENTITIES AND 6807 04:30:52,409 --> 04:30:58,915 IF WE GO TO THE NEXT SLIDE THESE 6808 04:30:58,915 --> 04:31:01,651 RED AND BLUE COLORS INDICATEOT 6809 04:31:01,651 --> 04:31:04,154 LEFT SIDE, YOU CAN ALSO CLICK 6810 04:31:04,154 --> 04:31:06,123 ONCE MORE, ON THE LEFT SIDE, 6811 04:31:06,123 --> 04:31:07,757 WHERE THE CERTAIN NEIGHBORHOOD 6812 04:31:07,757 --> 04:31:10,594 OF CELLS IS ENRICHED IN DISEASE 6813 04:31:10,594 --> 04:31:11,895 OR IN THE HEALTHY CONTROLS AND 6814 04:31:11,895 --> 04:31:14,397 ON THE RIGHT SIDE, YOU CAN SEE 6815 04:31:14,397 --> 04:31:15,932 WHETHER IT'S THE CELLULAR 6816 04:31:15,932 --> 04:31:18,435 NEIGHBORHOOD IS ENRICHED IN 6817 04:31:18,435 --> 04:31:19,035 ENSTAGE DISEASE VERSUS EARLY 6818 04:31:19,035 --> 04:31:20,203 STAGE DISEASE AND YOU IT'S NICE 6819 04:31:20,203 --> 04:31:23,073 TO SEE THAT SINCE HERE IN THE 82 6820 04:31:23,073 --> 04:31:24,808 CELLS WE CAN IDENTIFY SUBSTATES 6821 04:31:24,808 --> 04:31:26,543 OF 82S THAT ARE VERY MUCH 6822 04:31:26,543 --> 04:31:27,677 ENRICHED IN VERY EARLY DISEASE 6823 04:31:27,677 --> 04:31:32,916 OR IN THE GRAY COLOR THOSE WOULD 6824 04:31:32,916 --> 04:31:34,885 ALL FIND IRRESPECTIVE OF THE 6825 04:31:34,885 --> 04:31:36,019 TISSUE DEGREE MODELS. 6826 04:31:36,019 --> 04:31:37,954 BUT THEY'RE QUITE DISTINCT FROM 6827 04:31:37,954 --> 04:31:42,125 NORMAL HEALTHY 82 CELLS. 6828 04:31:42,125 --> 04:31:42,359 NEXT. 6829 04:31:42,359 --> 04:31:44,895 SO WHAT WE DO NOW FOR ALL THE 6830 04:31:44,895 --> 04:31:48,999 DIFFERENT LINEAGES, WE THINK 6831 04:31:48,999 --> 04:31:49,633 THESE SUBCLASSES, SUBIDENTITY 6832 04:31:49,633 --> 04:31:53,303 CELL STATE ANDS CORRELATE THEM 6833 04:31:53,303 --> 04:31:55,705 WITH THIS CONTINUOUS DISEASE 6834 04:31:55,705 --> 04:32:00,911 PROGRESSION, FROM THE MICROCT 6835 04:32:00,911 --> 04:32:01,711 STAGING. 6836 04:32:01,711 --> 04:32:05,048 [MULTIPLE VOICES SPEAKING ] 6837 04:32:05,048 --> 04:32:07,450 >> NEXT, IF YOU COULD CLICK 6838 04:32:07,450 --> 04:32:08,151 IMEAN. 6839 04:32:08,151 --> 04:32:11,788 UNFORTUNATELY LOTS OF 6840 04:32:11,788 --> 04:32:14,424 ANIMATIONS. 6841 04:32:14,424 --> 04:32:15,192 NEXT. 6842 04:32:15,192 --> 04:32:20,130 SO ON THE X-AXIS, THE HEALTHY 6843 04:32:20,130 --> 04:32:22,132 DEC, AND THE Y-AXIS DISEASE 6844 04:32:22,132 --> 04:32:22,399 SEVERITY. 6845 04:32:22,399 --> 04:32:26,836 SO IN THE LOWER LEFT RECK TANGLE 6846 04:32:26,836 --> 04:32:31,474 YOU HAVE CELL STATES THAT OCCUR 6847 04:32:31,474 --> 04:32:34,578 IN OUR HEALTHY AND THE 6848 04:32:34,578 --> 04:32:38,181 EPITHELIAL STATES ARE IN BLUE, 6849 04:32:38,181 --> 04:32:43,753 AND YOU CAN CLICK 3 TIMES MORE. 6850 04:32:43,753 --> 04:32:46,289 SO THEN OF COURSE, WE CAN SEE 6851 04:32:46,289 --> 04:32:48,124 THE CELLS CO OCCUR AND VERY 6852 04:32:48,124 --> 04:32:50,293 SEVERE DISEASE, OR IN VERY MILD 6853 04:32:50,293 --> 04:32:53,263 OR EARLY DISEASE AND THEN ALSO 6854 04:32:53,263 --> 04:32:57,100 SOME CELLITATES ARE PRESENT 6855 04:32:57,100 --> 04:32:59,636 THROUGHOUT INCLUDING THE 6856 04:32:59,636 --> 04:33:01,004 ABERRANT BASAL CELLS WE HAVE 6857 04:33:01,004 --> 04:33:02,072 ALREADY HEARD ABOUT TODAY. 6858 04:33:02,072 --> 04:33:02,672 NEXT. 6859 04:33:02,672 --> 04:33:05,508 SO NOW WE CAN TRY TO INFER 6860 04:33:05,508 --> 04:33:07,911 DIFFERENT GENE REGULATORY 6861 04:33:07,911 --> 04:33:09,312 NETWORKS COMPUTATIONALLY AS 6862 04:33:09,312 --> 04:33:10,447 CELLS HAVE COMMONICATION NEOF 6863 04:33:10,447 --> 04:33:11,848 THE WORKS AND CHANGES PROGRAMS 6864 04:33:11,848 --> 04:33:14,551 AND WE ALSO WANT TO MAP THESE 6865 04:33:14,551 --> 04:33:16,286 CELL STATES INTO SPACE, SO THAT 6866 04:33:16,286 --> 04:33:18,455 WE CAN SEE, WHETHER THESE CELL 6867 04:33:18,455 --> 04:33:21,858 SETS NOT ONLY TALK HER IN AND 6868 04:33:21,858 --> 04:33:22,892 CALLED THAT DEC PROGRESSION TIME 6869 04:33:22,892 --> 04:33:27,063 BUT ALSO IN THE PATIENT 6870 04:33:27,063 --> 04:33:28,965 [INDISCERNIBLE]. 6871 04:33:28,965 --> 04:33:29,165 NEXT. 6872 04:33:29,165 --> 04:33:33,336 SO FOR THE REST OF MY TALK I 6873 04:33:33,336 --> 04:33:35,538 WANT TO DISCUSS HOW MAYBE THESE 6874 04:33:35,538 --> 04:33:37,307 DIFFERENT CELL STATES ARE 6875 04:33:37,307 --> 04:33:41,011 REPRESENTED IN THE PERIPHERAL 6876 04:33:41,011 --> 04:33:41,845 BODY FLUIDS. 6877 04:33:41,845 --> 04:33:43,213 OF COURSE THAT'S AN IMPORTANT 6878 04:33:43,213 --> 04:33:43,580 QUESTION. 6879 04:33:43,580 --> 04:33:44,848 GO TO THE NEXT SLIDE. 6880 04:33:44,848 --> 04:33:46,249 BECAUSE IT WOULD BE CLINICALLY 6881 04:33:46,249 --> 04:33:49,419 VERY USEFUL AND IN THIS PAPER, 6882 04:33:49,419 --> 04:33:51,087 ALSO DUE TO THE TOPIC, I TAKE 6883 04:33:51,087 --> 04:33:52,589 THE OPPORTUNITY TO HIGHLIGHT 6884 04:33:52,589 --> 04:33:53,657 THIS PAPER, AGAIN WHICH WE 6885 04:33:53,657 --> 04:33:55,058 PUBLISHED A FEW YEARINGS AGO, 6886 04:33:55,058 --> 04:34:05,568 WHERE WE MADE USE OF MASS SPEC 6887 04:34:07,937 --> 04:34:08,672 QUANTIFICATION OF BRANCHING O 6888 04:34:08,672 --> 04:34:10,540 SAL VERMEN INFECTED OULAR 6889 04:34:10,540 --> 04:34:12,942 LAVAGE, AND WE INTEGRATED OUR 6890 04:34:12,942 --> 04:34:14,778 OWN SINGLE CELL TRANSCRIPTOMIC 6891 04:34:14,778 --> 04:34:16,946 DATA OF IPS PATIENTS WITH 2 6892 04:34:16,946 --> 04:34:17,881 OTHER DIFFERENT INDEPENDENT 6893 04:34:17,881 --> 04:34:21,384 COHORTS TO SORT OF LEARN THE 6894 04:34:21,384 --> 04:34:22,652 REPRESENTATION OF THE DIFFERENT 6895 04:34:22,652 --> 04:34:27,424 CELL STATES IN THE PERIPHERAL 6896 04:34:27,424 --> 04:34:30,460 FLUIDS AND SHOW YOU QUITE WELL 6897 04:34:30,460 --> 04:34:34,864 WORKED FOR SOME EXAMPLES. 6898 04:34:34,864 --> 04:34:35,098 NEXT. 6899 04:34:35,098 --> 04:34:39,269 SO FOR THE BRONCHIAL LAVAGE 6900 04:34:39,269 --> 04:34:40,804 FLUID, THEY TOOK THE FLUID FROM 6901 04:34:40,804 --> 04:34:41,971 THE PROTEINS AND THE DEALS 6902 04:34:41,971 --> 04:34:46,476 AROUND A THOUSAND PROTEINS AND 6903 04:34:46,476 --> 04:34:48,378 THIS WAS A 128 AND PATIENTS ON 6904 04:34:48,378 --> 04:34:51,648 THE INITIAL DIAGNOSIS, SO 6905 04:34:51,648 --> 04:34:53,350 REPRESENTING RATHER EARLY STAGES 6906 04:34:53,350 --> 04:35:02,359 OF THE DISEASE. 6907 04:35:02,359 --> 04:35:02,826 NEXT. 6908 04:35:02,826 --> 04:35:04,327 IN SHOWS DECONVOLUNTEERSULATION 6909 04:35:04,327 --> 04:35:08,665 OF THESE PROTEINS WITH SINGLE 6910 04:35:08,665 --> 04:35:09,833 CELL TRANSCRIPTOMIC MARKER 6911 04:35:09,833 --> 04:35:10,133 SIGNATURES. 6912 04:35:10,133 --> 04:35:12,035 YOU CAN SEE THIS MAKES SENSE IF 6913 04:35:12,035 --> 04:35:13,203 WE HAD SOME [INDISCERNIBLE] 6914 04:35:13,203 --> 04:35:14,904 CONTROLS HERE AND ALL THESE 6915 04:35:14,904 --> 04:35:16,806 DIFFERENT STROMAL CELL 6916 04:35:16,806 --> 04:35:18,541 POPULATIONS INCLUDING THE MY O 6917 04:35:18,541 --> 04:35:24,280 FIBROBLASTS, APPARENTLY GIVE 6918 04:35:24,280 --> 04:35:27,283 RISE TO SOME PROTEINS IN THE 6919 04:35:27,283 --> 04:35:30,987 ILD, ALSO SAME TRUE FOR THE 6920 04:35:30,987 --> 04:35:34,958 BASALOID CELLS. 6921 04:35:34,958 --> 04:35:35,158 NEXT. 6922 04:35:35,158 --> 04:35:39,996 SO HERE'S EXAMPLES FOR 6923 04:35:39,996 --> 04:35:41,498 CORRELATION OF [INDISCERNIBLE] 6924 04:35:41,498 --> 04:35:42,532 SO THEOX GENERATEDDATION 6925 04:35:42,532 --> 04:35:43,800 CAPACITY WITH ALL THESE 6926 04:35:43,800 --> 04:35:44,801 DIFFERENT MARKERS HERE WE 6927 04:35:44,801 --> 04:35:47,971 MEASURE IN THE LAVAGE FLUID AND 6928 04:35:47,971 --> 04:35:52,909 YOU CAN SEE ON THE AVERAGE MORE 6929 04:35:52,909 --> 04:35:56,713 NEGATIVELY CORRELATED WITH THE 6930 04:35:56,713 --> 04:35:58,615 PLCO AS THE OTHER ENRICHED 6931 04:35:58,615 --> 04:36:00,817 PROTEIN THAT WE MEASURED, RANDOM 6932 04:36:00,817 --> 04:36:01,618 PROTEIN WE MEASURED. 6933 04:36:01,618 --> 04:36:05,889 NEXT, THIS IS STILL JUST THE 6934 04:36:05,889 --> 04:36:08,158 LUNG, SO WE HAVE OTHER LUNG 6935 04:36:08,158 --> 04:36:11,060 FUNCTION PARAMETER SO WE CREATED 6936 04:36:11,060 --> 04:36:12,729 A METALUNG ORGANOID FUNCTION AND 6937 04:36:12,729 --> 04:36:17,534 WHERE WE AMERICANED THESE AND 6938 04:36:17,534 --> 04:36:18,601 CORRECTED FOR [INDISCERNIBLE] 6939 04:36:18,601 --> 04:36:18,835 CHAMBER. 6940 04:36:18,835 --> 04:36:20,537 NEXT, ALL THESE PATIENTS ARE NOW 6941 04:36:20,537 --> 04:36:22,939 ON A DIFFERENT MAYBE POINTING TO 6942 04:36:22,939 --> 04:36:24,441 THE TRAJECTORY OF LOOSING THE 6943 04:36:24,441 --> 04:36:28,945 LUNG FUNCTION DUE TO DISEASE. 6944 04:36:28,945 --> 04:36:29,145 NEXT. 6945 04:36:29,145 --> 04:36:32,816 AND SO THAT IT SHOWS THE 6946 04:36:32,816 --> 04:36:35,418 ENRICHMENT OF OR THE POSITIVE OR 6947 04:36:35,418 --> 04:36:38,855 NEGATIVE SORT OF CORRELATION OF 6948 04:36:38,855 --> 04:36:41,357 THE PROTEINS MEASURED IN THE 6949 04:36:41,357 --> 04:36:43,860 LAVAGE GROUP, WITH LUNG 6950 04:36:43,860 --> 04:36:44,127 FUNCTION. 6951 04:36:44,127 --> 04:36:46,262 SO THE MORE PROTEINOT RIGHT, THE 6952 04:36:46,262 --> 04:36:51,201 BETTER THE LUNG FUNCTION IN THE 6953 04:36:51,201 --> 04:36:54,637 ILD PATIENTS AND ON THE RIGHT, 6954 04:36:54,637 --> 04:36:56,372 WHICH ARE KNOWN PROTEINS 6955 04:36:56,372 --> 04:37:03,179 UPREGULATED IN IPS, NEXT. 6956 04:37:03,179 --> 04:37:05,348 NEXT. 6957 04:37:05,348 --> 04:37:07,684 AND WE HAVE MANY MORE CLINICAL 6958 04:37:07,684 --> 04:37:09,285 FEATURES AND 72 PROTEINS HAD A 6959 04:37:09,285 --> 04:37:10,553 GOOD CORRELATION WITH AT LEAST 1 6960 04:37:10,553 --> 04:37:11,855 OF THESE CLINICAL FEATURES, SO 6961 04:37:11,855 --> 04:37:14,290 HERE YOU CAN APPRECIATE THE 6962 04:37:14,290 --> 04:37:15,558 [INDISCERNIBLE] 1 IS 6963 04:37:15,558 --> 04:37:18,161 HIGHLIGHTED, IT'S VERY 6964 04:37:18,161 --> 04:37:19,329 NEGATIVELY, VERY POSITIVELY 6965 04:37:19,329 --> 04:37:21,030 CORRELATED WITH LUNG FUNCTION 6966 04:37:21,030 --> 04:37:23,900 BUT ALSO OTHER THINGS LIKE FOR 6967 04:37:23,900 --> 04:37:25,902 EXAMPLE, THE CD4, CT8 RATIO IS 6968 04:37:25,902 --> 04:37:27,437 VERY PREDICTIVE OF ALL THESE 6969 04:37:27,437 --> 04:37:36,713 PROTEINS THAT CORRELATED WITH 6970 04:37:36,713 --> 04:37:37,313 LUNG FUNCTION, NEXT. 6971 04:37:37,313 --> 04:37:39,148 SO THE QUESTION WAS IF WE USE 6972 04:37:39,148 --> 04:37:41,117 THE PROTEIN FEATURES WILL IT 6973 04:37:41,117 --> 04:37:43,286 PREDICT CLINICAL FEATURES ALSO 6974 04:37:43,286 --> 04:37:44,988 IN TRANSCRIPTOMIC DATA IN OTHER 6975 04:37:44,988 --> 04:37:48,758 COHORTS WOE WE TRAINED A RANDOM 6976 04:37:48,758 --> 04:37:50,927 MODEL AND APPLIED THAT MODEL TO 6977 04:37:50,927 --> 04:37:53,062 OTHER DATA SETS. 6978 04:37:53,062 --> 04:37:55,832 NEXT. 6979 04:37:55,832 --> 04:37:57,901 INCLUDING OUR OWN, SINGLE CELL 6980 04:37:57,901 --> 04:37:59,903 DATA AND A CONTROL FROM CHICAGO, 6981 04:37:59,903 --> 04:38:04,240 WHERE CORRECTLY THE REDUCED LUNG 6982 04:38:04,240 --> 04:38:06,976 FUNCTION WAS PREDICTED IN THE 6983 04:38:06,976 --> 04:38:08,111 SINGLE CELL TRANSCREPT ORDER OF 6984 04:38:08,111 --> 04:38:10,113 MICRONSIC DATA BUT THE TRAINING 6985 04:38:10,113 --> 04:38:11,381 WAS IN THE PROTEOMIC DATA SO 6986 04:38:11,381 --> 04:38:13,249 THERE WAS AN INFORMATION 6987 04:38:13,249 --> 04:38:13,816 TRANSFER THAT WORKED. 6988 04:38:13,816 --> 04:38:14,150 NEXT. 6989 04:38:14,150 --> 04:38:16,886 AND MUCH MORE IMPORTANTLY, THIS 6990 04:38:16,886 --> 04:38:19,389 ALSO WORKED IN THESE MICROCT 6991 04:38:19,389 --> 04:38:20,890 STAGINGS WHERE IT'S SUITABLE 6992 04:38:20,890 --> 04:38:22,258 PROGRESSION BECAUSE IT'S WITHIN 6993 04:38:22,258 --> 04:38:25,528 PATIENT, BUT IT CORRECTLY 6994 04:38:25,528 --> 04:38:27,263 PREDICTS A GRADUAL DECLINE IN 6995 04:38:27,263 --> 04:38:28,431 LUNG FUNCTION DEPENDENT ON THE 6996 04:38:28,431 --> 04:38:30,600 DEGREE OF TISSUE MODELING 6997 04:38:30,600 --> 04:38:32,368 INDICATING THAT INDEED THESE 6998 04:38:32,368 --> 04:38:36,472 BIOMARKERS REALLY REFLECT AND 6999 04:38:36,472 --> 04:38:41,144 REPORT TISSUE REMODELING. 7000 04:38:41,144 --> 04:38:41,611 NEXT. 7001 04:38:41,611 --> 04:38:42,579 SO WHERE'S THE SIGNAL COMING 7002 04:38:42,579 --> 04:38:42,779 FROM. 7003 04:38:42,779 --> 04:38:44,547 CAN YOU DO CORRELATIONS TO 7004 04:38:44,547 --> 04:38:46,983 PROTEOMIC DATA AND THE SINGLE 7005 04:38:46,983 --> 04:38:48,017 CELL TRANSCRIPTOMIC DATA AND 7006 04:38:48,017 --> 04:38:49,852 WOULD SUGGEST THAT THE BASAL 7007 04:38:49,852 --> 04:38:50,820 CELLS AND HAD EVEN MORE 7008 04:38:50,820 --> 04:38:52,789 CONTRIBUTION TO THE SIGNAL, AND 7009 04:38:52,789 --> 04:38:53,856 FOR EXAMPLE, THE FIBROBLASTS 7010 04:38:53,856 --> 04:38:56,426 WHERE I SHOWED IN EXAMPLES 7011 04:38:56,426 --> 04:38:56,926 BEFORE. 7012 04:38:56,926 --> 04:38:57,327 NEXT. 7013 04:38:57,327 --> 04:39:00,296 SO FOR THE ALVEOLAR, WE HAVE 7014 04:39:00,296 --> 04:39:01,931 HEARD ABOUT THE BASAL CELLS AND 7015 04:39:01,931 --> 04:39:03,700 THE WE THINK THE CELLS CAN GIVE 7016 04:39:03,700 --> 04:39:05,468 RISE OF THESE CELLS AND THE 7017 04:39:05,468 --> 04:39:08,071 MARKERS INCLUDING THE PROTEIN, 7018 04:39:08,071 --> 04:39:15,812 WOULD COME UP, WITHIN THAT 7019 04:39:15,812 --> 04:39:16,346 TRAJECTORY. 7020 04:39:16,346 --> 04:39:16,546 NEXT. 7021 04:39:16,546 --> 04:39:18,147 AND THAT CAN ALSO BE SEEN WHEN 7022 04:39:18,147 --> 04:39:21,951 YOU LOOK AT THE HETEROGENEITY 7023 04:39:21,951 --> 04:39:25,855 AND IPF, THAT THIS 7024 04:39:25,855 --> 04:39:26,756 ANTICORRELATES WITH THE 7025 04:39:26,756 --> 04:39:27,490 [INDISCERNIBLE] PROGRAM. 7026 04:39:27,490 --> 04:39:31,260 SO WE GET MORE INTERESTED IN THE 7027 04:39:31,260 --> 04:39:32,895 CRTAC PROTEIN, WHICH POSITIVELY 7028 04:39:32,895 --> 04:39:34,530 CORRELATED WITH THE LUNG 7029 04:39:34,530 --> 04:39:35,164 FUNCTION. 7030 04:39:35,164 --> 04:39:35,665 NEXT. 7031 04:39:35,665 --> 04:39:36,332 NEXT. 7032 04:39:36,332 --> 04:39:37,133 NEXT. 7033 04:39:37,133 --> 04:39:37,700 NEXT. 7034 04:39:37,700 --> 04:39:38,468 NEXT. 7035 04:39:38,468 --> 04:39:40,570 SO IT'S EXPRESSED MOST HAD THE 7036 04:39:40,570 --> 04:39:42,605 LUNG, IT'S EXPRESSED QUITE 7037 04:39:42,605 --> 04:39:44,607 SPECIFICALLY IN AT2 CELLS, DOWN 7038 04:39:44,607 --> 04:39:46,175 REGULATED IN ALL 3 COHORTS IN 7039 04:39:46,175 --> 04:39:47,677 THE AT2 CELLS AND VERY 7040 04:39:47,677 --> 04:39:48,778 IMPORTANTLY IT'S ONLY DOWN 7041 04:39:48,778 --> 04:39:55,051 REGULATED IN THE ILD, AND NOT IN 7042 04:39:55,051 --> 04:39:55,551 COPD, NEXT. 7043 04:39:55,551 --> 04:40:00,223 AND IF YOU CORRELATE WITHIN ALL 7044 04:40:00,223 --> 04:40:02,659 THIS C-POSITIVE 82 CELLS, THE 7045 04:40:02,659 --> 04:40:04,761 CPF PROTEIN WITH ALL YEENS AND 7046 04:40:04,761 --> 04:40:06,496 ON THE X-AXIS YOU SEE THE 7047 04:40:06,496 --> 04:40:08,698 CHICAGO COHORT AND ON THE Y-AXIS 7048 04:40:08,698 --> 04:40:10,667 YOU SEE THE NATIONAL COHORT AND 7049 04:40:10,667 --> 04:40:12,735 THEY'RE COLOR COATED AND THEY 7050 04:40:12,735 --> 04:40:19,275 ALL AGREE ON THESE GENES HERE, 7051 04:40:19,275 --> 04:40:23,413 SO THE [INDISCERNIBLE] IS A 7052 04:40:23,413 --> 04:40:25,548 PROGRAM AND ANTICORRELATE WIDE 7053 04:40:25,548 --> 04:40:27,517 GENES SUCH AS SOX 4 AND NEXT AND 7054 04:40:27,517 --> 04:40:30,219 NEXT, AND HERE CAN YOU SEE 7055 04:40:30,219 --> 04:40:32,188 DIFFERENT PATHWAYS THAT ARE 7056 04:40:32,188 --> 04:40:34,357 POSITIVELY OR NETIONATIVELY 7057 04:40:34,357 --> 04:40:35,658 CORRELATED WITH THE 7058 04:40:35,658 --> 04:40:37,226 [INDISCERNIBLE] IN 82, AND FOX 7059 04:40:37,226 --> 04:40:39,829 FORWAS INTERESTING BECAUSE IT'S 7060 04:40:39,829 --> 04:40:45,234 THE MOST NEGATIVELY REGULATED 7061 04:40:45,234 --> 04:40:45,835 ANTICORRELATED TRANSCRIPTIONAL 7062 04:40:45,835 --> 04:40:46,703 REGULATIONULATOR, NEXT WHICH WE 7063 04:40:46,703 --> 04:40:48,237 KNEW FROM THE MOUSE STUDIES SO 7064 04:40:48,237 --> 04:40:49,872 WHEN YOU MODEL, THE ACTIVATION 7065 04:40:49,872 --> 04:40:52,709 OF AT2 CELLS IN THE BLEOMYCIN 7066 04:40:52,709 --> 04:40:54,277 INJURY MODEL AND GOING TO THESE 7067 04:40:54,277 --> 04:40:55,311 TRANSITIONAL CELLS THAT WE HEARD 7068 04:40:55,311 --> 04:40:59,382 A LOT ABOUT TODAY, YOU CAN SEE 7069 04:40:59,382 --> 04:41:02,652 SOX 4, AND IT WOULD COME UP IN 7070 04:41:02,652 --> 04:41:06,522 THIS TRANSITIONAL CELLS. 7071 04:41:06,522 --> 04:41:08,257 AND NEXT, THE VERY SAME GENES 7072 04:41:08,257 --> 04:41:11,694 COME UP IN THE HUMAN PHASE AND I 7073 04:41:11,694 --> 04:41:13,963 WOULD SUGGEST THESE CELLS, AT 7074 04:41:13,963 --> 04:41:16,399 LEAST FUNCTIONAL OR TO LOOK TO 7075 04:41:16,399 --> 04:41:20,136 THE IDI CELLS IN YOU HUMAN CASE 7076 04:41:20,136 --> 04:41:23,139 AND IT SEEMS THE 1 LOSS WITHIN 7077 04:41:23,139 --> 04:41:24,040 [INDISCERNIBLE] SO VERY EARLY 7078 04:41:24,040 --> 04:41:28,311 MARK OFF OF THE TRANSITION. 7079 04:41:28,311 --> 04:41:28,745 NEXT. 7080 04:41:28,745 --> 04:41:31,848 SO CAN THIS BE SEEN IN THE 7081 04:41:31,848 --> 04:41:32,415 BLOOD? 7082 04:41:32,415 --> 04:41:36,419 WE MEASURED 2 PLASMA COHORTS, 7083 04:41:36,419 --> 04:41:39,088 NEXT AND IN THIS PLOT YOU CAN 7084 04:41:39,088 --> 04:41:42,058 SEE HOW PROTEINS DATA DETECTED 7085 04:41:42,058 --> 04:41:45,027 BOTH IN THE LAVAGE AND IN THE 7086 04:41:45,027 --> 04:41:47,864 PLASMA, AND THEY ARE STRONGLY 7087 04:41:47,864 --> 04:41:53,669 MORE EXPRESSED IN THE PLASMA OR 7088 04:41:53,669 --> 04:41:54,704 LAVAGE, [INDISCERNIBLE], THEY 7089 04:41:54,704 --> 04:41:57,106 ARE LOCALLY PRODUCE AND NOT JUST 7090 04:41:57,106 --> 04:41:59,609 [INDISCERNIBLE] FROM THE LUNG 7091 04:41:59,609 --> 04:42:01,043 AND THIS INCLUDES SURFACTIN 7092 04:42:01,043 --> 04:42:01,944 PROTEIN B AND [INDISCERNIBLE] 7093 04:42:01,944 --> 04:42:05,915 FOR THE CELLS AND MANY MARKERS 7094 04:42:05,915 --> 04:42:10,286 WE KNOW INCLUDING THE CRTAC 1 7095 04:42:10,286 --> 04:42:10,520 PROTEIN. 7096 04:42:10,520 --> 04:42:10,720 NEXT. 7097 04:42:10,720 --> 04:42:13,022 AND THEN ALSO IN THESE 2, 7098 04:42:13,022 --> 04:42:15,591 INDEPENDENT COHORTS THAT WERE 7099 04:42:15,591 --> 04:42:16,559 ACTUALLY QUITE DIFFERENT, 1 7100 04:42:16,559 --> 04:42:19,262 SHOWED THAT POSITIVE CORRELATION 7101 04:42:19,262 --> 04:42:24,433 WITH LUNG FUNCTION PARAMETERS IN 7102 04:42:24,433 --> 04:42:30,473 BOTH IN BOTH OF THESE COHORTS. 7103 04:42:30,473 --> 04:42:30,706 NEXT. 7104 04:42:30,706 --> 04:42:34,177 SO WHAT I'VE SHOWN YOU IS THAT 7105 04:42:34,177 --> 04:42:37,380 WE CAN FIND GOOD BIOMARKERS THAT 7106 04:42:37,380 --> 04:42:40,283 SEEM TO REFLECT THEITATE WHICH 7107 04:42:40,283 --> 04:42:42,985 CRTAC 1 IS EXAMPLE FOR LUNG 7108 04:42:42,985 --> 04:42:44,554 PROYINITTOR BASED BIOMARKER THAT 7109 04:42:44,554 --> 04:42:46,322 REPORPTS LUNG FUNCTION DECLINE 7110 04:42:46,322 --> 04:42:47,123 IN ILD SPECIFICALLY. 7111 04:42:47,123 --> 04:42:50,026 UF COURSE WE NEED BETTER 7112 04:42:50,026 --> 04:42:50,993 DESIGNED LONG NUDEINAL SETTING 7113 04:42:50,993 --> 04:42:54,497 TO STUDY THESE THINGS MUCH MORE 7114 04:42:54,497 --> 04:42:56,899 AND ALSO LARGER STUDIES TO 7115 04:42:56,899 --> 04:42:57,800 UNDERSTAND HOW DIFFERENT 7116 04:42:57,800 --> 04:43:00,203 CO-MORBIDITIES WILL AFFECT THESE 7117 04:43:00,203 --> 04:43:02,872 MEASUREMENTS, AND I WOULD 7118 04:43:02,872 --> 04:43:07,276 SUGGEST THAT MAYBE ALSO THIS PC 7119 04:43:07,276 --> 04:43:08,477 LS PERTURBATION STUDIES WILL 7120 04:43:08,477 --> 04:43:11,514 HELP TO PREDICT BIOMARKERS 7121 04:43:11,514 --> 04:43:14,283 PANELS TO MAKE SENSE TO LOOK FOR 7122 04:43:14,283 --> 04:43:15,184 IN THE BLOOD. 7123 04:43:15,184 --> 04:43:19,055 SO WITH THIS I'M DONE AND THE 7124 04:43:19,055 --> 04:43:20,656 NEXT SLIDE, I HAVE A FEW 7125 04:43:20,656 --> 04:43:23,593 ACKNOWLEDGMENTS OF THE TEAM AND 7126 04:43:23,593 --> 04:43:24,827 I THANK YOU FOR YOUR ATTENTION 7127 04:43:24,827 --> 04:43:29,966 AND HAPPY TO TAKE ANY QUESTIONS. 7128 04:43:29,966 --> 04:43:34,036 >> THANK YOU HERBERT, GREAT 7129 04:43:34,036 --> 04:43:34,237 TALK. 7130 04:43:34,237 --> 04:43:40,042 NOW WE CAN OPEN THIS FOR 7131 04:43:40,042 --> 04:43:44,213 DISCUSSION I WAS VERY INTERESTED 7132 04:43:44,213 --> 04:43:45,948 IN ACTUALLY ASKING YOU HERBERT 7133 04:43:45,948 --> 04:43:46,682 SPECIFICALLY NOW, YOU KNOW IN 7134 04:43:46,682 --> 04:43:51,387 THE FIRST PART OF YOUR TALK, 7135 04:43:51,387 --> 04:43:53,489 ALTHOUGH THE SIVENGLE CELL RNA 7136 04:43:53,489 --> 04:43:55,625 SEQ YOU ANALYZED YOU FOCUSED ON 7137 04:43:55,625 --> 04:43:57,526 THE TYPE 2 CELLS. 7138 04:43:57,526 --> 04:44:03,232 AND I WONDERED IF YOU WOULD HAE 7139 04:44:03,232 --> 04:44:05,101 LOOKED AT THE LARGE AIRWAY 7140 04:44:05,101 --> 04:44:06,235 EPITHELIAL CELLS IN THESE 7141 04:44:06,235 --> 04:44:07,436 DISEASED INDIVIDUALS AS IT GETS 7142 04:44:07,436 --> 04:44:09,372 MORE SEVERE OR MORE DECLINE, 7143 04:44:09,372 --> 04:44:11,107 REGARDLESS OF HOW YOU LOOK AT 7144 04:44:11,107 --> 04:44:16,612 IT, WOULD YOU BE SEEING SOME 7145 04:44:16,612 --> 04:44:20,816 KIND OF A LET'S SAY, SEVERE OR 7146 04:44:20,816 --> 04:44:23,753 SEVERITY ALSO IN THE LARGE 7147 04:44:23,753 --> 04:44:24,387 AIRWAY EPITHELIAL, SEMESTERULAR 7148 04:44:24,387 --> 04:44:28,391 TO WHAT, YOU KNOW WHAT MOUMITA 7149 04:44:28,391 --> 04:44:29,392 WAS TELLING US? 7150 04:44:29,392 --> 04:44:32,228 >> YEAH, THANKS FOR THE 7151 04:44:32,228 --> 04:44:35,865 QUESTION. 7152 04:44:35,865 --> 04:44:38,801 SO HERE, AT2S WERE GIVEN IN 7153 04:44:38,801 --> 04:44:40,069 DIFFERENTITATES OF COURSE I 7154 04:44:40,069 --> 04:44:43,572 THINK THEY'RE VERY IMPORTANT FOR 7155 04:44:43,572 --> 04:44:43,806 IPF. 7156 04:44:43,806 --> 04:44:45,875 BUT OF COURSE WE SEE LOTS OF 7157 04:44:45,875 --> 04:44:47,710 DIFFERENCES IN THE CELL TYPES, 7158 04:44:47,710 --> 04:44:52,248 THIS COMPLICATION THAT DUE TO 7159 04:44:52,248 --> 04:44:53,482 THE BRONCHIALIZATION, PROCESS, 7160 04:44:53,482 --> 04:44:54,750 YOU SEE WITH DISEASE 7161 04:44:54,750 --> 04:44:56,285 PROGRESSION, YOU SEE ALL THESE 7162 04:44:56,285 --> 04:44:58,020 AIRWAY PHENOTYPES AM CANNING UP 7163 04:44:58,020 --> 04:44:59,622 BUT YOU KNOW THE PAPER WOULD 7164 04:44:59,622 --> 04:45:01,190 SUGGIEST THIS COULD ALSO BE 7165 04:45:01,190 --> 04:45:06,162 DERIVE FRIDAY 82 CELLS, BUT 7166 04:45:06,162 --> 04:45:07,663 YEAH, I CERTAINLY THINK THE 7167 04:45:07,663 --> 04:45:08,931 AIRWAY ALSO CHANGES AND ACTUALLY 7168 04:45:08,931 --> 04:45:11,500 WHEN WE LOOK AT -- SO WE DO 7169 04:45:11,500 --> 04:45:14,403 LASER CAPTURING OF THE FOCI FOR 7170 04:45:14,403 --> 04:45:16,806 INSTANCE AND WE CAN SELECT SOME 7171 04:45:16,806 --> 04:45:18,941 FROM THE ALVEOLAR STAGE AND 7172 04:45:18,941 --> 04:45:20,810 EARLY STAGE COURSE, OR FROM THE 7173 04:45:20,810 --> 04:45:22,778 AIRWAYS AND THEY'RE A BIT 7174 04:45:22,778 --> 04:45:27,183 DIFFERENT PROFILES AND SOMETIMES 7175 04:45:27,183 --> 04:45:28,918 WE FIND INTERESTING THINGS LIKE 7176 04:45:28,918 --> 04:45:31,020 ON THE AIRWAY SIDE, YOU HAVE THE 7177 04:45:31,020 --> 04:45:32,321 BASAL CELL LAYER AND A BASAL 7178 04:45:32,321 --> 04:45:34,423 LAYER ON TOP OF IT AND IT SEEMS 7179 04:45:34,423 --> 04:45:38,561 THAT EVEN THESE FIBROBLASTS THEY 7180 04:45:38,561 --> 04:45:40,196 HAVE A DIFFERENT 8 HOURS NATURE 7181 04:45:40,196 --> 04:45:44,200 THAN THE 1S IN THE ALVEOLAR 7182 04:45:44,200 --> 04:45:44,633 SPACE. 7183 04:45:44,633 --> 04:45:46,669 >> YEAH, IMRAIT. 7184 04:45:46,669 --> 04:45:50,706 THERE IS A QUESTION NEERAJ, GO 7185 04:45:50,706 --> 04:45:50,940 AHEAD. 7186 04:45:50,940 --> 04:45:52,008 >> HERBERT EXCELLENT TALK, I 7187 04:45:52,008 --> 04:45:55,511 HAVE A QUESTION REGARDING WHY, 7188 04:45:55,511 --> 04:45:57,813 MAYBE I MISSED IT, YOU DIDN'T 7189 04:45:57,813 --> 04:46:04,153 SEE THE DOWN REGULATION IN COPD, 7190 04:46:04,153 --> 04:46:08,591 AND CRTAC IS A KNOWN PROGNOSTIC 7191 04:46:08,591 --> 04:46:09,992 MARKER FOR LUNG CARCINOMA MARKER 7192 04:46:09,992 --> 04:46:11,961 SO HOW DO WE DIFFERENTIATE 7193 04:46:11,961 --> 04:46:14,397 BETWEEN THE 2 PHENOTYPES. 7194 04:46:14,397 --> 04:46:14,830 >> YEAH, THANKS. 7195 04:46:14,830 --> 04:46:16,365 I GET MUCH MORE INTERESTED AGAIN 7196 04:46:16,365 --> 04:46:17,900 IN THIS PROTEIN NOW, WE SHOULD 7197 04:46:17,900 --> 04:46:19,935 HAVE CONTINUED TO STUDY IT, BACK 7198 04:46:19,935 --> 04:46:22,972 THEN BECAUSE IT'S SUPER 7199 04:46:22,972 --> 04:46:24,173 INTERESTING, BUT WE DON'T KNOW 7200 04:46:24,173 --> 04:46:25,141 MUCH ABOUT IT. 7201 04:46:25,141 --> 04:46:29,245 FORTUNATELY THERE WERE THEN, 7202 04:46:29,245 --> 04:46:33,482 SOME STUDIES ALSO IN THE COVID 7203 04:46:33,482 --> 04:46:37,553 CONTEXT AND SEVERAL APPLICATIONS 7204 04:46:37,553 --> 04:46:39,622 SHOWED IT'S THE MOST BIOMARKER 7205 04:46:39,622 --> 04:46:42,825 DOWN REGULATED OF THE 2% OF THE 7206 04:46:42,825 --> 04:46:45,294 NORMAL BASE LINE REMAINING 7207 04:46:45,294 --> 04:46:46,796 EXPRESSION IN SEVERE COVID. 7208 04:46:46,796 --> 04:46:49,665 AND WE CHECKED MANY DATA SETS, 7209 04:46:49,665 --> 04:46:51,300 SO IN COPD IT'S NOT REGULATED 7210 04:46:51,300 --> 04:46:53,235 AND YOU COULD THINK THAT BECAUSE 7211 04:46:53,235 --> 04:46:55,704 THE GRAPH I SHOWED YOU IS 7212 04:46:55,704 --> 04:46:56,639 TRANSCRIPTOMICS DATA FROM THE 7213 04:46:56,639 --> 04:46:59,141 GROUP AND QUITE HIGH NUMBER OF 7214 04:46:59,141 --> 04:47:01,877 PATIENTS, SO IT COULD BE SORT OF 7215 04:47:01,877 --> 04:47:04,713 A ARTIFACT THAT INDEED, IT'S 7216 04:47:04,713 --> 04:47:07,016 MAYBE DOWN REGULATED IN 82 BUT 7217 04:47:07,016 --> 04:47:07,950 THEN IT'S COMPENSATED SOMEHOW. 7218 04:47:07,950 --> 04:47:09,819 BUT WHEN YOU LOOK INTO SINGLE 7219 04:47:09,819 --> 04:47:12,054 CELL DATA, IT'S ALSO THERE, IT'S 7220 04:47:12,054 --> 04:47:19,862 NOT REALLY REGULATED. 7221 04:47:19,862 --> 04:47:22,131 SO IT MAKE ITS MUCH MORE 7222 04:47:22,131 --> 04:47:24,567 INTERESTING TO ME BECAUSE IT'S 7223 04:47:24,567 --> 04:47:25,534 SIGNIFICANT IN THIS CONTEXT. 7224 04:47:25,534 --> 04:47:27,336 >> HAVE YOU LOOKEDDA THE OTHER 7225 04:47:27,336 --> 04:47:28,838 LUNG DEC SUCH AS 7226 04:47:28,838 --> 04:47:29,705 [INDISCERNIBLE], THAT WOULD BE 7227 04:47:29,705 --> 04:47:33,809 INTERESTING TO SEE. 7228 04:47:33,809 --> 04:47:34,076 >> NO. 7229 04:47:34,076 --> 04:47:41,784 >> SO YEAH, IT SEEMS THERE'S 7230 04:47:41,784 --> 04:47:44,086 SOME RAP WITH COMPLEMENT 7231 04:47:44,086 --> 04:47:48,057 ACTUALLY SO IN ANOTHER PAPER WE 7232 04:47:48,057 --> 04:47:50,359 DISCUSS A DIFFERENT BIOMARKER, 7233 04:47:50,359 --> 04:47:53,195 CFHA 1 AND IT'S KNOWN CO 7234 04:47:53,195 --> 04:47:55,698 COMPLEMENT VECTOR H AND IT WAS 7235 04:47:55,698 --> 04:47:57,066 EXPRESSED BY [INDISCERNIBLE] AND 7236 04:47:57,066 --> 04:47:58,701 IT WAS NEGATIVELY CORRELATE WIDE 7237 04:47:58,701 --> 04:48:04,974 LUNG FUNCTION AND IT'S SORT OF 7238 04:48:04,974 --> 04:48:05,774 REGULATING THE COMPLEMENT 7239 04:48:05,774 --> 04:48:07,209 PATHWAY AND IT TURNS OUT WITH 7240 04:48:07,209 --> 04:48:10,546 THE LARGE SCALE STUDIES THAT IT 7241 04:48:10,546 --> 04:48:11,881 ISHT ACTING WITH ANOTHER PARTNER 7242 04:48:11,881 --> 04:48:14,650 IN THE COMPANY, AND REGULATORY 7243 04:48:14,650 --> 04:48:15,050 PATHWAYS. 7244 04:48:15,050 --> 04:48:19,822 SO IT SEEMS TO BE CONVERGING NOW 7245 04:48:19,822 --> 04:48:21,223 THAT BOTH BIOMARKERS WE FOUND 7246 04:48:21,223 --> 04:48:24,393 COULD ACT ON COMPLEMENT WHICH IS 7247 04:48:24,393 --> 04:48:26,328 KNOWN SINCE PROBABLY 30 YEARS, 7248 04:48:26,328 --> 04:48:29,331 THAT IT'S UPREGULATED AND 7249 04:48:29,331 --> 04:48:32,568 INCREASED IPS, TO COMPLEMENT 7250 04:48:32,568 --> 04:48:36,372 THIS CASE. 7251 04:48:36,372 --> 04:48:37,506 >> THANK YOU. 7252 04:48:37,506 --> 04:48:39,675 MSO ANOTHER QUESTION THAT'S KIND 7253 04:48:39,675 --> 04:48:40,242 OF -- 7254 04:48:40,242 --> 04:48:41,777 >> SO ANOTHER QUESTION THAT'S 7255 04:48:41,777 --> 04:48:44,146 KIND OF IMPRESSED ME REALLY WAS 7256 04:48:44,146 --> 04:48:47,183 PEOPLE TALKING ABOUT PROTEOMICS 7257 04:48:47,183 --> 04:48:50,486 AND THEN THEY USE SINGLE CELL 7258 04:48:50,486 --> 04:48:52,121 RNA TRANSCRIPTOMICS AND YOU LOOK 7259 04:48:52,121 --> 04:48:54,290 AT THE SAME SAMPLES AND THE 7260 04:48:54,290 --> 04:48:55,624 CORRELATION IS REALLY LONG, A 7261 04:48:55,624 --> 04:48:57,026 LOT OF PEOPLE DISCUSSED THIS BUT 7262 04:48:57,026 --> 04:48:58,827 IN YOUR DATA CHA IS IMPRESSIVE 7263 04:48:58,827 --> 04:49:03,532 IS THAT YOU'RE TAKING LAVAGE 7264 04:49:03,532 --> 04:49:04,567 PROTEOMIC ANALYSIS AND THEN 7265 04:49:04,567 --> 04:49:08,904 LOOKING INTO SINGLE CELL RNA SEQ 7266 04:49:08,904 --> 04:49:10,072 FROM DISEASES INDIVIDUALS AND 7267 04:49:10,072 --> 04:49:15,110 ACTUALLY SEEING, YOU KNOW 7268 04:49:15,110 --> 04:49:16,078 CORRELATION SPECIFICALLY AS IT 7269 04:49:16,078 --> 04:49:18,614 RELATES TO DEC AND SO ON, AND -- 7270 04:49:18,614 --> 04:49:20,816 DEC AND SO ON AND WHAT I 7271 04:49:20,816 --> 04:49:22,551 WONDERED WAS, AND YOU DID SOME 7272 04:49:22,551 --> 04:49:24,987 KIND OF AN AI ANALYSIS, I GUESS, 7273 04:49:24,987 --> 04:49:26,388 RANDOM FOR US OR SOMETHING, IS 7274 04:49:26,388 --> 04:49:30,559 THAT RIGHT IN SO IS THERE 7275 04:49:30,559 --> 04:49:32,027 SOMETHING THAT PEOPLE ARE MISS 7276 04:49:32,027 --> 04:49:34,463 NOTHING TERMS OF WHY PROTEOMIC 7277 04:49:34,463 --> 04:49:35,664 AND TRANSCREPT ORDER OF 7278 04:49:35,664 --> 04:49:38,200 MICRONSIC ARE NOT NECESSARILY 7279 04:49:38,200 --> 04:49:39,268 JIVING PROPERLY, I WONDER IF YOU 7280 04:49:39,268 --> 04:49:43,872 COULD COMMENT ON THAT. 7281 04:49:43,872 --> 04:49:44,673 YEAH, THANKS. 7282 04:49:44,673 --> 04:49:47,176 SO OBVIOUSLY NOT EVERYTHING 7283 04:49:47,176 --> 04:49:48,677 CORRELATES SO WE DID OFTEN IN 7284 04:49:48,677 --> 04:49:51,447 OTHER STUDIES AS WELL, WHEN YOU 7285 04:49:51,447 --> 04:49:52,948 DO TISSUE PROTEOMICS AND 7286 04:49:52,948 --> 04:49:55,784 TRANSKRPT ORDER OF MICRONSICS 7287 04:49:55,784 --> 04:49:56,952 AND CORRELATIONS, SO THERE'S 7288 04:49:56,952 --> 04:49:59,788 DIFFERENT WAYS HOW YOU CAN 7289 04:49:59,788 --> 04:50:00,923 CORRELATE THE DYNAMIC RANGE OF 7290 04:50:00,923 --> 04:50:02,558 THE PROAM I DON'T MEAN AND I 7291 04:50:02,558 --> 04:50:05,327 DYNAMIC RANGE OF THE TRANSCRIPT 7292 04:50:05,327 --> 04:50:06,962 THEMSELVES AND ANY ANYWAY THEY 7293 04:50:06,962 --> 04:50:08,831 DON'T CORRELATE WELL BUT IN THE 7294 04:50:08,831 --> 04:50:09,765 DIFFERENT CONDITIONS, COULD 7295 04:50:09,765 --> 04:50:13,802 ALREADY CORRELATE A BIT BETTER. 7296 04:50:13,802 --> 04:50:17,206 BUT THEN THERE ARE MANY TEAMS 7297 04:50:17,206 --> 04:50:18,741 THAT FORCE NICE REFLECTIONS LIKE 7298 04:50:18,741 --> 04:50:20,376 FOR INSTANCE ECM PROTEINS WILL 7299 04:50:20,376 --> 04:50:22,778 BE FOUND FOR COLLAGEN 4 IN THE 7300 04:50:22,778 --> 04:50:26,982 AGING CONTEXT, THE PROTEIN COULD 7301 04:50:26,982 --> 04:50:29,518 GET DOWN REGULATED WHILE THE 7302 04:50:29,518 --> 04:50:30,886 TRANSCREPT GETS UPREGULATED AND 7303 04:50:30,886 --> 04:50:35,357 VICE VERSA, BECAUSE OF SOME 7304 04:50:35,357 --> 04:50:37,660 FEEDBACK CONNECTIONS. 7305 04:50:37,660 --> 04:50:38,927 BUT HERE -- SO IN THIS 7306 04:50:38,927 --> 04:50:40,629 PARTICULAR CASE WE JUST TRY OUT 7307 04:50:40,629 --> 04:50:44,066 SORT OF, WE LEARN THAT SIGNATURE 7308 04:50:44,066 --> 04:50:49,004 IN THE PROTEOME, AND THEN WE 7309 04:50:49,004 --> 04:50:52,308 JUST ASK CAN IT ALSO PREDICT THE 7310 04:50:52,308 --> 04:50:53,475 DIRECT IN THE TRANSCREPT ORDER 7311 04:50:53,475 --> 04:50:54,310 OF MICRONSIC DATAY SOPHISTICATED 7312 04:50:54,310 --> 04:50:55,911 JUST BECAUSE IT HAS MANY MARKERS 7313 04:50:55,911 --> 04:50:58,013 IT COULD STILL WORK, NOT 7314 04:50:58,013 --> 04:50:59,048 DEPENDENT ON 1 PROTEIN AND IT'S 7315 04:50:59,048 --> 04:51:00,716 THE PLOT I SHOWED IN THE END FOR 7316 04:51:00,716 --> 04:51:04,353 THE PLASMA WHERE WE HAD ACTUALLY 7317 04:51:04,353 --> 04:51:06,455 MUCH LESS, AND LAVAGE WHICH IN A 7318 04:51:06,455 --> 04:51:08,324 WAY MAKES SENSE BECAUSE IT GETS 7319 04:51:08,324 --> 04:51:11,827 WAY MORE COMPLICATED YOU KNOW IF 7320 04:51:11,827 --> 04:51:14,430 THAT'S A PROBLEM OF HOW IN WHICH 7321 04:51:14,430 --> 04:51:16,498 WAYS IS SORT OF THE EXCHANGE 7322 04:51:16,498 --> 04:51:17,900 RATE BETWEEN TISSUE AND BLOOD 7323 04:51:17,900 --> 04:51:18,934 REGULATED WHICH IS DIFFERENT FOR 7324 04:51:18,934 --> 04:51:23,872 EACH AND EVERY PROTEIN. 7325 04:51:23,872 --> 04:51:25,541 SO THERE WAS A LOWER CORRELATION 7326 04:51:25,541 --> 04:51:32,815 AND THEN I'M ACTUALLY SHOWING 7327 04:51:32,815 --> 04:51:35,050 THE 1S THAT CORRELATE WELL, BUT 7328 04:51:35,050 --> 04:51:36,585 SOME DON'T CORRELATE WELL, SO 7329 04:51:36,585 --> 04:51:37,786 I'M SHOWING THE 1 DIRECTION HERE 7330 04:51:37,786 --> 04:51:39,154 WHICH IS GOOD. 7331 04:51:39,154 --> 04:51:42,691 >> GOT IT. 7332 04:51:42,691 --> 04:51:44,893 MAKES SENSE CARLA YOU GO AHEAD. 7333 04:51:44,893 --> 04:51:46,161 >> HI, THERE, CAN YOU HEAR ME 7334 04:51:46,161 --> 04:51:47,563 OKAY IN. 7335 04:51:47,563 --> 04:51:47,930 >> YES. 7336 04:51:47,930 --> 04:51:50,532 >> HI, THANK YOU ALL FOR THE 7337 04:51:50,532 --> 04:51:51,367 GREAT TALK IT'S REALLY NICE TO 7338 04:51:51,367 --> 04:51:54,403 BE PART OF THIS. 7339 04:51:54,403 --> 04:51:57,606 I JUST WANTED TO OFFER AND/OR 7340 04:51:57,606 --> 04:51:59,775 ASK ESPECIALLY SINCE YOU'RE 7341 04:51:59,775 --> 04:52:01,410 COLLECTING LAVAGE FLUID, WE HAVE 7342 04:52:01,410 --> 04:52:05,047 RECENTLY DEVELOPED A PROTOCOL TO 7343 04:52:05,047 --> 04:52:06,548 GROW EPITHELIAL ORGANOIDS FROM 7344 04:52:06,548 --> 04:52:10,452 LAVAGE FLUID AND SO, WE WOULD 7345 04:52:10,452 --> 04:52:12,421 LOVE TO COLLABORATE OR PURSUE IT 7346 04:52:12,421 --> 04:52:14,857 WITH YOU, WITH ANY OF YOU THAT 7347 04:52:14,857 --> 04:52:16,592 ARE COLLECTING LAVAGE FROM YOUR 7348 04:52:16,592 --> 04:52:17,760 PATIENTS SO THAT WE CAN SEE HOW 7349 04:52:17,760 --> 04:52:19,962 THE AIR WAY OR ALVERMEN INFECTED 7350 04:52:19,962 --> 04:52:22,030 O LIE EPITHELIAL CELL 7351 04:52:22,030 --> 04:52:22,631 COMOPPOSITE BEHAVIORIAL 7352 04:52:22,631 --> 04:52:23,766 PHENOTYPENTS ARE CORRELATING 7353 04:52:23,766 --> 04:52:25,501 WITH THE DISEASES THAT YOU'RE 7354 04:52:25,501 --> 04:52:30,606 STUDYING AND SOME OF THEIR 7355 04:52:30,606 --> 04:52:31,206 BIOMARKERS. 7356 04:52:31,206 --> 04:52:35,477 NYEAH, THAT SOUNDS EXCITING. 7357 04:52:35,477 --> 04:52:38,881 >> IS THAT WORKING WELL? 7358 04:52:38,881 --> 04:52:39,882 >> YES. 7359 04:52:39,882 --> 04:52:42,117 YEAH, IT ACTUALLY, WE PUSHLISHED 7360 04:52:42,117 --> 04:52:46,655 IT THIS SPRING IN THE 7361 04:52:46,655 --> 04:52:50,125 [INDISCERNIBLE] JOURNAL AND WE 7362 04:52:50,125 --> 04:52:51,093 CAN ESTABLISH AIRWAY ORGANOIDS 7363 04:52:51,093 --> 04:52:54,463 AND THEY CAN BE PASSAGED AND THE 7364 04:52:54,463 --> 04:52:55,631 ALVEOLAR ORGANIZED CELLS ALSO 7365 04:52:55,631 --> 04:52:58,333 CAN BE DERIVED AND THEY -- THEY 7366 04:52:58,333 --> 04:53:01,336 DON'T GO AS MANY PASSAGES, 7367 04:53:01,336 --> 04:53:04,139 THEY'RE A LITTLE MORE FINICKY 7368 04:53:04,139 --> 04:53:06,909 HOWEVER YOU DO GET PLENTY OF 7369 04:53:06,909 --> 04:53:08,076 GOOD ALVEOLAR CELLS TO WORK 7370 04:53:08,076 --> 04:53:08,310 WITH. 7371 04:53:08,310 --> 04:53:10,846 YEAH, HAPPY TO TALK MORE WITH 7372 04:53:10,846 --> 04:53:16,852 ANY OF YOU. 7373 04:53:16,852 --> 04:53:18,720 >> GREAT. 7374 04:53:18,720 --> 04:53:19,555 PLEASE GO AHEAD. 7375 04:53:19,555 --> 04:53:20,956 >> EXCELLENT TALK BY BOTH 7376 04:53:20,956 --> 04:53:25,027 SPEAKERS, I HAVE A QUESTION FOR 7377 04:53:25,027 --> 04:53:25,994 DR. GHOSH ABOUT THE MITOCHONDRIA 7378 04:53:25,994 --> 04:53:26,261 FUNCTION. 7379 04:53:26,261 --> 04:53:28,197 WHEN YOU LOOK AT THE 2 GROUPS 7380 04:53:28,197 --> 04:53:32,634 LOW AND HIGH, YOU SEE BASICALLY 7381 04:53:32,634 --> 04:53:33,402 BOTH MITOCHONDRIAOXIDATIVE 7382 04:53:33,402 --> 04:53:36,371 PHOSPHORYLATION AND DPLI COLSIS, 7383 04:53:36,371 --> 04:53:46,915 INCREASE IN THIS LOW, AND -- TD 7384 04:53:49,785 --> 04:53:50,752 CORRELATION OF THIS IN. 7385 04:53:50,752 --> 04:53:52,254 >> NO WE DID NOT LOOK AT 7386 04:53:52,254 --> 04:53:53,222 ABSOLUTE LEVEL AND BASICALLY 7387 04:53:53,222 --> 04:53:55,557 THAT'S WHAT WE WERE EXPECTING 7388 04:53:55,557 --> 04:53:58,694 WHEN WE SAW THE MORE OX PH OS, 7389 04:53:58,694 --> 04:54:00,762 SO WHEN THEY'RE NOT DOING 7390 04:54:00,762 --> 04:54:02,030 ANYTHING, THEY'RE TBLI COLSIS 7391 04:54:02,030 --> 04:54:03,198 DEPENDENT AND WHEN THEY START 7392 04:54:03,198 --> 04:54:04,566 SENSING INJURY THEY WOULD GO TO 7393 04:54:04,566 --> 04:54:05,067 OX FIRST. 7394 04:54:05,067 --> 04:54:08,170 IN OUR CASE WE WERE SEEING BOTH 7395 04:54:08,170 --> 04:54:10,706 HIGH OX AND FLOX WE DIDN'T GO 7396 04:54:10,706 --> 04:54:12,908 AND ACTUALLY, OUR PLAN IS TO USE 7397 04:54:12,908 --> 04:54:14,510 LIKE STABILIZED ISOTOPE AND GET 7398 04:54:14,510 --> 04:54:15,911 AND TAKE OUT THE DEEPER DIVE 7399 04:54:15,911 --> 04:54:19,848 INTO IT BUT AT THIS POINT ALL WE 7400 04:54:19,848 --> 04:54:22,184 KNOW IS THAT THE HIGH ATP IS 7401 04:54:22,184 --> 04:54:28,123 COMING FROM BOTH WAY UP MAKING 7402 04:54:28,123 --> 04:54:28,690 AND [INDISCERNIBLE]. 7403 04:54:28,690 --> 04:54:30,392 SO YOU'RE SEEING LIKE THIS -- 7404 04:54:30,392 --> 04:54:34,263 OKAY, THANK YOU. 7405 04:54:34,263 --> 04:54:34,563 THANKS. 7406 04:54:34,563 --> 04:54:36,999 >> MOUMITA, I HAVE A QUESTION 7407 04:54:36,999 --> 04:54:38,500 FOR YOU, IT'S FASCINATING HAVE 7408 04:54:38,500 --> 04:54:39,768 YOU THIS SUSCEPTIBILITY OF THE 7409 04:54:39,768 --> 04:54:41,770 LARGE AIRWAY AND SHOWING THE 7410 04:54:41,770 --> 04:54:44,239 LUNG FUNCTION CORRELATION. 7411 04:54:44,239 --> 04:54:47,409 AND I WONDERED, 2 THINGS, I MEAN 7412 04:54:47,409 --> 04:54:50,879 IS IT POSSIBLE THAT ESSENTIALLY 7413 04:54:50,879 --> 04:54:51,914 THESE SUSCEPTIBLE INDIVIDUALS OR 7414 04:54:51,914 --> 04:54:52,881 WHAT YOU'RE THINKING RELATED TO 7415 04:54:52,881 --> 04:54:57,219 THAT, I WOULD SAY, YOU KNOW THAT 7416 04:54:57,219 --> 04:54:58,153 ESSENTIALLY THE ENTIRE LUNG IF 7417 04:54:58,153 --> 04:54:59,988 YOU WILL BECAUSE IT'S EXPOSED TO 7418 04:54:59,988 --> 04:55:01,623 CIGARETTE SMOKE IS SUSCEPTIBLE. 7419 04:55:01,623 --> 04:55:04,359 I MEAN WE'RE -- YOU KNOW WE 7420 04:55:04,359 --> 04:55:07,029 THINK ABOUT SMALL AIRWAY 7421 04:55:07,029 --> 04:55:07,963 EPITHELIAL CELLS, YOU KNOW CLUB 7422 04:55:07,963 --> 04:55:10,399 CELLS FROM THE SMALL AIRWAY, 7423 04:55:10,399 --> 04:55:11,667 BECOMING YOU KNOW TYPE 2 CELLS 7424 04:55:11,667 --> 04:55:14,002 IF THEY'RE NOT FUNCTIONING, 7425 04:55:14,002 --> 04:55:17,005 SOMETHING HAPPENS TO THE PATHWAY 7426 04:55:17,005 --> 04:55:19,541 GIVES RENK MA, BUT IN YOUR CASE 7427 04:55:19,541 --> 04:55:21,510 EVERYTHING'S NOT WORKING 7428 04:55:21,510 --> 04:55:23,412 ESSENTIALLY SO WHAT YOU DO YOU 7429 04:55:23,412 --> 04:55:24,479 THINK ABOUT THAT? 7430 04:55:24,479 --> 04:55:25,747 >> THAT'S EXACTLY WHATY WOO ARE 7431 04:55:25,747 --> 04:55:27,449 THINKING AND IN A COMPLETELY 7432 04:55:27,449 --> 04:55:29,051 DIFFERENT COHORT WHERE WE'RE 7433 04:55:29,051 --> 04:55:29,885 LOOKING AT SECOND HAND SMOKE 7434 04:55:29,885 --> 04:55:31,987 EXPOSE AND YOU ARE LOOKING AT 7435 04:55:31,987 --> 04:55:34,323 SIGNAL NAISAL BRUSHINGS AND 7436 04:55:34,323 --> 04:55:35,591 GETTING BASAL PROGENITOR FROM 7437 04:55:35,591 --> 04:55:37,192 NAISAL BRUSHING WE SEE SIMILAR 7438 04:55:37,192 --> 04:55:37,426 THING. 7439 04:55:37,426 --> 04:55:40,228 WE SEE LOSS OF PROGENITOR 7440 04:55:40,228 --> 04:55:41,630 FUNCTION AND CORRELATION, WITH 7441 04:55:41,630 --> 04:55:43,599 TOTAL LUNG CAPACITY, SO THATIA 7442 04:55:43,599 --> 04:55:48,103 HAPPENING IN THE NOSE, TO LUNG 7443 04:55:48,103 --> 04:55:48,570 FUNCTION. 7444 04:55:48,570 --> 04:55:52,341 SO, IT IS REALLY IT SEEMS THAT 7445 04:55:52,341 --> 04:55:53,875 AS THE WHOLE LUNG SMOKE FIRST OR 7446 04:55:53,875 --> 04:55:54,910 SECOND HAND THAT EVERYTHING, 7447 04:55:54,910 --> 04:55:57,179 LIKE YOU KNOW THIS PROGENITOR 7448 04:55:57,179 --> 04:56:02,284 DYSFUNCTION IS HAPPENING ALL THE 7449 04:56:02,284 --> 04:56:03,919 WAY, STARTING FROM NAISAL 7450 04:56:03,919 --> 04:56:05,420 BRUSHING TO, THAT'S WHY IN THE 7451 04:56:05,420 --> 04:56:07,623 CURRENT STUDY WE ADDED NAISAL 7452 04:56:07,623 --> 04:56:08,991 BRUSHING BECAUSE IT WOULD BE 7453 04:56:08,991 --> 04:56:11,393 EASIER TO COLLECT THAN DOING 7454 04:56:11,393 --> 04:56:12,694 BRONCHIO SCOPEY BUT WE WANT TO 7455 04:56:12,694 --> 04:56:13,729 DO BOTH NONAPOPTOTIC MAKE SURE 7456 04:56:13,729 --> 04:56:16,498 THAT YOU KNOW NORMAL CASE FOR 7457 04:56:16,498 --> 04:56:17,199 NAISAL REPRESENT BRONCHIAL BUT 7458 04:56:17,199 --> 04:56:19,301 IN TEASE WE DO NOT KNOW WHETHER 7459 04:56:19,301 --> 04:56:21,937 THAT CHANGES, SO THAT'S REALLY 7460 04:56:21,937 --> 04:56:24,973 THE PLAN, IF THEY HAVE BEHAVE 7461 04:56:24,973 --> 04:56:27,042 SIMILARLY, THEN IT WOULD BE 7462 04:56:27,042 --> 04:56:28,210 EASIER, THESE PEOPLE DO NOT HAVE 7463 04:56:28,210 --> 04:56:28,910 A DISEASE. 7464 04:56:28,910 --> 04:56:32,247 IF WE WANT TO COLLECT CELLS FROM 7465 04:56:32,247 --> 04:56:34,616 THEM, DOING NAISAL BRUSHING WILL 7466 04:56:34,616 --> 04:56:37,586 BE MUCH MORE PEOPLE WOULD BE 7467 04:56:37,586 --> 04:56:40,122 MUCH MORE WILLING TO COME AND DO 7468 04:56:40,122 --> 04:56:43,225 THAT RATHER THAN DOING A BRONCH 7469 04:56:43,225 --> 04:56:43,492 COSCOPY. 7470 04:56:43,492 --> 04:56:44,660 NRIGHT, IN EMERGING ITS OF WHAT 7471 04:56:44,660 --> 04:56:46,461 WE TALKED ABOUT SUSCEPTIBILITY, 7472 04:56:46,461 --> 04:56:49,164 RESILIENCE AND SO ON, I THINK 7473 04:56:49,164 --> 04:56:51,700 OBVIOUSLY THESE PEOPLE ARE 7474 04:56:51,700 --> 04:56:53,368 SUSCEPTIBLE, THERE MUST BE 7475 04:56:53,368 --> 04:56:54,336 SUSCEPTIBILITY GENES AND WE DO 7476 04:56:54,336 --> 04:56:57,673 SEE THAT AS WELL, I MEAN MUCUS 7477 04:56:57,673 --> 04:56:59,307 IN THE AIRWAY, TRANSLATES IN THE 7478 04:56:59,307 --> 04:57:02,744 NOSE AS WELL FOR EXAMPLE WHEN 7479 04:57:02,744 --> 04:57:05,647 THAT HAPPENS, JOSE, YOU HAD A 7480 04:57:05,647 --> 04:57:06,014 QUESTION? 7481 04:57:06,014 --> 04:57:09,551 >> YEAH, IT WAS A COMMENT ON 7482 04:57:09,551 --> 04:57:11,086 WHAT MOUMITA WAS SAYING, I THINK 7483 04:57:11,086 --> 04:57:12,587 IT'S INTERESTING YOU RAISED IN 7484 04:57:12,587 --> 04:57:16,058 IDEA OF USING NAISAL PHARYNGIAL 7485 04:57:16,058 --> 04:57:17,826 SWAPS AND THAT YOU'RE SEEING 7486 04:57:17,826 --> 04:57:19,461 THIS NICE CORRELATION BETWEEN 7487 04:57:19,461 --> 04:57:21,730 WHAT'S HAPPENING IN THE VERY 7488 04:57:21,730 --> 04:57:24,700 UPPER AIRWAY AND WITH THE LOWER 7489 04:57:24,700 --> 04:57:28,303 LUNG FUNCTION. 7490 04:57:28,303 --> 04:57:29,771 WE'VE SEEN IN SOME OF OUR 7491 04:57:29,771 --> 04:57:32,140 STUDIES PARTICULARLY WITHIN THE 7492 04:57:32,140 --> 04:57:33,909 REALM OF COVID-19 THAT YOU CAN 7493 04:57:33,909 --> 04:57:36,178 ACTUALLY HAVE VERY INVERSE 7494 04:57:36,178 --> 04:57:37,679 EFFECTS IN TERMS OF HOW DRIVER 7495 04:57:37,679 --> 04:57:41,083 THAT YOU PICK UP IN THE NAISAL 7496 04:57:41,083 --> 04:57:43,285 MUCOSA, OF SEVERE DISEASE, MAY 7497 04:57:43,285 --> 04:57:44,786 ACTUALLY BE THEN DETRIMENT OF 7498 04:57:44,786 --> 04:57:46,521 MAY BE BENEFICIAL IN LOWER 7499 04:57:46,521 --> 04:57:47,589 AIRWAY AND VICE VERSA, RIGHT IN 7500 04:57:47,589 --> 04:57:50,225 SO I THINK THAT EACH DEC IS 7501 04:57:50,225 --> 04:57:52,160 LIKELY TO HAVE IT'S OWN 7502 04:57:52,160 --> 04:57:53,328 RELATIONSHIP, AND SO, WE SHOULD 7503 04:57:53,328 --> 04:57:55,931 MAYBE START TO THINK ABOUT 7504 04:57:55,931 --> 04:57:57,099 CATALOGING THESE BECAUSE OFTEN 7505 04:57:57,099 --> 04:57:58,834 TIMES THERE'S THE -- YOU KNOW 7506 04:57:58,834 --> 04:58:00,202 HOW HIGH CAN I GOT TO UNDERSTAND 7507 04:58:00,202 --> 04:58:04,673 WHAT'S HAPPENING IN THE LOWER 7508 04:58:04,673 --> 04:58:06,675 COMPARTMENT, AND CLEARLY BASED 7509 04:58:06,675 --> 04:58:07,509 -- YOU'VE THOUGHT ABOUT THIS 7510 04:58:07,509 --> 04:58:09,244 ISSUE AS WELL, BUT I THINK COULD 7511 04:58:09,244 --> 04:58:13,048 BE AN INTERESTING OUTPUT OF WHAT 7512 04:58:13,048 --> 04:58:13,849 WE'RE DISCUSSING HERE. 7513 04:58:13,849 --> 04:58:16,318 >> I COULD NOT AGREE MORE 7514 04:58:16,318 --> 04:58:18,720 BECAUSE ALSO THERE IS, LIKE WITH 7515 04:58:18,720 --> 04:58:19,421 [INDISCERNIBLE] DIFFERENT THINGS 7516 04:58:19,421 --> 04:58:21,289 WE ARE DOING, I DO BELIEVE THERE 7517 04:58:21,289 --> 04:58:23,158 ARE DIFFERENCES IN BRUSHINGS, 7518 04:58:23,158 --> 04:58:24,993 THE BASAL CELLS, COLLECTED BY 7519 04:58:24,993 --> 04:58:26,962 BRUSHINGS AND BASAL CELLS 7520 04:58:26,962 --> 04:58:28,029 COLLECTED BY BIOPSIES BECAUSE 7521 04:58:28,029 --> 04:58:31,032 THOSE CELLS ARE REALLY TOUCHING 7522 04:58:31,032 --> 04:58:31,466 BASAL MEMBRANE. 7523 04:58:31,466 --> 04:58:33,802 WHEN YOU ARE TALKING ABOUT STEM 7524 04:58:33,802 --> 04:58:35,904 CELLS, PROGENITOR CELLS THERE IS 7525 04:58:35,904 --> 04:58:37,139 A SIGNIFICANT DISRCHES BETWEEN 7526 04:58:37,139 --> 04:58:43,044 THEM AND SO, AND PROBABLY THAT 7527 04:58:43,044 --> 04:58:43,979 BECOMES MORE ABERRANT WHEN 7528 04:58:43,979 --> 04:58:45,180 LOOKING AT DISEASE VERSUS 7529 04:58:45,180 --> 04:58:46,515 HEALTHY SOPHISTICATEDY THERE ARE 7530 04:58:46,515 --> 04:58:48,049 A LOT MORE NUANCED THING GOING 7531 04:58:48,049 --> 04:58:50,719 ON HERE THAN JUST LIKE 7532 04:58:50,719 --> 04:58:53,688 COLLECTING FROM ANY COMPARTMENT. 7533 04:58:53,688 --> 04:58:55,023 >> SO WE HAVE 1 LAST QUESTION 7534 04:58:55,023 --> 04:58:58,960 BEFORE THE TOP OF THE HOUR, 7535 04:58:58,960 --> 04:59:00,662 MICHA, GO AHEAD. 7536 04:59:00,662 --> 04:59:03,999 >> SO, YEAH THIS, IS FOR 7537 04:59:03,999 --> 04:59:05,934 DR. SCHILLER, AND I LOOK HOW YOU 7538 04:59:05,934 --> 04:59:07,302 OPENED YOUR TALK ABOUT AS 7539 04:59:07,302 --> 04:59:09,504 TALKING ABOUT TISSUE STATE AS A 7540 04:59:09,504 --> 04:59:10,572 CONCEPT AND I GUESS MY QUESTION 7541 04:59:10,572 --> 04:59:13,341 IS SORT OF HOW DO WE GO ABOUT 7542 04:59:13,341 --> 04:59:15,544 FROM STUDYING IT TO -- LIKE WHAT 7543 04:59:15,544 --> 04:59:16,845 DOES A THERAPEUTIC TARGET LOOK 7544 04:59:16,845 --> 04:59:19,014 LIKE AT THAT SYSTEM SCALE, DO WE 7545 04:59:19,014 --> 04:59:20,782 HAVE TO HIT MULTIPLE CELL TYPES 7546 04:59:20,782 --> 04:59:21,850 IN MULTIPLE WAYS, ARE YOU GOING 7547 04:59:21,850 --> 04:59:23,518 TO BE ABLE TO FIND SMSK CONTROL 7548 04:59:23,518 --> 04:59:24,619 POINTS THAT WILL PUSH THIS 7549 04:59:24,619 --> 04:59:27,856 AROUND BECAUSE WE'RE LOOKING AT 7550 04:59:27,856 --> 04:59:29,558 MULTIPLE LINEAGES CHANGE NOTHING 7551 04:59:29,558 --> 04:59:30,625 MULTIPLE WAYS AND COORDINATIONS 7552 04:59:30,625 --> 04:59:31,693 AND TALKING TO EACH OTHER IN 7553 04:59:31,693 --> 04:59:33,595 DIFFERENT WAYS SO IF THAT'S A 7554 04:59:33,595 --> 04:59:35,997 THERAPEUTIC TARGET, HOW DO WE 7555 04:59:35,997 --> 04:59:38,233 THINK ABOUT THAT CLINICALLY OR 7556 04:59:38,233 --> 04:59:38,867 FROMAGE ENGINEERING STANDPOINT. 7557 04:59:38,867 --> 04:59:40,769 WHAT DO YOU DO WITH THAT? 7558 04:59:40,769 --> 04:59:42,604 >> YEAH, THAT'S A GREAT 7559 04:59:42,604 --> 04:59:43,605 QUESTION. 7560 04:59:43,605 --> 04:59:44,372 THANKS. 7561 04:59:44,372 --> 04:59:46,608 INDEED MY INTUITION WOULD BE WE 7562 04:59:46,608 --> 04:59:48,376 NEED THESE COMBINATION 7563 04:59:48,376 --> 04:59:51,746 THERAPIES, SO THAT'S WHY SORT OF 7564 04:59:51,746 --> 04:59:53,148 INDICATE HOPEFULLY WE CAN HAVE A 7565 04:59:53,148 --> 04:59:55,550 WAY OF NOT DOING EACH AND EVERY 7566 04:59:55,550 --> 04:59:56,117 EXPERIMENT, RIGHT? 7567 04:59:56,117 --> 04:59:57,919 LIKE EACH AND EVERY COMBINATION, 7568 04:59:57,919 --> 04:59:59,754 THAT'S WHAT SEEMINGLY SOME OF 7569 04:59:59,754 --> 05:00:01,890 THESE, SOME OF US WOULD BE GOD 7570 05:00:01,890 --> 05:00:03,491 IN PREDICTING COMBINATIONS AND 7571 05:00:03,491 --> 05:00:09,030 WE CAN GO BACK TO THE LAB AND DO 7572 05:00:09,030 --> 05:00:09,731 THE ACTUAL EXPERIMENT. 7573 05:00:09,731 --> 05:00:11,900 YEAH, AND THEN, YOU KNOW WHETHER 7574 05:00:11,900 --> 05:00:15,570 THIS -- HOW EASY IT IS TO GO TO 7575 05:00:15,570 --> 05:00:19,307 CLINICAL STUDIES SETTING WITH 7576 05:00:19,307 --> 05:00:20,342 COMBINATION THERAPIES, NOT SURE 7577 05:00:20,342 --> 05:00:23,912 ABOUT I THINK THAT'S PROBABLY 7578 05:00:23,912 --> 05:00:26,181 WHERE MOST SUCCESS COULD COME 7579 05:00:26,181 --> 05:00:29,217 FROM BECAUSE IT WAS A QUESTION 7580 05:00:29,217 --> 05:00:31,086 TODAY ABOUT ALL THESE DIFFERENT 7581 05:00:31,086 --> 05:00:36,191 MARKERS OF THIS TRANSITION 7582 05:00:36,191 --> 05:00:37,492 STATES FOR EXAMPLE, YEAH, SO YOU 7583 05:00:37,492 --> 05:00:39,461 HAVE SO MANY TACKERETS RIGHT? 7584 05:00:39,461 --> 05:00:41,463 AND THAT'S ONLY 1 LINEAGE. 7585 05:00:41,463 --> 05:00:43,732 BUT I GUESS THERE ARE THESE 7586 05:00:43,732 --> 05:00:47,335 CONTROL POINTS, LIKE A CERTAIN, 7587 05:00:47,335 --> 05:00:48,603 LIKE, THE [INDISCERNIBLE] 7588 05:00:48,603 --> 05:00:49,537 FACTORS IS 4 CHAINS AND IT'S 7589 05:00:49,537 --> 05:00:52,874 DOING A LOT, RIGHT? 7590 05:00:52,874 --> 05:00:53,675 SO ... 7591 05:00:53,675 --> 05:00:54,643 >> GREAT. 7592 05:00:54,643 --> 05:00:54,876 THANKS. 7593 05:00:54,876 --> 05:00:57,746 >> THANK YOU FOR THE 7594 05:00:57,746 --> 05:00:59,180 DISCUSSIONS, I THINK DR. LU, YOU 7595 05:00:59,180 --> 05:01:01,383 WANT TO CLOSE, I WILL HAND IT TO 7596 05:01:01,383 --> 05:01:01,683 YOU. 7597 05:01:01,683 --> 05:01:03,385 NYEAH, SURE, THANK YOU SO MUCH, 7598 05:01:03,385 --> 05:01:05,654 GREAT SECTION, I THINK WE ALL 7599 05:01:05,654 --> 05:01:09,658 CAN AGREE, WE HAD A GREAT, 7600 05:01:09,658 --> 05:01:10,725 GREAT, MEETING TODAY. 7601 05:01:10,725 --> 05:01:12,994 SIGNIFY CERTAINLY LEARNED A LOT 7602 05:01:12,994 --> 05:01:16,264 AND HUGE THANKS TO ALL OUR 7603 05:01:16,264 --> 05:01:20,168 CO-CHAIRINGS AND CO MODERATORS 7604 05:01:20,168 --> 05:01:21,269 AND ALSO SPEAKERS. 7605 05:01:21,269 --> 05:01:22,237 LOOKING FORWARD TO HAVING 7606 05:01:22,237 --> 05:01:23,171 ANOTHER EXCITING DAY TOMORROW. 7607 05:01:23,171 --> 05:01:27,275 SO TOMORROW WE ARE STARTING AT 7608 05:01:27,275 --> 05:01:27,642 10:30. 7609 05:01:27,642 --> 05:01:30,845 LIKE TODAY, SO SPEAKERS AND 7610 05:01:30,845 --> 05:01:32,213 MODERATORS MAY JOIN AROUND 7611 05:01:32,213 --> 05:01:33,715 10:00 O'CLOCK SO WE CAN TEST 7612 05:01:33,715 --> 05:01:36,418 YOUR AUDIO AND VIDEO. 7613 05:01:36,418 --> 05:01:37,686 AND I'M GOING TO CLOSE THE 7614 05:01:37,686 --> 05:01:38,186 MEETING TODAY. 7615 05:01:38,186 --> 05:01:40,221 HAVE A GREAT EVENING. 7616 05:01:40,221 --> 05:01:41,256 THANK YOU. 7617 05:01:41,256 --> 05:01:42,524 >> THANK YOU. 7618 05:01:42,524 --> 05:01:52,767 >> THANKS.