1 00:00:05,520 --> 00:00:10,160 >>WE HAVE OUR 3 AFTERNOON 2 00:00:10,160 --> 00:00:15,400 SPEAKERS WHO ANNETTE WILL 3 00:00:15,400 --> 00:00:18,240 INTRODUCE IN A MOMENT AFTER 4 00:00:18,240 --> 00:00:20,640 BRIEF PRESENTATION ON THE 5 00:00:20,640 --> 00:00:26,400 MUCOSAL IMMUNOLOGY STUDIES TEAM. 6 00:00:26,400 --> 00:00:30,760 AND A COUPLE OF ANNOUNCEMENTS I 7 00:00:30,760 --> 00:00:34,200 NEED TO MAKE. 8 00:00:34,200 --> 00:00:36,600 LET'S SEE, ANY INTERESTED MEMBER 9 00:00:36,600 --> 00:00:38,280 OF THE PUBLIC MAY FILE WRITTEN 10 00:00:38,280 --> 00:00:40,680 COMMENTS WITH THE EXECUTIVE 11 00:00:40,680 --> 00:00:42,120 COMMITTEE, SECRETARY OF 12 00:00:42,120 --> 00:00:44,320 COMMITTEE WITHIN 15 DAYS OF THE 13 00:00:44,320 --> 00:00:44,560 MEETING. 14 00:00:44,560 --> 00:00:46,360 THESE COMMENTS WILL BE INCLUDED 15 00:00:46,360 --> 00:00:49,640 IN THE MINUTES OF THE--TO THE 16 00:00:49,640 --> 00:00:51,560 EXTENT PRACTICE RESEARCHICCABLE 17 00:00:51,560 --> 00:00:53,040 AND MAILING AND INFORMATION WAS 18 00:00:53,040 --> 00:00:54,520 PUBLISHED IN THE FEDERAL 19 00:00:54,520 --> 00:00:57,120 REGISTER NOTICE ANNOUNCING 20 00:00:57,120 --> 00:00:58,840 TODAY'S MEETING OF OUR DIVISION 21 00:00:58,840 --> 00:01:01,120 OF ALLERGY AND IMMUNOLOGY AND 22 00:01:01,120 --> 00:01:06,920 TRANSPLANTATION SUBCOMMITTEE OF 23 00:01:06,920 --> 00:01:07,160 COUNCIL. 24 00:01:07,160 --> 00:01:12,560 ANYONE WHO IS SPEAKING MUST BE 25 00:01:12,560 --> 00:01:16,200 ON CAMERA, SO PLEASE MAKE SURE 26 00:01:16,200 --> 00:01:19,840 YOU ACTIVATE YOUR VIDEO IF YOU 27 00:01:19,840 --> 00:01:22,240 INTEND TO SPEAK AND I NEED TO 28 00:01:22,240 --> 00:01:24,560 REMIND OUR STAFF AND COUNCIL 29 00:01:24,560 --> 00:01:25,840 MEMBERS, WE PREFER YOU DO NOT 30 00:01:25,840 --> 00:01:31,440 USE THE CHAT FEATURE OTHERWISE A 31 00:01:31,440 --> 00:01:35,240 FACA RECORD WILL BE CREATED AND 32 00:01:35,240 --> 00:01:42,760 MAKES A LOT OF WORK FOR OTHER 33 00:01:42,760 --> 00:01:43,000 STAFF. 34 00:01:43,000 --> 00:01:47,080 AND I THINK THAT TAKES US UP TO 35 00:01:47,080 --> 00:01:51,840 JUST 1 LAST COMMENT WHICH IS 36 00:01:51,840 --> 00:01:56,040 DOCTORS RANDOLPH AND RAY AND 37 00:01:56,040 --> 00:01:59,120 MR. IDBO ARE LEAVING OUR COUNCIL 38 00:01:59,120 --> 00:02:00,400 AFTER SEVERAL YEARS OF VERY 39 00:02:00,400 --> 00:02:03,160 VALUABLE SERVICE TO THE 40 00:02:03,160 --> 00:02:05,600 INSTITUTE AND AS TONY FAUCI 41 00:02:05,600 --> 00:02:07,320 MENTIONED THIS MORNING, WE'RE 42 00:02:07,320 --> 00:02:09,680 VERY GRATEFUL FOR THAT AND WE 43 00:02:09,680 --> 00:02:10,240 WILL MISS YOU. 44 00:02:10,240 --> 00:02:12,960 SO THANK YOU ALL FOR YOUR 45 00:02:12,960 --> 00:02:16,240 PARTICIPATION OVER THESE LAST 46 00:02:16,240 --> 00:02:16,720 FEW YEARS. 47 00:02:16,720 --> 00:02:21,960 >> IT WAS MY PRIVILEGE TO SERVE. 48 00:02:21,960 --> 00:02:22,680 >> THANKS,. 49 00:02:22,680 --> 00:02:24,000 >> YEP. 50 00:02:24,000 --> 00:02:24,280 >> OKAY. 51 00:02:24,280 --> 00:02:25,120 ANNETTE, WHY DON'T YOU GO AHEAD, 52 00:02:25,120 --> 00:02:29,000 I THINK YOU HAVE SOME SLIDES TO 53 00:02:29,000 --> 00:02:32,440 PROJECT, BACKGROUND ON TODAY'S 54 00:02:32,440 --> 00:02:33,560 SESSION AND WHILE YOU'RE 55 00:02:33,560 --> 00:02:35,360 BRINGING THOSE UP, I WILL JUST 56 00:02:35,360 --> 00:02:37,240 MENTION THAT WE HAVE SEVERAL 57 00:02:37,240 --> 00:02:42,400 CONCEPT CLEARANCES TO GO OVER 58 00:02:42,400 --> 00:02:43,680 LATER IN THE AFTERNOON AND WE 59 00:02:43,680 --> 00:02:51,560 WILL GO THROUGH THOSE AS WE 60 00:02:51,560 --> 00:02:51,880 USUALLY DO. 61 00:02:51,880 --> 00:02:53,320 >> OKAY, IF YOU'RE READY FOR ME, 62 00:02:53,320 --> 00:02:57,720 I WILL START, GOOD AFTERNOON, 63 00:02:57,720 --> 00:03:04,000 EVERYONE, I'M ANNETTE ROTHERMEL, 64 00:03:04,000 --> 00:03:05,920 WITH THE AUTOIMMUNITY MUCOSAL 65 00:03:05,920 --> 00:03:08,240 IMMUNOLOGY BRANCH. 66 00:03:08,240 --> 00:03:10,440 I AM EXCITED TO INTRODUCE THE 67 00:03:10,440 --> 00:03:16,080 SPEAKERS AND THE STUDIES TEAM. 68 00:03:16,080 --> 00:03:16,880 THE MUCOSAL IMMUNOLOGY STUDY 69 00:03:16,880 --> 00:03:18,760 TEAM WHICH IS NICK TAMED MIST 70 00:03:18,760 --> 00:03:19,800 WAS DEVELOPED TO PROMOTE BASIC 71 00:03:19,800 --> 00:03:21,920 RESEARCH LEAD HAPPENING TO 72 00:03:21,920 --> 00:03:23,640 FUNDAMENTAL DISCOVERIES ABOUT 73 00:03:23,640 --> 00:03:24,840 MUCOSAL IMMUNOLOGY. 74 00:03:24,840 --> 00:03:26,840 SO DISCOVERYING NEW CELLS, NEW 75 00:03:26,840 --> 00:03:29,960 PATHWAYS, NEW REGULATORY 76 00:03:29,960 --> 00:03:30,360 MECHANISMS. 77 00:03:30,360 --> 00:03:31,920 THE GOAL WAS TO CREATE A 78 00:03:31,920 --> 00:03:36,320 COLLABORATIVE GROUP OF 79 00:03:36,320 --> 00:03:37,160 SCIENTISTS WITH DIVERSE 80 00:03:37,160 --> 00:03:40,560 EXPERTISE AND WORKING ACROSS A 81 00:03:40,560 --> 00:03:41,560 NUMBER OF MUCOSAL SERVICES WITH 82 00:03:41,560 --> 00:03:44,640 THE IDEA OF SHARING INFORMATION, 83 00:03:44,640 --> 00:03:48,200 CROSS FERTILIZING PROJECTS AND 84 00:03:48,200 --> 00:03:49,040 DEVELOPING KEY COLLABORATIONS. 85 00:03:49,040 --> 00:03:52,160 THE PRSM ITSELF INCLUDES AN 86 00:03:52,160 --> 00:03:53,720 INFRASTRUCTURE AND OPPORTUNITIES 87 00:03:53,720 --> 00:03:56,280 FUND OR IOF AND THIS IS TO ALLOW 88 00:03:56,280 --> 00:03:58,360 TIMELY SUPPORT OF PILOT PROJECTS 89 00:03:58,360 --> 00:04:00,600 ON EMERGING AREAS OF SCIENCE AND 90 00:04:00,600 --> 00:04:02,080 TO SUPPORT EARLY CAREER 91 00:04:02,080 --> 00:04:06,560 INVESTIGATORS WORKING IN MUCOSAL 92 00:04:06,560 --> 00:04:09,920 IMMUNOLOGY. 93 00:04:09,920 --> 00:04:10,680 THE PROGRAM WAS--SORRY. 94 00:04:10,680 --> 00:04:18,440 THE PROGRAM WAS INITIATED IN 95 00:04:18,440 --> 00:04:21,600 2009 WITH SUPPORT FOR 96 00:04:21,600 --> 00:04:23,240 EXPLORATORY AWARDS N2001 THIS 97 00:04:23,240 --> 00:04:26,800 WAS EXPANDED TO SUPPORT SINGLE 98 00:04:26,800 --> 00:04:28,520 COOPERATIVE AWARDS, SO U01 99 00:04:28,520 --> 00:04:30,200 AWARDS AND THIS TIME IT WAS 100 00:04:30,200 --> 00:04:31,800 SUPPORTED BY THE INFRASTRUCTURE 101 00:04:31,800 --> 00:04:32,320 AND OPPORTUNITIES FUND. 102 00:04:32,320 --> 00:04:35,000 THE PROGRAM WAS RENEWED TWICE, 103 00:04:35,000 --> 00:04:39,080 ONCE IN 2006 AND AGAIN LAST 104 00:04:39,080 --> 00:04:39,480 YEAR. 105 00:04:39,480 --> 00:04:40,760 THERE HAS BEEN INCREASING 106 00:04:40,760 --> 00:04:42,080 INTEREST IN FOCUSING VACCINATION 107 00:04:42,080 --> 00:04:46,000 TO GENERATE IMMUNE RESPONSES AT 108 00:04:46,000 --> 00:04:47,400 MUCOSAL SURFACES AND YOU HEARD 109 00:04:47,400 --> 00:04:50,400 ABOUT THAL MORNING IN 110 00:04:50,400 --> 00:04:54,640 DR. FAUCI'S REMARKS AND ALSO IN 111 00:04:54,640 --> 00:04:55,680 DR. HOLLAND'S REMARKS AND THIS 112 00:04:55,680 --> 00:04:57,320 IS OF COURSE UNDERSTANDINGLET 113 00:04:57,320 --> 00:04:59,040 TARGETING IMMUNE RESPONSE OF 114 00:04:59,040 --> 00:05:00,440 PATHOGEN ENTRY IS THE BEST WAY 115 00:05:00,440 --> 00:05:07,320 TO LIMIT INFECTION AND LIMIT 116 00:05:07,320 --> 00:05:07,880 TRANSMISSION. 117 00:05:07,880 --> 00:05:08,560 THE SUCCESSFUL APPROACHES WILL 118 00:05:08,560 --> 00:05:09,440 NEED TO CONSIDER THE 119 00:05:09,440 --> 00:05:12,600 ARCHITECTURE OF THE SURFACE AND 120 00:05:12,600 --> 00:05:13,560 THEIR UNIQUE CELLULAR 121 00:05:13,560 --> 00:05:16,120 COMPOSITIONS AND THESE ARE AREAS 122 00:05:16,120 --> 00:05:17,880 OF INTENSE MUCOSAL IMMUNOLOGY 123 00:05:17,880 --> 00:05:19,240 RESEARCH INCLUDING WITHIN MIST. 124 00:05:19,240 --> 00:05:23,120 FOR EXAMPLE, THE VERY IMPORTANT 125 00:05:23,120 --> 00:05:24,280 TO FULLY UNDERSTAND ANTIGEN 126 00:05:24,280 --> 00:05:27,640 ACQUISITION AT THE MUCOSAL 127 00:05:27,640 --> 00:05:29,360 SURFACE AND UNDERSTAND ANTIGEN 128 00:05:29,360 --> 00:05:30,520 PRESENTING ACTIVITIES AND THE 129 00:05:30,520 --> 00:05:32,080 RESPONSES OF THE UNDERLYING 130 00:05:32,080 --> 00:05:35,840 IMMUNE RESPONSE TO THOSE 131 00:05:35,840 --> 00:05:36,120 ACTIVITIES. 132 00:05:36,120 --> 00:05:38,520 IT'S CRITICAL TO UNDERSTAND THE 133 00:05:38,520 --> 00:05:40,480 ROLE OF INNATE LYMPHOID CELLS 134 00:05:40,480 --> 00:05:41,880 WHICH DOMINATE AT THE BARRIER 135 00:05:41,880 --> 00:05:43,760 SURFACES AND OF COURSE IT'S 136 00:05:43,760 --> 00:05:45,360 IMPORTANT TO UNDERSTAND THE 137 00:05:45,360 --> 00:05:47,240 INNATE ROLES OF THE EPITHELIAL 138 00:05:47,240 --> 00:05:48,600 CELLS THEMSELVES AND THE MUCUS. 139 00:05:48,600 --> 00:05:51,400 WE ALSO KNOW THAT THE MUCOSAL 140 00:05:51,400 --> 00:05:52,480 IMMUNE SYSTEM COMMUNICATES WITH 141 00:05:52,480 --> 00:05:53,800 OTHER SYSTEMS, WE HEARD ABOUT 142 00:05:53,800 --> 00:05:54,840 THAL MORNING AND WE WILL HEAR 143 00:05:54,840 --> 00:05:56,960 MORE TODAY AND WE KNOW THAT THIS 144 00:05:56,960 --> 00:06:01,440 CROSS TALK INFLUENCES IMMUNE 145 00:06:01,440 --> 00:06:01,680 RESPONSES. 146 00:06:01,680 --> 00:06:02,440 SO THIS LEADS US TO THE FACAS 147 00:06:02,440 --> 00:06:04,400 ACCOUNT THAT THERE ARE NO 148 00:06:04,400 --> 00:06:06,960 OPPORTUNITIES FOR COLLABORATIONS 149 00:06:06,960 --> 00:06:09,160 AMONG MUCOSAL IMMUNOLOGISTS AND 150 00:06:09,160 --> 00:06:10,640 VACCOLOGYISTS SEEKING TO ENHANCE 151 00:06:10,640 --> 00:06:12,120 IMMUNITY AT THE SURFACES WITH 152 00:06:12,120 --> 00:06:15,200 JUST A FEW LISTED HERE AND 153 00:06:15,200 --> 00:06:16,520 OBVIOUS OPPORTUNITY IS TO 154 00:06:16,520 --> 00:06:19,040 LEVERAGE THE EXPERTISE OF 155 00:06:19,040 --> 00:06:20,320 MUCOSAL IMMUNOLOGISTS AND MYTHS 156 00:06:20,320 --> 00:06:21,840 AND OTHER DATE SUPPORTED 157 00:06:21,840 --> 00:06:24,040 PROGRAMS SUCH AS THE AIR WAY 158 00:06:24,040 --> 00:06:27,080 BIOLOGY RESEARCHERS IN SAMPLING 159 00:06:27,080 --> 00:06:28,560 AND ANALYZING MUCOSALY IMMUNE 160 00:06:28,560 --> 00:06:28,840 RESPONSES. 161 00:06:28,840 --> 00:06:32,040 THERE'S ALSO AN OPPORTUNITY TO 162 00:06:32,040 --> 00:06:33,920 USE STATE-OF-THE-ART SAMPLE 163 00:06:33,920 --> 00:06:35,320 ANALYSIS, AND SAMPLE SPARING 164 00:06:35,320 --> 00:06:38,040 ASSAYS TO STUDY MUCOSAL 165 00:06:38,040 --> 00:06:38,480 IMMUNOLOGY. 166 00:06:38,480 --> 00:06:42,120 AND ALSO TO TAKE ADVANTAGE OF 167 00:06:42,120 --> 00:06:43,960 THE INTEREST IN ADJUSTICE ACCESS 168 00:06:43,960 --> 00:06:49,600 EXPRENT OTHER FORMULATIONS TO 169 00:06:49,600 --> 00:06:50,360 PROMOTE MUCOSAL IMMUNOLOGY. 170 00:06:50,360 --> 00:06:52,000 AND THERE'S AN OPPORTUNITY TO 171 00:06:52,000 --> 00:06:53,400 STUDY MULTIPLE MUCOSAL SURFACES 172 00:06:53,400 --> 00:06:55,160 BECAUSE THERE THERE ARE VERY 173 00:06:55,160 --> 00:06:55,800 IMPORTANT DIFFERENCES OF THE 174 00:06:55,800 --> 00:06:58,000 ARCHITECTURE OF THE CELLULAR 175 00:06:58,000 --> 00:07:00,320 COMPOSITION AND THE DISTINCT 176 00:07:00,320 --> 00:07:03,000 PATHOGENS AT THESE SURFACES. 177 00:07:03,000 --> 00:07:04,440 WITH THIS, I WOULD LIKE TO 178 00:07:04,440 --> 00:07:05,840 WELCOME OUR SPEAKERS TODAY. 179 00:07:05,840 --> 00:07:06,840 THERE REALLY ISN'T SUFFICIENT 180 00:07:06,840 --> 00:07:08,960 TIME TO DESCRIBE THEIR MANY 181 00:07:08,960 --> 00:07:12,920 ACCOMPLISHMENTS, SO, I WILL BE 182 00:07:12,920 --> 00:07:13,880 BRIEF. 183 00:07:13,880 --> 00:07:16,920 DR. DAVID ARTIS IS THE MICHAEL 184 00:07:16,920 --> 00:07:22,280 COORS PROFESSOR OF IMMUNOLOGY 185 00:07:22,280 --> 00:07:25,720 AND DR. GWENDALYN RANDOLPH AT 186 00:07:25,720 --> 00:07:28,800 CORNELL UNIVERSE AND DR. ARTIS, 187 00:07:28,800 --> 00:07:32,560 FOCUS ON REGULATE ANDA ADAPTIVE 188 00:07:32,560 --> 00:07:33,960 IMMUNE RESPONSES AT BARRIER 189 00:07:33,960 --> 00:07:35,520 SURFACES IN EXPHELGT DISEASE AND 190 00:07:35,520 --> 00:07:37,240 INCLUDE A SIGNIFICANT EFFORT TO 191 00:07:37,240 --> 00:07:38,200 TRANSLATE THESE FINDINGS THAT 192 00:07:38,200 --> 00:07:41,200 ARE FOUND IN PRECLINICAL ANIMAL 193 00:07:41,200 --> 00:07:42,280 MODELS INTO PATIENT BASED 194 00:07:42,280 --> 00:07:46,560 STUDIES OF IMMUNE MEDIATED 195 00:07:46,560 --> 00:07:48,520 DISEASES. 196 00:07:48,520 --> 00:07:50,280 DR. GWEN RANDOLPH IS THE 197 00:07:50,280 --> 00:07:51,760 PROFESSOR OF PATHOLOGY AND 198 00:07:51,760 --> 00:07:53,720 IMMUNOLOGY AT WASHINGTON 199 00:07:53,720 --> 00:07:54,320 UNIVERSITY. 200 00:07:54,320 --> 00:07:55,760 DR. RANDOLPH'S FOCUS HAS BEEN TO 201 00:07:55,760 --> 00:07:57,280 DEFINE THE TRAFFICKING OF 202 00:07:57,280 --> 00:07:58,640 CELLULAR AND MOLECULAR CARGO OUT 203 00:07:58,640 --> 00:08:00,880 OF TISSUES TO THE DISTAL 204 00:08:00,880 --> 00:08:01,800 LYMPHNODE OR DOWN STREAM ORGANS 205 00:08:01,800 --> 00:08:03,200 AND TO UNDERSTAND THE 206 00:08:03,200 --> 00:08:05,400 RELATIONSHIP OF THIS TRAFFICKING 207 00:08:05,400 --> 00:08:12,520 TO CHRONIC INFLAMMATORY 208 00:08:12,520 --> 00:08:13,280 DISEASES. 209 00:08:13,280 --> 00:08:14,560 DR. DEBROSKI HERBERT IS WITH THE 210 00:08:14,560 --> 00:08:15,800 UNIVERSITY OF PENNSYLVANIA 211 00:08:15,800 --> 00:08:18,040 SCHOOL OF VETERINARY MEDICINE 212 00:08:18,040 --> 00:08:19,800 AND PROFESSOR OF IMMUNOLOGY AT 213 00:08:19,800 --> 00:08:20,640 UNIVERSITY OF PENNSYLVANIA. 214 00:08:20,640 --> 00:08:23,720 THROUGH THE STUDY OF PARASITIC 215 00:08:23,720 --> 00:08:30,960 ELEMENTS AND PROTOSWROAA, 216 00:08:30,960 --> 00:08:34,080 DR. HERBERT HAS MADE PROGRESS IN 217 00:08:34,080 --> 00:08:35,440 STUDIES MACROPHAGES AND 218 00:08:35,440 --> 00:08:36,600 RESPIRATORY GI TRACT. 219 00:08:36,600 --> 00:08:38,080 SO WE'RE PLEASED TO HAVE THE 220 00:08:38,080 --> 00:08:38,800 DISTINGUISHED GROUP OF 221 00:08:38,800 --> 00:08:39,840 SCIENTISTS TALK ABOUT WHAT 222 00:08:39,840 --> 00:08:42,160 THEY'RE DOING IN MIST AND WE 223 00:08:42,160 --> 00:08:45,040 WELCOME THEM, DR. ARTIS, 224 00:08:45,040 --> 00:08:46,240 DR. RANDOLPH AND DR. HERBERT. 225 00:08:46,240 --> 00:08:48,760 WITH THIS I WILL CLOSE AND TURN 226 00:08:48,760 --> 00:08:56,320 IT OVER TO DR. ARTIS FOR HIS 227 00:08:56,320 --> 00:09:04,160 FIRST PRESENTATION. 228 00:09:04,160 --> 00:09:04,680 THANK YOU. 229 00:09:04,680 --> 00:09:08,120 >> CAN YOU HEAR ME OKAY? 230 00:09:08,120 --> 00:09:08,800 >> YES. 231 00:09:08,800 --> 00:09:10,320 >> THANK YOU ANNETTE SO I'LL 232 00:09:10,320 --> 00:09:12,840 JUST SHARE THIS SCREEN, LET'S 233 00:09:12,840 --> 00:09:13,360 HOPE THIS WORKS. 234 00:09:13,360 --> 00:09:16,240 CAN YOU SEE IT OKAY? 235 00:09:16,240 --> 00:09:19,000 AND IF WE MAKE IT IS THAT IN 236 00:09:19,000 --> 00:09:20,760 PRESENTATION MODE. 237 00:09:20,760 --> 00:09:22,280 >> YES, THANK YOU. 238 00:09:22,280 --> 00:09:22,640 >> EXCELLENT. 239 00:09:22,640 --> 00:09:26,160 OKAY, THANK YOU DAN, THANK YOU 240 00:09:26,160 --> 00:09:28,080 ANNETTE FOR HOSTING THIS SESSION 241 00:09:28,080 --> 00:09:29,640 AND INVITING US TO TELL YOU A 242 00:09:29,640 --> 00:09:31,120 LITTLE BIT ABOUT WHAT'S 243 00:09:31,120 --> 00:09:35,320 HAPPENING IN THE MUCOSAL 244 00:09:35,320 --> 00:09:36,160 IMMUNOLOGY STUDIES TEAM. 245 00:09:36,160 --> 00:09:39,080 I'LL GO FAIRLY QUICKLY SO WE 246 00:09:39,080 --> 00:09:39,640 STAY ON SCHEDULE. 247 00:09:39,640 --> 00:09:42,480 I'VE HAD THE GOOD FORTUNE OF 248 00:09:42,480 --> 00:09:44,120 HAVING NIAID FUNDING SINCE I 249 00:09:44,120 --> 00:09:46,520 STARTED MY CAREER IN 202004 WAS 250 00:09:46,520 --> 00:09:47,600 AN INDEPENDENT INVESTIGATOR AND 251 00:09:47,600 --> 00:09:50,640 I THINK I ACTUALLY GOT 1 OF THE 252 00:09:50,640 --> 00:09:54,280 THE ORIGINAL MIST R21S BACK IN 253 00:09:54,280 --> 00:09:54,480 2009. 254 00:09:54,480 --> 00:09:56,480 I HAD FOCUS ON THE GOTTEN ABOUT 255 00:09:56,480 --> 00:09:58,040 THE R21 PART BUT I THINK I GOT 1 256 00:09:58,040 --> 00:10:00,800 OF THOSE AS WELL AND I'VE BEEN 257 00:10:00,800 --> 00:10:02,440 EXTREMELY GRATEFUL AND VERY 258 00:10:02,440 --> 00:10:04,960 FORTUNATE TO HAVE WORKED WITH A 259 00:10:04,960 --> 00:10:07,880 BUNCH OF COLLABORATORS OVER THE 260 00:10:07,880 --> 00:10:09,720 LAST 12 OR SO, 13 YEARS. 261 00:10:09,720 --> 00:10:11,120 SO TODAY, I THOUGHT I WOULD GIVE 262 00:10:11,120 --> 00:10:13,800 YOU AN UPDATE ON SOME OF THE 263 00:10:13,800 --> 00:10:16,480 WORK THAT MY GROUP IS DOING AT 264 00:10:16,480 --> 00:10:17,200 THE MOMENT. 265 00:10:17,200 --> 00:10:19,080 PARTLY FUNDED BY MIST AND THE 266 00:10:19,080 --> 00:10:20,440 REGULATION OF IMMUNITY AND 267 00:10:20,440 --> 00:10:21,800 INFLAMMATION OF THE BARRIER 268 00:10:21,800 --> 00:10:22,120 SURFACES. 269 00:10:22,120 --> 00:10:24,840 TODAY I WILL FOCUS PRIMARILY ON 270 00:10:24,840 --> 00:10:26,320 TYPE 2 INFLAMMATION, SO THE 271 00:10:26,320 --> 00:10:29,080 RESPONSE OF COURSE WE SEESHT 272 00:10:29,080 --> 00:10:31,080 WITH ALLERGIC RESPONSES, 273 00:10:31,080 --> 00:10:32,680 IMMUNITY TO HELMET INFECTION, 274 00:10:32,680 --> 00:10:34,840 TISSUE REPAIR AND IN SOME 275 00:10:34,840 --> 00:10:35,680 CIRCUMSTANCES, CANCER. 276 00:10:35,680 --> 00:10:36,920 SO ANNETTE GAVE A VERY NICE 277 00:10:36,920 --> 00:10:39,000 INTRODUCTION AND I USED THIS 278 00:10:39,000 --> 00:10:40,640 CARTOON TO HIGHLIGHT ALL THE KEY 279 00:10:40,640 --> 00:10:43,800 CELLULAR PLAYERS THAT WE THINK 280 00:10:43,800 --> 00:10:46,760 ABOUT OF BARRIER SURFACES LIKE 281 00:10:46,760 --> 00:10:54,600 SKIN, LUNG, GUT AND GI AND 282 00:10:54,600 --> 00:10:58,720 EUROGENERATEDDAL AREA, BUT TOUGH 283 00:10:58,720 --> 00:11:00,640 CELLS, ENDOCRINE CELLS, CELLS IN 284 00:11:00,640 --> 00:11:03,120 THE EPITHELIAL LAYER, OF COURSE 285 00:11:03,120 --> 00:11:04,400 PROFESSIONAL APCs LIKE 286 00:11:04,400 --> 00:11:08,080 DENDRITIC CELLS AND OTHERS, THE 287 00:11:08,080 --> 00:11:09,800 GRANULAR SIGHTS THAT WE 288 00:11:09,800 --> 00:11:12,760 ASSOCIATE WITH TYPE 2 289 00:11:12,760 --> 00:11:18,160 INFLAMMATION, EOSIN O FILLS, AND 290 00:11:18,160 --> 00:11:19,720 BASOPHILS AND T-HELPER SUBSETS. 291 00:11:19,720 --> 00:11:20,960 TODAY I CAN'T TELL YOU ABOUT 292 00:11:20,960 --> 00:11:22,720 EVERYTHING OF COURSE BUT I CAN 293 00:11:22,720 --> 00:11:26,760 FOCUS ON 2 RECENT ADVANCES THAT 294 00:11:26,760 --> 00:11:29,000 HAVE OCCURRED PRIMARILY IN THE 295 00:11:29,000 --> 00:11:30,640 LIFETIME OF MIST, BELIEVE IT OR 296 00:11:30,640 --> 00:11:33,240 NOT SO THE DISCOVERY AND 297 00:11:33,240 --> 00:11:35,080 ELABORATION FUNCTION OF INNATE 298 00:11:35,080 --> 00:11:36,600 LYMPHOID CELLS PARTICULARLY A 299 00:11:36,600 --> 00:11:38,880 BIRRIER SURFACES AND MORE 300 00:11:38,880 --> 00:11:40,920 RECENTLY OUR UNDERSTANDING OF 301 00:11:40,920 --> 00:11:42,040 THE NEWER IMMUNE IRPT ACTIONS 302 00:11:42,040 --> 00:11:43,480 THAT ARE OCCURRING AT THESE 303 00:11:43,480 --> 00:11:45,000 BARRIER SURFACES AND HOW THEY 304 00:11:45,000 --> 00:11:46,840 SHAPE IMMUNITY AND INFLAMMATION 305 00:11:46,840 --> 00:11:47,400 IN TISSUE REPAIR. 306 00:11:47,400 --> 00:11:48,560 SO TRYING TO GIVE YOU A QUICK 307 00:11:48,560 --> 00:11:50,240 OVERVIEW AND THEN I WILL TRY AND 308 00:11:50,240 --> 00:11:53,240 SHOW YOU SOME REALLY, REALLY NEW 309 00:11:53,240 --> 00:11:55,360 UNPUBLISHED DATA SO THIS IS THE 310 00:11:55,360 --> 00:11:58,240 WORLD PREMIER ONLY FOR DAITIs 311 00:11:58,240 --> 00:11:58,480 TODAY. 312 00:11:58,480 --> 00:12:00,800 SO, AND THE REST OF THE WORLD 313 00:12:00,800 --> 00:12:02,080 HAS LOVED IT. 314 00:12:02,080 --> 00:12:05,280 SO INNATE LYMPHOID CELLS IS A 315 00:12:05,280 --> 00:12:08,080 QUICK REMINDER, THEY'RE A 316 00:12:08,080 --> 00:12:09,640 HETEROO GENIUS FAMILY, THEY'RE 317 00:12:09,640 --> 00:12:12,880 FROM A 92 DEPEBDENT PROGENITOR. 318 00:12:12,880 --> 00:12:14,360 THERE'S HETEROGENERATED AITY 319 00:12:14,360 --> 00:12:16,600 WITHIN THE FAMILY, BROADLY THE 320 00:12:16,600 --> 00:12:18,600 NOMENCLATURE THAT'S BEEN USED IS 321 00:12:18,600 --> 00:12:19,760 GROUP 1, 2, 3. 322 00:12:19,760 --> 00:12:21,800 AND INNATE CELLS MARKED BY 323 00:12:21,800 --> 00:12:23,600 DIFFERENT EXPRESSION OF 324 00:12:23,600 --> 00:12:26,360 DIFFERENT TRANSCRIPTION FACTORS, 325 00:12:26,360 --> 00:12:27,560 EXCUSE ME, AND DIFFERENT 326 00:12:27,560 --> 00:12:29,640 SIGNATURE SIGHT SO KINE 327 00:12:29,640 --> 00:12:32,760 RECEPTORS, GROUP 1 INNATE 328 00:12:32,760 --> 00:12:35,040 LYMPHOID CELLS CLUSTER NK CELLS 329 00:12:35,040 --> 00:12:38,280 AND T-BET CELLS THAT PRODUCE 330 00:12:38,280 --> 00:12:38,840 INTERFERON-GAMMA, GROUP 2 331 00:12:38,840 --> 00:12:40,960 EXPRESS HIGH LEVELS AND 332 00:12:40,960 --> 00:12:44,200 SUSTAINED LEVELS OF GATA 3 AND 333 00:12:44,200 --> 00:12:45,480 TH2 ASSOCIATED CYTOKINES IN 334 00:12:45,480 --> 00:12:49,240 GROWTH FACTORS AND GROUP 3, 335 00:12:49,240 --> 00:12:50,960 ASSOCIATED IN INNATE LYMPHOID 336 00:12:50,960 --> 00:12:53,840 CELLS THAT EXPRESS RORGAMMA T 337 00:12:53,840 --> 00:12:56,480 AND R17A AND SOME OTHER PROIN 338 00:12:56,480 --> 00:12:57,760 FLAMMATORY CYTOKINES. 339 00:12:57,760 --> 00:13:04,480 I SHOULD SAY MY CO-PI ON OUR 340 00:13:04,480 --> 00:13:07,000 MIST GRANT IS PROFESSOR GREG 341 00:13:07,000 --> 00:13:09,120 WITH CORNELL AND HE WAS UNABLE 342 00:13:09,120 --> 00:13:10,920 TO BE HERE TODAY AND PRESENTOT 343 00:13:10,920 --> 00:13:12,400 PROJECT BUT WHAT I WANT TO FOCUS 344 00:13:12,400 --> 00:13:16,880 ON IS THE GROUP 2 LYMPHOID CELLS 345 00:13:16,880 --> 00:13:20,240 MARKED AS I SAID BY RECEPTORS 346 00:13:20,240 --> 00:13:24,000 FOR IL25, IL33 AND TSLP. 347 00:13:24,000 --> 00:13:25,560 COURSE THEY ALL EXPRESS 348 00:13:25,560 --> 00:13:28,440 RECEPTORS FOR IL2 AND 7. 349 00:13:28,440 --> 00:13:30,640 THE ILC2 POPULATION OF ALL THE 350 00:13:30,640 --> 00:13:33,160 ILCs IS THE MOST ABUNT ANT IN 351 00:13:33,160 --> 00:13:35,160 THE BODIES, AS FAR AS WE CAN 352 00:13:35,160 --> 00:13:38,000 TELL IT'S THE MOST UBIQUITOUS IN 353 00:13:38,000 --> 00:13:38,920 DISTRIBUTION HIGHLY ENRICHED IN 354 00:13:38,920 --> 00:13:41,160 THE SKIN ALONG THE INTESTINE AND 355 00:13:41,160 --> 00:13:44,320 IN THE WHITE ADIPOSE, BUT FOUND 356 00:13:44,320 --> 00:13:46,320 ON IN ALMOST EVERY TISSUE WE 357 00:13:46,320 --> 00:13:49,120 EVER LOOKED AT, LIVER, PANCREAS, 358 00:13:49,120 --> 00:13:51,120 MUSCLE, ALL OF THE TISSUES, BOTH 359 00:13:51,120 --> 00:13:55,880 IN HUMAN SAMPLES THAT WE HAVEK 360 00:13:55,880 --> 00:13:56,080 HAVE 361 00:13:56,080 --> 00:13:59,040 ACCESS TO AND ALSO IN MODELS. 362 00:13:59,040 --> 00:14:01,120 SO IN 2009-2010 IT WAS IN THE 363 00:14:01,120 --> 00:14:02,760 BRIDGE .3 LABS FIRST REPORTED, 364 00:14:02,760 --> 00:14:05,400 THESE WHAT WE NOW CALL INNATE 365 00:14:05,400 --> 00:14:06,360 LYMPHOID CELLS, THEY MIGHT CALL 366 00:14:06,360 --> 00:14:12,160 THAT AT THE TIME, COLLEAGUES AND 367 00:14:12,160 --> 00:14:15,000 ASSOCIATES IN ENGLANDUTES USING 368 00:14:15,000 --> 00:14:17,840 HELMET MODEL SYSTEMS AS POTENT 369 00:14:17,840 --> 00:14:20,160 PRODUCERS OF IL4, 5, AND 13 IN 370 00:14:20,160 --> 00:14:20,920 DIFFERENT CIRCUMSTANCES IN 371 00:14:20,920 --> 00:14:22,280 DIFFERENT TISSUES AND 372 00:14:22,280 --> 00:14:24,080 SUBSEQUENTLY THERE'S BEEN AN 373 00:14:24,080 --> 00:14:27,320 ENORMOUS EXPLOSION IN INTEREST 374 00:14:27,320 --> 00:14:28,640 OF THESE CELLS, OF COURSE THEY 375 00:14:28,640 --> 00:14:30,320 PLAY AN IMPORTANT ROLE IN 376 00:14:30,320 --> 00:14:32,160 REGULATING FOOD ALLERGY AND 377 00:14:32,160 --> 00:14:33,720 REGULATE SAID INFLAMMATION IN 378 00:14:33,720 --> 00:14:35,960 THE AIR WAYS AND ALLERGY AND 379 00:14:35,960 --> 00:14:38,400 ITCH AND SKIN IN CONTROLLING 380 00:14:38,400 --> 00:14:39,840 ADIPOSE TISSUE, HOMEIO STASES 381 00:14:39,840 --> 00:14:41,440 AND I WILL SHOW YOU A FEW 382 00:14:41,440 --> 00:14:42,880 EXAMPLES OF THOSE BUT JUST TO 383 00:14:42,880 --> 00:14:43,160 SUMMARIZE? 384 00:14:43,160 --> 00:14:45,560 OF THE WORK FROM LABS ALL OVER 385 00:14:45,560 --> 00:14:48,400 THE COUNTRY AND ALL OVER THE 386 00:14:48,400 --> 00:14:49,800 WORLD CONTRIBUTED TO THE 387 00:14:49,800 --> 00:14:51,400 EMERGENCE OF THIS FIELD. 388 00:14:51,400 --> 00:14:53,840 SO 1 OF THE THINGS WE DID VERY 389 00:14:53,840 --> 00:14:55,440 EARLY ON, I'M EMBARRASSED TO SAY 390 00:14:55,440 --> 00:14:57,960 WE NEVER PUBLISHED THIS BUT IT 391 00:14:57,960 --> 00:14:59,840 WASN'T 1 PAPER BUT OUR REVIEWER 392 00:14:59,840 --> 00:15:02,400 TOLD US TO TAKE IT OUT SO WE DO 393 00:15:02,400 --> 00:15:05,120 WAWE'RE TOLD BUT HERE WE DID 394 00:15:05,120 --> 00:15:08,400 EARLY RNA SEQ, WHERE WE SOUGHT 395 00:15:08,400 --> 00:15:09,360 ILCs FROM DIFFERENT TISSUES. 396 00:15:09,360 --> 00:15:11,480 IF YOU LOOK AT THE COLORED BAR 397 00:15:11,480 --> 00:15:13,280 ALONG THE TOP, THE DETAILS DON'T 398 00:15:13,280 --> 00:15:15,480 MATTER BUT THE COLOR COATING 399 00:15:15,480 --> 00:15:17,800 GREENOT LEFT-HAND SIDE ARE 400 00:15:17,800 --> 00:15:19,800 ILC2s, SORTED FROM WHITE 401 00:15:19,800 --> 00:15:20,800 ADIPOSE, RED COLORATION IS THOSE 402 00:15:20,800 --> 00:15:24,040 SORTED FROM THE LUNG, THE GOLD 403 00:15:24,040 --> 00:15:27,040 THOSE SORTED FROM THE COLON, AND 404 00:15:27,040 --> 00:15:29,680 THE LIGHT BLUE COLOR SORTED FROM 405 00:15:29,680 --> 00:15:30,640 THE SMALL INTESTINE. 406 00:15:30,640 --> 00:15:32,720 AND AGAIN THE GENE PATTERNS THAT 407 00:15:32,720 --> 00:15:33,600 MATTER, BUT WHAT'S KEY HERE IS 408 00:15:33,600 --> 00:15:36,960 THAT YOU CAN SEE THESE TISSUE 409 00:15:36,960 --> 00:15:37,880 SPECIFIC SETS OF GENE 410 00:15:37,880 --> 00:15:38,400 EXPRESSION. 411 00:15:38,400 --> 00:15:39,840 SO THESE CELLS ARE DERIVED FROM 412 00:15:39,840 --> 00:15:44,360 A COMMON BONE MARROW DERIVED 413 00:15:44,360 --> 00:15:45,680 LYMPHOID PROGENITOR, THEY SEE 414 00:15:45,680 --> 00:15:47,200 THESE DIFFERENT BARRIER SURFACES 415 00:15:47,200 --> 00:15:49,680 IN OTHER TISSUES DURING 416 00:15:49,680 --> 00:15:50,600 EMBRYONIC DEVELOPMENT, THEY'RE 417 00:15:50,600 --> 00:15:53,240 FAIRLY LONG LIVED AND THEY CARRY 418 00:15:53,240 --> 00:15:55,160 CHARACTERISTICS OF GENE 419 00:15:55,160 --> 00:15:56,760 EXPRESSIONS SPECIFIC TO TISSUE 420 00:15:56,760 --> 00:15:59,480 IN WHICH THEY ARE SEEDED IN 421 00:15:59,480 --> 00:16:01,040 TISSUE AND FOR A LONG PERIOD. 422 00:16:01,040 --> 00:16:03,320 SO THEY SHOULD SOME 423 00:16:03,320 --> 00:16:05,240 CHARACTERISTICS WITH MYELOID AND 424 00:16:05,240 --> 00:16:07,880 OF COURSE WITH LYMPHOID LINEAGES 425 00:16:07,880 --> 00:16:08,280 AS WELL. 426 00:16:08,280 --> 00:16:10,360 SO JUST A FEW EXAMPLES, LAURA 427 00:16:10,360 --> 00:16:11,240 [INDISCERNIBLE] WHO I USED TO 428 00:16:11,240 --> 00:16:12,920 WORK WITH, SHE WAS A RECIPIENT 429 00:16:12,920 --> 00:16:22,400 OF 1 OF THE MISS JUNIOR SCHOLAR, 430 00:16:22,400 --> 00:16:23,680 AWARDS FOR TRANSITION TO 431 00:16:23,680 --> 00:16:24,640 INDEPENDENT INVESTIGATOR, AND IS 432 00:16:24,640 --> 00:16:25,840 NOW FUNDED SHE WAS 1 OF THE 433 00:16:25,840 --> 00:16:27,800 FIRST TO SHOW THE ROLE OF 434 00:16:27,800 --> 00:16:30,160 ILC2s IN THE CONTEXT OF 435 00:16:30,160 --> 00:16:31,920 INFLUENZA INFECTION, NOT HERE IN 436 00:16:31,920 --> 00:16:33,680 IMMUNITY TO THE VIRUS BUT 437 00:16:33,680 --> 00:16:34,640 RAGHTENER TISSUE REPAIR AND 438 00:16:34,640 --> 00:16:36,360 PROTECTION AND SHE SHOWED THAT 439 00:16:36,360 --> 00:16:39,240 NAISLY IN A PAPER THAT IS VERY, 440 00:16:39,240 --> 00:16:42,280 VERY HIGHEE CITED AND 1 OF THE 441 00:16:42,280 --> 00:16:44,800 MOST ILC2 PAPERS CITED AND SHOW 442 00:16:44,800 --> 00:16:46,320 ALL THE EXPRESS LEVELS OF THE 443 00:16:46,320 --> 00:16:50,120 USUAL GENES BUT PARTICULARLY FOR 444 00:16:50,120 --> 00:16:50,960 REGGULEIN AND DECORIN, GENES 445 00:16:50,960 --> 00:16:53,480 THAT WE DIDN'T CLASSICALLY 446 00:16:53,480 --> 00:16:54,560 ASSOCIATE WITH TYPE 2 447 00:16:54,560 --> 00:16:57,440 INFLAMMATION AND SHOWING THE 448 00:16:57,440 --> 00:16:58,400 HISTOLOGY. 449 00:16:58,400 --> 00:17:00,000 IF YOU INFECT MICE WITH 450 00:17:00,000 --> 00:17:02,240 INFLUENZA, OF COURSE YOU GET AIR 451 00:17:02,240 --> 00:17:05,240 WAY, IT'S AS A TROAPISM FOR 452 00:17:05,240 --> 00:17:07,280 EPITHELIAL CELLS, CYTOPATHIC SO 453 00:17:07,280 --> 00:17:08,880 IT KILLS THE EPITHELIUM, SO 454 00:17:08,880 --> 00:17:12,320 THERE'S A LOT OF EPITHELIAL 455 00:17:12,320 --> 00:17:14,160 BARRIER DAMAGE AND A LOT OF 456 00:17:14,160 --> 00:17:16,320 REPAIR IN INFLUENZA, IF YOU TAKE 457 00:17:16,320 --> 00:17:19,480 AWAY ILC2, THAT REPAIRS PROCESS, 458 00:17:19,480 --> 00:17:20,640 THE ESSENTIAL REPAIR PANEL, CAN 459 00:17:20,640 --> 00:17:21,840 YOU SEE THIS IS ALMOST GONE, 460 00:17:21,840 --> 00:17:24,200 THEY DIE OF A NONLETHAL DOSE OF 461 00:17:24,200 --> 00:17:29,080 INFLUENZA AND IF YOU ADD BACK 462 00:17:29,080 --> 00:17:30,360 AMP FORREGUE LYNN, CAN YOU 463 00:17:30,360 --> 00:17:32,720 RESTORE THIS EPITHEL YE REPAIR 464 00:17:32,720 --> 00:17:33,680 RESPONSE. 465 00:17:33,680 --> 00:17:35,120 IN THE ADIPOSE TISSUE, DISTANT 466 00:17:35,120 --> 00:17:37,720 FROM THE BARRIER SURFACES, WE 467 00:17:37,720 --> 00:17:38,600 KNOW THAT ILC2'S PRESENT. 468 00:17:38,600 --> 00:17:42,040 IN FACT THE LARGEST DEPOT OF 469 00:17:42,040 --> 00:17:44,720 ILC2s AND IN HUMAN AND MOUSES 470 00:17:44,720 --> 00:17:45,880 THE WHITE ADIPOSE TISSUE, WE 471 00:17:45,880 --> 00:17:47,080 USED TO THINK IT WAS THE LUNG 472 00:17:47,080 --> 00:17:49,480 BUT MOST OF THEM IN THE STEADY 473 00:17:49,480 --> 00:17:52,120 STATE OR AT LEAST IN THE WHITE 474 00:17:52,120 --> 00:17:53,760 ADIPOSE, WE KNOW IN THE STEADY 475 00:17:53,760 --> 00:17:57,040 STATE THAT THE WHITE ADIPOSE IS 476 00:17:57,040 --> 00:17:58,360 A PREDOMINANTLY TYPE 2 477 00:17:58,360 --> 00:17:58,920 REGULATORY T-CELL TYPE 478 00:17:58,920 --> 00:17:59,960 ENVIRONMENT AND IN THE CONTEXT 479 00:17:59,960 --> 00:18:03,640 OF A BC THERE'S A SWITCH TO MORE 480 00:18:03,640 --> 00:18:04,200 PROINFLAMMATORY CYTOKINE 481 00:18:04,200 --> 00:18:10,360 RESPONSE AND WE KNOW FROM RICH 482 00:18:10,360 --> 00:18:14,240 LOCKSLY, OR OLEFSKY, THEY CAN 483 00:18:14,240 --> 00:18:21,280 MAKE EOH SIN O FILLS IN THE AND 484 00:18:21,280 --> 00:18:23,920 THEN ALSO SHOWING PROTECTIVE 485 00:18:23,920 --> 00:18:27,400 ROLE FOR ADIPOSE RESIDENT 486 00:18:27,400 --> 00:18:30,160 ILC2s THROUGH AN IL13 487 00:18:30,160 --> 00:18:32,040 DEPENDENT PATHWAY PROPOSING THE 488 00:18:32,040 --> 00:18:34,160 BEIGING OF WHITE ADIPOSE WHICH 489 00:18:34,160 --> 00:18:36,600 CONTROLS METABOLISM AND PREVENTS 490 00:18:36,600 --> 00:18:38,800 WEIGHT GAIN ALSO IMPORTANT IN 491 00:18:38,800 --> 00:18:39,960 THERMOGENESIS, AND PLAYING AN 492 00:18:39,960 --> 00:18:41,640 IMPORTANT ROLE BURNING CALORIES 493 00:18:41,640 --> 00:18:42,920 AND PREVENTING OBESITY AND I 494 00:18:42,920 --> 00:18:45,000 WON'T SHOW YOU ALL OF THOSE DATA 495 00:18:45,000 --> 00:18:47,360 JUST IN CARTOON FORM, THE 496 00:18:47,360 --> 00:18:48,440 ILC2s PROMOTE PRODUCTION OF 497 00:18:48,440 --> 00:18:52,280 THE PEPTIDES THAT DRIVE THE 498 00:18:52,280 --> 00:18:56,400 BEIGE AND WHITE DIP O SIGHTS TO 499 00:18:56,400 --> 00:18:57,720 THE WHITE ADIPOSITY AND WEIGHT 500 00:18:57,720 --> 00:18:58,200 GAIN. 501 00:18:58,200 --> 00:18:59,600 BACK TO MUCOSAL BARRIERS HERE IN 502 00:18:59,600 --> 00:19:02,680 THE GUT, WE KNOW THAT ILC2s 503 00:19:02,680 --> 00:19:04,400 ARE PARTICULARLY ENRICHED IN THE 504 00:19:04,400 --> 00:19:06,240 LARGE INTESTINE, AND HERE IN A 505 00:19:06,240 --> 00:19:08,160 MOUSE MODEL AGAIN, WE CAN SEE 506 00:19:08,160 --> 00:19:10,680 THAT IF WE TAKE AWAY THIS TISSUE 507 00:19:10,680 --> 00:19:12,360 PROTECTIVE AND FROM REGUE LYNN, 508 00:19:12,360 --> 00:19:13,760 THESE ANIMALS ARE MUCH MORE 509 00:19:13,760 --> 00:19:16,520 SUSCEPTIBLE TO A MOUSE MODEL OF 510 00:19:16,520 --> 00:19:17,000 INTESTINAL DAMAGE AND 511 00:19:17,000 --> 00:19:19,600 INFLAMMATION DRIVEN BY CHEMICAL 512 00:19:19,600 --> 00:19:20,920 DSS THAT MOST ARE AWARE OF, I'M 513 00:19:20,920 --> 00:19:22,280 SURE IN THE DRINKING WATER AND 514 00:19:22,280 --> 00:19:25,120 HERE IF WE TAKE ON THE KD--SALLY 515 00:19:25,120 --> 00:19:27,400 WHARKS YOU CAN SEE IN THE PANEL 516 00:19:27,400 --> 00:19:28,480 HISTOLOGICALLY GOING TO THE 517 00:19:28,480 --> 00:19:29,520 IMUGOLOGY JUST IN THE INTEREST 518 00:19:29,520 --> 00:19:30,800 OF TIME THESE MICE GET VERY SICK 519 00:19:30,800 --> 00:19:35,960 AND IF WE ADD BACK WILD-TYPE 520 00:19:35,960 --> 00:19:39,560 INSUFFICIENT ILC2s WE CAN 521 00:19:39,560 --> 00:19:40,760 RESTORE THE BARRIER GUT FUNCTION 522 00:19:40,760 --> 00:19:42,400 AND THAT IS LARGELY ABSENT WHEN 523 00:19:42,400 --> 00:19:46,760 WE ADD BACK THE ILC2S FOR THE 524 00:19:46,760 --> 00:19:47,000 REGULATOR. 525 00:19:47,000 --> 00:19:48,800 AND WE ALSO HAVE BEEN ABLE WITH 526 00:19:48,800 --> 00:19:52,360 THE HELP OF MIST FUNDING TO 527 00:19:52,360 --> 00:19:56,880 DEVELOP A TRANSLATIONAL ARM TO 528 00:19:56,880 --> 00:20:03,360 THIS RESEARCH SO WHEN WE MOVE TO 529 00:20:03,360 --> 00:20:04,880 NEW YORK CITY, AND TO CONSENT 530 00:20:04,880 --> 00:20:08,600 PATIENTS THROUGH A COUPLE OF OUR 531 00:20:08,600 --> 00:20:10,360 IRBs, AND TO ACCESS NOT ONLY 532 00:20:10,360 --> 00:20:14,640 PERIPHERAL BLOOD AND SAMPLES FOR 533 00:20:14,640 --> 00:20:15,520 MICROBIAL SEQUENCING AND METRICS 534 00:20:15,520 --> 00:20:17,600 TAB O LOAMICS ANALYSIS BUT ALSO 535 00:20:17,600 --> 00:20:20,000 TAKE LIVE TISSUE BIOPSIES DURING 536 00:20:20,000 --> 00:20:21,480 THEIRENDOSCOPY PROCEDURES AND WE 537 00:20:21,480 --> 00:20:23,160 CAN LIVE TRY O PRESERVE THOSE 538 00:20:23,160 --> 00:20:24,640 CELLS WITH EPITHELIAL CELLS AND 539 00:20:24,640 --> 00:20:29,120 IMMUNE CELLS FOR SUBSEQUENT AND 540 00:20:29,120 --> 00:20:32,480 THIS IS WORK I DO IN CLOSE 541 00:20:32,480 --> 00:20:33,880 COLLABORATION WITH RANDY WALMAN 542 00:20:33,880 --> 00:20:37,240 AND ALSO WITH ELEN SHERYL AND 543 00:20:37,240 --> 00:20:37,720 ROBERT [INDISCERNIBLE]. 544 00:20:37,720 --> 00:20:40,560 I HAVE TO APOLOGIZE, I HAVE A 545 00:20:40,560 --> 00:20:42,320 BIT OF A COLD. 546 00:20:42,320 --> 00:20:45,080 SO WE'RE ABLE--I WON'T SHOW YOU 547 00:20:45,080 --> 00:20:48,000 ALL OF THESE DATA, I CAN 548 00:20:48,000 --> 00:20:48,680 IMMUNOLOGICALLY PROFILE A SINGLE 549 00:20:48,680 --> 00:20:51,560 CELL BASIS FROM THE VERY SMALL 550 00:20:51,560 --> 00:20:52,640 INTESTINAL BIOPSIES WE GET FROM 551 00:20:52,640 --> 00:20:56,480 PATIENTS AS WELL, WHICH IS A 552 00:20:56,480 --> 00:20:58,440 EFFORT TO TRACK PATIENTS NOT 553 00:20:58,440 --> 00:20:59,520 ONLY CROSS SECTIONALLY BUT OVER 554 00:20:59,520 --> 00:21:01,040 TIME AS THEIR DISEASE EVOLVES 555 00:21:01,040 --> 00:21:02,680 AND THEY GET DIFFERENT 556 00:21:02,680 --> 00:21:05,200 THERAPEUTIC INTERVENTIONS AND SO 557 00:21:05,200 --> 00:21:05,680 FORTH. 558 00:21:05,680 --> 00:21:10,520 SO BACK TO ILC2s, THEY'RE 559 00:21:10,520 --> 00:21:13,520 REGULATED AND MARKED BY T1 ST2 560 00:21:13,520 --> 00:21:18,760 OR ST2 IN HUMANS, THE RECEPTOR 561 00:21:18,760 --> 00:21:20,640 FOR IL33, THE FAMILY OF 562 00:21:20,640 --> 00:21:21,360 CYTOKINES AND WORK FROM 563 00:21:21,360 --> 00:21:22,680 [INDISCERNIBLE] IN MY LAB SHOWED 564 00:21:22,680 --> 00:21:25,480 A FEW YEARS AGO THAT THE SOURCES 565 00:21:25,480 --> 00:21:28,200 OF IL33, HAVE REMAINED A LITTLE 566 00:21:28,200 --> 00:21:29,600 BIT CONTENTIOUS, WE'VE USED THE 567 00:21:29,600 --> 00:21:32,000 REPORTER MOUSE TO SHOW THAT THE 568 00:21:32,000 --> 00:21:36,680 DOMINANT SOURCES IN GUT AT LEAST 569 00:21:36,680 --> 00:21:38,040 APPEAR TO BE NONHEMATOPOIETIC 570 00:21:38,040 --> 00:21:38,880 CELLS AND THESE STROMAL LIKE 571 00:21:38,880 --> 00:21:40,880 CELLS THAT ARE MARKED BY THESE 572 00:21:40,880 --> 00:21:42,200 DIFFERENT MARKERS SO THIS GAME 573 00:21:42,200 --> 00:21:43,680 IMPORTANT BECAUSE I THINK IN 574 00:21:43,680 --> 00:21:45,520 DIFFERENT TISSUES, THE SOURCES 575 00:21:45,520 --> 00:21:46,920 OF IL33 ARE QUITE DIFFERENT IN 576 00:21:46,920 --> 00:21:49,120 THE SKIN AND THE LUNG FOR 577 00:21:49,120 --> 00:21:52,120 EXAMPLE, THE CELL TYPES THAT 578 00:21:52,120 --> 00:21:53,520 WERE MAKING IL33 CHANGE 579 00:21:53,520 --> 00:21:56,720 DRAMATICALLY, SO I THINK WE'RE 580 00:21:56,720 --> 00:21:57,920 LEARNING THAT EVERY BARRIER 581 00:21:57,920 --> 00:21:59,880 SURFACE OF COURSE IS VERY 582 00:21:59,880 --> 00:22:03,040 DIFFERENT AND NUANCED IN TERMS 583 00:22:03,040 --> 00:22:05,960 OF BASAL CELL INFECTION AND 584 00:22:05,960 --> 00:22:08,880 CONTEXT OF INFLAMMATION, HE 585 00:22:08,880 --> 00:22:09,880 SHOWED VERY NICE MICROSCOPY, I 586 00:22:09,880 --> 00:22:10,960 WILL JUMP OVER THIS IN THE 587 00:22:10,960 --> 00:22:12,840 INTEREST OF TIME BUT HE SHOWED 588 00:22:12,840 --> 00:22:15,040 VERY NICELY THAT ALMOST EVERY 589 00:22:15,040 --> 00:22:17,320 VISCERAL ORGAN THAT WE LOOK AT 590 00:22:17,320 --> 00:22:20,320 IS ENVELOPES IN THIS BARRIER, 591 00:22:20,320 --> 00:22:22,440 LIKE AN INTERNAL BARRIER, ALMOST 592 00:22:22,440 --> 00:22:24,400 LIKE THE EPITHELIAL BARRIERS AT 593 00:22:24,400 --> 00:22:26,320 MUCOSAL SITES AND THOSE 594 00:22:26,320 --> 00:22:28,400 BARRIERS, THOSE MESOTHELIAL 595 00:22:28,400 --> 00:22:30,120 CELLS CAN EXPRESS IL13 AND THEY 596 00:22:30,120 --> 00:22:32,360 ARE MAKING THE PROTEIN BUT 597 00:22:32,360 --> 00:22:34,680 THEY'RE NOT SECRETING IT UNTIL 1 598 00:22:34,680 --> 00:22:35,520 DAMAGES OR INFLAMES THAT 599 00:22:35,520 --> 00:22:38,000 PARTICULAR TISSUE, SO IT PEERS, 600 00:22:38,000 --> 00:22:39,520 THIS PARTICULAR CYTOKINE AND 601 00:22:39,520 --> 00:22:42,040 POISE TO RECRUIT AND ACTIVATE 602 00:22:42,040 --> 00:22:43,640 ILC2s, VERY, VERY RAPIDLY 603 00:22:43,640 --> 00:22:46,440 PRIOR TO THE EMERGING ADAPTIVE 604 00:22:46,440 --> 00:22:47,600 IMMUNE RESPONSE AND MIGHT BE 1 605 00:22:47,600 --> 00:22:50,040 OF THE KEY COMPONENTS OF 606 00:22:50,040 --> 00:22:51,480 INFLAMMATORY AND TISSUE 607 00:22:51,480 --> 00:22:54,760 PROTECTIVE RESPONSES LISTED BY 608 00:22:54,760 --> 00:22:55,120 ILC2s. 609 00:22:55,120 --> 00:22:56,360 SO MECHANISTICALLY, WE'VE BEEN 610 00:22:56,360 --> 00:23:00,480 INTERESTED IN HOW IL33 PROMOTES 611 00:23:00,480 --> 00:23:01,920 THESE ILC2 RESPONSES AND TISSUES 612 00:23:01,920 --> 00:23:08,040 HERE AGAIN, THIS IS WORK DONE BY 613 00:23:08,040 --> 00:23:10,640 ANN FLAMAR, WHICH SHE SHOWED 614 00:23:10,640 --> 00:23:12,960 VERY NICELY, IN VIVO OR EXVIVO 615 00:23:12,960 --> 00:23:15,840 IN IL33 AND LOOKED TO GENE 616 00:23:15,840 --> 00:23:16,880 DIFFERENTIAL EXPRESSION. 617 00:23:16,880 --> 00:23:19,840 ALL THE USUAL GENES ON THE 618 00:23:19,840 --> 00:23:22,440 LEFT-HAND SIDE, AND UPREGULATED 619 00:23:22,440 --> 00:23:26,320 AS YOU WOULD EXPECT, A PRO TYPE 620 00:23:26,320 --> 00:23:27,640 2 ALLERGIC TYPE RESPONSE. 621 00:23:27,640 --> 00:23:31,960 ACTUALLY THE MOST HIGHLY 622 00:23:31,960 --> 00:23:33,760 UPREGULATED GENE FOLLOWING 623 00:23:33,760 --> 00:23:36,120 ACTIVATION WITH IL33 IS THE GTPH 624 00:23:36,120 --> 00:23:39,800 1 WHICH ENCODES THE ENZYME 625 00:23:39,800 --> 00:23:41,600 TRANSCRIPT O FAN HYDROX LACE 1, 626 00:23:41,600 --> 00:23:44,840 WHICH IS 1 OF THE KEY ENZYMES IN 627 00:23:44,840 --> 00:23:46,840 SEROTONIN PRODUCTION WHICH IS A 628 00:23:46,840 --> 00:23:48,240 HINT TO THE NEUROOF IMMUNE 629 00:23:48,240 --> 00:23:50,080 ACCESS THAT I WILL FOCUS ON IN 630 00:23:50,080 --> 00:23:51,880 THE LAST 10 MINUTES OR SO. 631 00:23:51,880 --> 00:23:53,880 WHAT WAS MOST REMARKABLE WAS 632 00:23:53,880 --> 00:23:56,920 WHEN WE GOT THIS RESULT 633 00:23:56,920 --> 00:23:58,160 OURSELVES WE WENT BACK AND 634 00:23:58,160 --> 00:24:00,520 LOOKEDDA THE BETOZITTED RNA SEQ 635 00:24:00,520 --> 00:24:01,800 DATA SETS AND OTHER CELL TYPES 636 00:24:01,800 --> 00:24:04,960 THAT HAVE BEEN REPORTED THAT ARE 637 00:24:04,960 --> 00:24:07,520 STIMULATED WITH IL33 AND THE 638 00:24:07,520 --> 00:24:10,960 PREDOMINANT TRANSCRIPT IN ALL OF 639 00:24:10,960 --> 00:24:13,240 THOSE DEPOSITED DATA SETS WAS 640 00:24:13,240 --> 00:24:15,040 TPH 1, IT WAS LARGELY IGNORE 641 00:24:15,040 --> 00:24:16,120 INDEED THE LITERATURE FOR A LONG 642 00:24:16,120 --> 00:24:18,360 TIME AND I THINK THAT'S 643 00:24:18,360 --> 00:24:19,360 INTERESTING AS WITH RETROSPECT 644 00:24:19,360 --> 00:24:20,600 AS WE LOOK AT THAT AND I WON'T 645 00:24:20,600 --> 00:24:21,680 SHOW YOU THE DAILY BASIS THEA 646 00:24:21,680 --> 00:24:24,760 BUT HERE WE WERE ABLE TO 647 00:24:24,760 --> 00:24:26,520 GENERATE DIFFERENT LINEAGE KNOCK 648 00:24:26,520 --> 00:24:31,120 OUTS FOR TPH 1 AND SHOW A 649 00:24:31,120 --> 00:24:33,200 CRITICAL FUNCTION OF THE PATH 650 00:24:33,200 --> 00:24:35,520 WAAND THE EFFECTIVE ILC2s IN 651 00:24:35,520 --> 00:24:35,840 IN VIVO. 652 00:24:35,840 --> 00:24:37,520 BUT I WILL JUMP OVER THAT FOR 653 00:24:37,520 --> 00:24:37,840 NOW. 654 00:24:37,840 --> 00:24:38,800 ONE TECHNOLOGY TRANSFER I WANT 655 00:24:38,800 --> 00:24:40,240 TO ADD HERE IS THAT A LOT OF THE 656 00:24:40,240 --> 00:24:42,760 WORK WE'VE BEEN DOING IN THE 657 00:24:42,760 --> 00:24:43,800 EXTRAMURAL PROGRAM, WE'VE HAD 658 00:24:43,800 --> 00:24:45,400 GREAT PARTNERS IN THE INTRAMURAL 659 00:24:45,400 --> 00:24:45,800 PROGRAM. 660 00:24:45,800 --> 00:24:47,000 I KNOW THAT'S OFF TOPIC FOR 661 00:24:47,000 --> 00:24:48,760 TODAY BUT I KNOW IT'S PART OF 662 00:24:48,760 --> 00:24:51,360 THE BIGGER CONVERSATION EARLIER 663 00:24:51,360 --> 00:24:54,200 WITH THE LATE [INDISCERNIBLE] 664 00:24:54,200 --> 00:24:56,160 AND RON GERMANE, THEY SHOWED 665 00:24:56,160 --> 00:24:58,640 VERY NICELY DIFFERENT SUBSETS OF 666 00:24:58,640 --> 00:25:00,920 ILC2s WHICH THEY TERMED 667 00:25:00,920 --> 00:25:03,920 NATURAL ILC2s OR INFLAMMATORY 668 00:25:03,920 --> 00:25:05,000 ILC2s AND USING THEIR DATA 669 00:25:05,000 --> 00:25:07,320 SETS THEY WERE ABLE TO IDENTIFY 670 00:25:07,320 --> 00:25:09,400 THE IL13 AND PLAY AN IMPORTANT 671 00:25:09,400 --> 00:25:14,520 ROLE OF RC2s THAT BILL POLE 672 00:25:14,520 --> 00:25:15,680 INTERMED INFLAMMATORY ILC2s 673 00:25:15,680 --> 00:25:16,000 SUBSETS. 674 00:25:16,000 --> 00:25:19,160 IESM VERY HONORED THAT IN A WEEK 675 00:25:19,160 --> 00:25:20,880 OR SO, THE INTERNATIONAL 676 00:25:20,880 --> 00:25:22,440 CYTOKINE SOCIETY WILL BE 1 OF 677 00:25:22,440 --> 00:25:24,840 THE RECIPIENTS OF THE BILL POLE 678 00:25:24,840 --> 00:25:25,880 AWARD FOR CYTOKINE RESEARCH SO 679 00:25:25,880 --> 00:25:27,760 IT'S A GREAT HONOR TO GET THAT 680 00:25:27,760 --> 00:25:31,520 AND TO REMEMBER HIS CONTRIBUTION 681 00:25:31,520 --> 00:25:32,000 TO THE FIELD. 682 00:25:32,000 --> 00:25:33,960 SO IN TERMS OF JUST--WE 683 00:25:33,960 --> 00:25:36,720 SUMMARIZE SO FAR THE REGULATION 684 00:25:36,720 --> 00:25:38,560 AND EFFECTOR FUNCTIONS OF 685 00:25:38,560 --> 00:25:41,920 ILC2s, THIS IS A CARTOON WE 686 00:25:41,920 --> 00:25:43,600 MADE, I'M SURE THERE'S BETTER 1S 687 00:25:43,600 --> 00:25:46,760 THAN THIS BUT THE UPPER PANEL OF 688 00:25:46,760 --> 00:25:48,440 THE EXTRINSIC FACTORS, 689 00:25:48,440 --> 00:25:49,120 CHEMOKINES AND PROSTAGLANDINS WE 690 00:25:49,120 --> 00:25:51,960 KNOW TO BE ACTIVATOR OF THE ILC2 691 00:25:51,960 --> 00:25:53,360 RESPONSE AND DIFFERENT TISSUES 692 00:25:53,360 --> 00:26:00,120 AND THE LOWER PANEL, EFFECTOR 693 00:26:00,120 --> 00:26:02,880 FUNCTIONS, IL5, EOH SIN O 694 00:26:02,880 --> 00:26:04,240 PHILIA, IL13 DRIIVE GOBLET 695 00:26:04,240 --> 00:26:06,600 RESPONSES AND MANY, MANY OTHERS, 696 00:26:06,600 --> 00:26:09,920 BEIGING 697 00:26:09,920 --> 00:26:11,560 BEIGING THAT I MENTIONED AND 2 698 00:26:11,560 --> 00:26:12,720 YEARS AGO WE WROTE THIS ARTICLE 699 00:26:12,720 --> 00:26:14,520 AND IT'S WAY OUT OF DATE ALREADY 700 00:26:14,520 --> 00:26:17,200 BUT I THINK ITY ABOUT BEGINS TO 701 00:26:17,200 --> 00:26:18,280 ELABORATE THE DIVERSITY 702 00:26:18,280 --> 00:26:22,560 FUNCTIONS OF THESE CELLS IN 703 00:26:22,560 --> 00:26:22,960 DIFFERENT TISSUE 704 00:26:22,960 --> 00:26:23,360 MICROENVIRONMENTS. 705 00:26:23,360 --> 00:26:25,080 SO JUST IN THE LAST 5 MINUTES OR 706 00:26:25,080 --> 00:26:26,400 SO, WE'VE BEEN VERY INTERESTED. 707 00:26:26,400 --> 00:26:28,240 WE KNOW THAT THESE CELLS DO SO 708 00:26:28,240 --> 00:26:29,560 MUCH IN DIFFERENT TISSUE 709 00:26:29,560 --> 00:26:32,080 SETTINGS BUT THEY CAN'T BE 710 00:26:32,080 --> 00:26:35,400 ENTIRELY REGULATED BY CYTOKINES 711 00:26:35,400 --> 00:26:36,440 BECAUSE THESE CYTOKINES HAVE 712 00:26:36,440 --> 00:26:37,640 SIMILAR THINGS TO OTHER CELL 713 00:26:37,640 --> 00:26:40,280 TYPES OF THE SAME TIME, SO FIRST 714 00:26:40,280 --> 00:26:42,120 OFF CLOSER JOIN THE LAB A FEW 715 00:26:42,120 --> 00:26:44,720 YEARS AGO AND HE USED THE 716 00:26:44,720 --> 00:26:47,120 MICROSCOPY TO VISUALIZE FOR 717 00:26:47,120 --> 00:26:48,400 ILC2'S WEAR IN DIFFERENT 718 00:26:48,400 --> 00:26:49,720 SITUATIONS, I WILL SHOW YOU THE 719 00:26:49,720 --> 00:26:50,880 MOUSE FIRST OF ALL. 720 00:26:50,880 --> 00:26:55,280 THIS IS ON THE LEFT-HAND SIDE, 721 00:26:55,280 --> 00:26:58,040 SOME CLASSIC OF COURSE AN AERIAL 722 00:26:58,040 --> 00:27:00,400 VIEW LOOKING DOWN AND PROARPIA 723 00:27:00,400 --> 00:27:02,160 OF THE LC MOUSE AND MARKED IN 724 00:27:02,160 --> 00:27:05,920 RED AND WE CAN SEE A DEGREE OF 725 00:27:05,920 --> 00:27:07,640 PROXIMITY AND SELECTIVE 726 00:27:07,640 --> 00:27:09,240 PROXIMITY OF THESE COLONERGIC 727 00:27:09,240 --> 00:27:11,360 NEWONS THAT ARE MARKED BY THE 728 00:27:11,360 --> 00:27:12,080 NEUROPEPTIDE AND NEUROMED AND 729 00:27:12,080 --> 00:27:12,280 YOU. 730 00:27:12,280 --> 00:27:15,080 AND YOU CAN SEE THAT PERHAPS 731 00:27:15,080 --> 00:27:16,360 NICEOT RIGHT HAND SIDE WHEN YOU 732 00:27:16,360 --> 00:27:17,960 CAN USE CLARITY AND YOU 733 00:27:17,960 --> 00:27:20,000 CONSTRUCTIONS OF THE TISSUES, I 734 00:27:20,000 --> 00:27:22,360 THINK GWEN WILL SHOW MUCH NICER 735 00:27:22,360 --> 00:27:23,360 IMAGES THAN I WILL SHOW YOU 736 00:27:23,360 --> 00:27:24,920 TODAY BUT YOU CAN ALMOST SEE 737 00:27:24,920 --> 00:27:26,960 HERE THE UPPER PANEL IF I PAUSE 738 00:27:26,960 --> 00:27:29,560 IT IS THE LUMEN OF THE INTESTINE 739 00:27:29,560 --> 00:27:33,640 AND THE UPPER PANEL IS THE 740 00:27:33,640 --> 00:27:36,240 LAMINA PROPRIA, AND THE 741 00:27:36,240 --> 00:27:37,240 NEUROPOSITIVE NEURONS FOR THE 742 00:27:37,240 --> 00:27:38,440 FLEXUS AND SO FORTH. 743 00:27:38,440 --> 00:27:41,400 YOU CAN SEE THESE ELABORATE AND 744 00:27:41,400 --> 00:27:42,000 SOPHISTICATED EXTENSIONS OF 745 00:27:42,000 --> 00:27:44,560 NEURONS ALL THE WAY THROUGH THE 746 00:27:44,560 --> 00:27:47,200 SOUTHERN MUCOSA TOLET TIPS OF 747 00:27:47,200 --> 00:27:50,440 THE VIIIA, RIGHT TO THE MICROBI 748 00:27:50,440 --> 00:27:51,920 OTA, DIETARY ANTIGENS AND 749 00:27:51,920 --> 00:27:52,960 INFECTIOUS AGENTS AND THINGS ARE 750 00:27:52,960 --> 00:27:54,520 SO I THINK WE'RE JUST BEGINNING 751 00:27:54,520 --> 00:27:56,360 TO UNDERSTAND THIS BIOLOGY. 752 00:27:56,360 --> 00:28:00,000 THIS IS 1 JUST USING LIGHT SHEET 753 00:28:00,000 --> 00:28:01,920 MICROSCOPY WHICH GIVES US NICE 754 00:28:01,920 --> 00:28:03,000 VISUALIZATION, SO LET'S SEE IF 755 00:28:03,000 --> 00:28:05,080 WE CAN STOP THIS GUY, THIS IS 756 00:28:05,080 --> 00:28:07,560 WHERE YOU CAN RECREATE, TAKE THE 757 00:28:07,560 --> 00:28:08,400 ENTIRE INTESTINE. 758 00:28:08,400 --> 00:28:10,160 SO HERE WE'RE LOOKING THROUGH 759 00:28:10,160 --> 00:28:12,520 THE LUMEN OF THE INTESTINE, SO 760 00:28:12,520 --> 00:28:14,200 THE FOOD MATERIALS AND SO FORTH, 761 00:28:14,200 --> 00:28:17,440 THIS IS THE MUSCULARIS ON THE 762 00:28:17,440 --> 00:28:19,080 OUTSIDE AND USING AN IL14 763 00:28:19,080 --> 00:28:21,680 REPORTER IN THE MAX, YOU CAN SEE 764 00:28:21,680 --> 00:28:23,240 AGAIN, THIS ELABORATE NETWORK OF 765 00:28:23,240 --> 00:28:25,440 NEURONS THROUGHOUT THE BARRIER 766 00:28:25,440 --> 00:28:28,920 SURFACE, WHERE IT'S HIGHLY 767 00:28:28,920 --> 00:28:30,480 ENRICHED FOR IMMUNE CELLS IN THE 768 00:28:30,480 --> 00:28:32,480 MICROBI OTA AND SO FORTH, SO 769 00:28:32,480 --> 00:28:33,240 WE'RE ACTIVELY STUDYING THAT 770 00:28:33,240 --> 00:28:33,760 RIGHT NOW. 771 00:28:33,760 --> 00:28:35,320 SO WHAT DOES THIS DO? 772 00:28:35,320 --> 00:28:38,440 WE KNOW IT'S A POTENT ACTIVATOR 773 00:28:38,440 --> 00:28:39,600 OF THESE ILC2s, WE CAN TAKE 774 00:28:39,600 --> 00:28:40,960 THEM OUT OF A MOUSE OR HUMAN. 775 00:28:40,960 --> 00:28:43,200 I WILL SHOW YOU THE MOUSE. 776 00:28:43,200 --> 00:28:46,840 THIS IS USING IL13 REPORTER AND 777 00:28:46,840 --> 00:28:48,640 YFP MOUSE JUST A SURROGATE FOR 778 00:28:48,640 --> 00:28:49,920 ACTIVATION, IF WE GIVE THEM A 779 00:28:49,920 --> 00:28:51,840 BRIEF PULSE WITHIN A FEW HOURS, 780 00:28:51,840 --> 00:28:55,840 YOU CAN SEE A NICE ACCUMULATION 781 00:28:55,840 --> 00:28:59,440 OF IL13 YFP POSITIVE ILC2s AND 782 00:28:59,440 --> 00:29:01,080 WE KNOW THAT'S IN THE MIDDLE AND 783 00:29:01,080 --> 00:29:03,280 WE KNOW IT'S SORT INTRINSIC IF 784 00:29:03,280 --> 00:29:05,400 WE SORT THEM IT LOOKS NICELY. 785 00:29:05,400 --> 00:29:08,520 THIS IS ALL PUBLISHED SO I WILL 786 00:29:08,520 --> 00:29:08,760 GO FAST. 787 00:29:08,760 --> 00:29:10,520 IN VIVO IT'S DRIVING 788 00:29:10,520 --> 00:29:11,840 INFLAMMATION TO OOH LC2s 789 00:29:11,840 --> 00:29:13,120 RESPONSES AND ALSO DRIVES 790 00:29:13,120 --> 00:29:14,320 RESPONSES IN THE GUT SHOWN IN 791 00:29:14,320 --> 00:29:16,400 THE UPPER RIGHT AND CAN DRIVE 792 00:29:16,400 --> 00:29:18,200 IMMUNITY TO A GUT PARASITE 793 00:29:18,200 --> 00:29:18,840 CALLED [INDISCERNIBLE]. 794 00:29:18,840 --> 00:29:21,960 THIS IS 1 THAT'S A POTENT 795 00:29:21,960 --> 00:29:23,280 STIMULUS FOR ILC2s IN VIVO AND 796 00:29:23,280 --> 00:29:26,680 A USEFUL MODEL FOR STUDYING 797 00:29:26,680 --> 00:29:27,080 THEIR BIOLOGY. 798 00:29:27,080 --> 00:29:29,600 SO FOR THE NEURONAL PART, WE'RE 799 00:29:29,600 --> 00:29:33,160 BEGINNING TO TAKE APART, WHAT WE 800 00:29:33,160 --> 00:29:36,040 CALL A NEURONAL STIMATTORY AND 801 00:29:36,040 --> 00:29:37,640 INHIBITORS FACTORS THAT ARE 802 00:29:37,640 --> 00:29:38,760 DRIVING TISSUE RESPONSES AND 803 00:29:38,760 --> 00:29:41,160 FOCUSING HERE TODAY ON ILC2s, 804 00:29:41,160 --> 00:29:45,200 AS I SAID BUT THIS COUNTS FOR 805 00:29:45,200 --> 00:29:46,320 OTHER ILC SUBETS AS WELL, SO 806 00:29:46,320 --> 00:29:48,080 THIS WILL BE A LOT MORE TO DO 807 00:29:48,080 --> 00:29:50,080 THAT, THIS IS A SUMMARY OF LOTS 808 00:29:50,080 --> 00:29:50,440 OF OTHER LABS. 809 00:29:50,440 --> 00:29:52,240 SO I WILL END WITH 1 LAST THING 810 00:29:52,240 --> 00:29:55,960 THAT'S BEEN A BIT OF A 811 00:29:55,960 --> 00:29:58,840 CONTROVERSY AS TO WHETHER THERE 812 00:29:58,840 --> 00:30:00,560 ARE REDUNDANT OR NONREDUNDANT 813 00:30:00,560 --> 00:30:03,040 ANT FUNCTIONS BETWEEN INNATE AND 814 00:30:03,040 --> 00:30:03,560 ADAPTIVE LYMPHOCYTES. 815 00:30:03,560 --> 00:30:05,600 SO SOME PEOPLE ARGUED THAT 816 00:30:05,600 --> 00:30:07,920 ILCs ARE THERE AS A SORT OF 817 00:30:07,920 --> 00:30:10,800 EVOLUTIONARY HANG OVER ONCE WE 818 00:30:10,800 --> 00:30:12,240 EVOLVED AN ADAPTIVE IMMUNE 819 00:30:12,240 --> 00:30:14,080 SYSTEM, 1 DIDN'T REALLY REQUIRE 820 00:30:14,080 --> 00:30:16,640 INNATE LYMPHOID CELLS AND 821 00:30:16,640 --> 00:30:17,920 ADAPTIVE LYMPHOCYTES VASTLY 822 00:30:17,920 --> 00:30:19,520 OUTNUMBER ILCs SO PERHAPS 823 00:30:19,520 --> 00:30:21,800 THEY'RE NOT REQUIRED. 824 00:30:21,800 --> 00:30:23,000 IT'S VARIOUS DIFFERENT THINGS 825 00:30:23,000 --> 00:30:25,960 LIKE THAT THAT GO BACK AND FORTH 826 00:30:25,960 --> 00:30:27,720 AND I'M FAIRLY NONPARTIS AN I'M 827 00:30:27,720 --> 00:30:34,440 JUST INTERESTED IN INTO THESE 828 00:30:34,440 --> 00:30:34,680 CELLS WORK 829 00:30:34,680 --> 00:30:35,320 COOPERATIVELY--COOPERATIVELY. 830 00:30:35,320 --> 00:30:36,840 EXCUSE ME A MINUTE. 831 00:30:36,840 --> 00:30:38,760 OR IN AN INTIRELY REDUNDANT WAY. 832 00:30:38,760 --> 00:30:39,760 SO THE WAY WE START THINKING 833 00:30:39,760 --> 00:30:43,200 ABOUT IT IN THE STEADY STATE, OF 834 00:30:43,200 --> 00:30:45,040 COURSE THE LUMEN OF THE GUT IS 835 00:30:45,040 --> 00:30:47,560 ANYTHING BUT STEADY SO CONSTANT 836 00:30:47,560 --> 00:30:50,480 EXPOSURE TO NEW AND KNOWN FOOD 837 00:30:50,480 --> 00:30:54,200 ANTIGENS, THE MICROBI OTA 838 00:30:54,200 --> 00:30:56,000 CONSTANTLY CHANGING, INFECTION, 839 00:30:56,000 --> 00:30:56,920 ALLERGENS, POLLUTANTS AND DRUGS 840 00:30:56,920 --> 00:30:58,320 AND SO FORTH, ALL THESE CELLS 841 00:30:58,320 --> 00:31:00,960 ARE RESIDENT IN THE LAMINA 842 00:31:00,960 --> 00:31:03,760 PROARP RIA AND MUCOSA AND IN THE 843 00:31:03,760 --> 00:31:04,400 EPI-BLAST THELLIAL COMPARTMENT 844 00:31:04,400 --> 00:31:05,200 AND ALONG WITH WHAT WE'RE 845 00:31:05,200 --> 00:31:07,080 UNDERSTANDING ABOUT THE ROLE OF 846 00:31:07,080 --> 00:31:08,080 INNOVATION AT BIRRIER SURFACES 847 00:31:08,080 --> 00:31:09,920 AND OF COURSE THE NEUROLOGISTS 848 00:31:09,920 --> 00:31:10,680 AND NEUROSCIENTISTS WILL TELL 849 00:31:10,680 --> 00:31:17,280 YOU THERE ARE MORE NEURONS AT 850 00:31:17,280 --> 00:31:18,240 BARRIER SURFACES THAN THERE ARE 851 00:31:18,240 --> 00:31:20,360 IN THE BRAIN, IT'S 1 OF THESE 852 00:31:20,360 --> 00:31:21,760 BUT I HEAR ABOUT IT ALL THE TIME 853 00:31:21,760 --> 00:31:26,400 AND WE WERE INTERESTED IF THERE 854 00:31:26,400 --> 00:31:28,160 WERE NONREDUNDANT TWEEZE ILC2s 855 00:31:28,160 --> 00:31:31,200 AND BOTH HIGH PRODUCERS OF IL5 856 00:31:31,200 --> 00:31:34,520 AND IL13 AND RECOMMEND LOTS OF 857 00:31:34,520 --> 00:31:35,160 OTHER SHARED FACTORS. 858 00:31:35,160 --> 00:31:38,880 SO BACK TO THESE 3 PAPERS THAT 859 00:31:38,880 --> 00:31:41,080 WERE PUBLISHED IN 2017 THAT 860 00:31:41,080 --> 00:31:44,320 REPORTED THAT NMU WAS A 861 00:31:44,320 --> 00:31:45,680 STIMULANT OF ILC2s, 1 FROM MY 862 00:31:45,680 --> 00:31:48,040 LAB AND 1 FROM VQ 863 00:31:48,040 --> 00:31:50,960 [INDISCERNIBLE] AND 1 FROM 864 00:31:50,960 --> 00:31:52,680 ENRICKY [INDISCERNIBLE] IN 865 00:31:52,680 --> 00:31:55,280 LISBANE, AND ALL THESE PATES 866 00:31:55,280 --> 00:31:56,960 DIFFERENT WAYS BUT IT SHOWED 867 00:31:56,960 --> 00:31:58,320 THAT ILC2s ARE MARKED BY 868 00:31:58,320 --> 00:32:00,800 WHAT,A PEERS IN THE 869 00:32:00,800 --> 00:32:01,960 HEMATOPOIETIC COMPARTMENT AND 870 00:32:01,960 --> 00:32:04,240 NEEDS TO BE EXCLUSIVE EXPRESSION 871 00:32:04,240 --> 00:32:06,200 OF RECEPTOR 1S IF YOU--THESE ARE 872 00:32:06,200 --> 00:32:08,200 DATA FROM MY OWN LAB AND THE 873 00:32:08,200 --> 00:32:10,920 OTHERS DID SOMETHING SIMILAR, IF 874 00:32:10,920 --> 00:32:12,640 YOU GET THE POSITIVE CELLS ARE 875 00:32:12,640 --> 00:32:15,600 ABOUT 95 TO A HUNDRED% OF THEM 876 00:32:15,600 --> 00:32:17,040 ARE ILC2s, SO THIS WAS 877 00:32:17,040 --> 00:32:20,080 POTENTIALLY A WAY TO TARGET 878 00:32:20,080 --> 00:32:22,120 ILC2s GENETICALLY IN THE 879 00:32:22,120 --> 00:32:23,680 PRESENCE OF A FUNCTIONAL 880 00:32:23,680 --> 00:32:25,240 ADAPTIVE IMMUNE SYSTEM WHICH HAS 881 00:32:25,240 --> 00:32:27,280 BEEN A CHALLENGE FOR QUITE A 882 00:32:27,280 --> 00:32:27,600 WHILE. 883 00:32:27,600 --> 00:32:28,920 HERE'S THE WAY WE DID IT. 884 00:32:28,920 --> 00:32:31,360 WE MADE A MOUSE WHERE WE 885 00:32:31,360 --> 00:32:34,520 TARGETED CREE EXPRESSION TO THE 886 00:32:34,520 --> 00:32:36,760 NMU RECEPTOR TO THE LOCUST AND 887 00:32:36,760 --> 00:32:38,280 THERE'S A GFP TAG IN THERE SO 888 00:32:38,280 --> 00:32:40,520 YOU CAN REPORT AN IMMUNE 889 00:32:40,520 --> 00:32:41,640 RECEPTOR, DELETE THESE CELLS AND 890 00:32:41,640 --> 00:32:43,600 YOU CAN GENE EDIT THEM IF IT 891 00:32:43,600 --> 00:32:45,000 WORKS, SO IT WORKS PRETTY 892 00:32:45,000 --> 00:32:46,880 NICELY, CAN YOU SEE HERE JUST 893 00:32:46,880 --> 00:32:51,080 LOOKING AT IMMUNE RECEPTOR 894 00:32:51,080 --> 00:32:51,600 EXPRESSION BY EGFP. 895 00:32:51,600 --> 00:32:55,040 THEY'RE THE ONLY CELLS WE COULD 896 00:32:55,040 --> 00:32:56,200 FIND ARE ILC2s THAT ARE 897 00:32:56,200 --> 00:32:57,640 POSITIVE SO THE REPORTER SEEMS 898 00:32:57,640 --> 00:33:01,320 TO BE WORKING FOR CREE AND EGFP 899 00:33:01,320 --> 00:33:02,520 AND THAT'S ENUM RATED HERE WHEN 900 00:33:02,520 --> 00:33:03,960 WE LOOK AT EVERY OTHER CELL TYPE 901 00:33:03,960 --> 00:33:06,040 WE THINK OF AND THEN WE CROSS IT 902 00:33:06,040 --> 00:33:07,800 TO A DTR TO ASK IF THIS, THIS 903 00:33:07,800 --> 00:33:09,600 WOULD TELL US IF IT'S A 904 00:33:09,600 --> 00:33:11,160 SUCCESSFUL DELETER AND IT LOOKS 905 00:33:11,160 --> 00:33:13,000 PRETTY GOOD AND IT APPEARS TO 906 00:33:13,000 --> 00:33:15,960 DELETE ACROSS MULTIPLE TISSUES. 907 00:33:15,960 --> 00:33:16,720 WE HAVEN'T UNPUBLISHED THIS 908 00:33:16,720 --> 00:33:20,040 STUFF YET AND THEN WE TOOK AMP O 909 00:33:20,040 --> 00:33:22,120 REGUE LYNN AS A POTENTIAL TARGET 910 00:33:22,120 --> 00:33:24,720 THAT WE KNOW IT'S MADE BY 911 00:33:24,720 --> 00:33:26,000 RC2s, AS WE TOLD YOU EARLIER 912 00:33:26,000 --> 00:33:28,240 ANDY WOO KNOW IT'S MADE BY TREGS 913 00:33:28,240 --> 00:33:28,600 AND TH2 CELLS. 914 00:33:28,600 --> 00:33:31,280 SO WE DID A HEAD-TO-HEAD 915 00:33:31,280 --> 00:33:33,920 DELETION OF REGULATE IN T-CELLS 916 00:33:33,920 --> 00:33:37,720 VERSUS ILC2s AND HERE WE USE 917 00:33:37,720 --> 00:33:41,000 THE DIFFERENT HELMET FOR THIS 1 918 00:33:41,000 --> 00:33:42,080 INHABITS THE LARGE INTESTINE AND 919 00:33:42,080 --> 00:33:44,720 WE GET NICE DELETION OF AMP O 920 00:33:44,720 --> 00:33:46,520 REGUE LYNN AND WE DON'T GET ON 921 00:33:46,520 --> 00:33:47,840 THE CD4, IT'S NOT SHOWN HERE. 922 00:33:47,840 --> 00:33:53,280 BUT HERE WHEN WE LOOK AT 923 00:33:53,280 --> 00:33:54,440 [INDISCERNIBLE] BUSHEDDENS AND 924 00:33:54,440 --> 00:33:55,600 THEREY'S NO DIFFERENCE WITH IF 925 00:33:55,600 --> 00:33:59,120 WE DELETE IT IN THE ILC2s AND 926 00:33:59,120 --> 00:34:00,640 THERE'S SHOWN A HISTOLOGICALLY 927 00:34:00,640 --> 00:34:00,880 AS WELL. 928 00:34:00,880 --> 00:34:02,320 SO I WENT OVER THAT KIND OF FAST 929 00:34:02,320 --> 00:34:03,800 IN THE INTEREST OF TIME BUT I 930 00:34:03,800 --> 00:34:07,360 WILL END BACK WITH THIS CARTOON 931 00:34:07,360 --> 00:34:13,080 AS WE START TO PIECE TOGETHER IN 932 00:34:13,080 --> 00:34:14,520 MY OWN CAREER HOW WE'VE LEARNED 933 00:34:14,520 --> 00:34:17,400 SO MUCH ABOUT THE ROLE OF THE 934 00:34:17,400 --> 00:34:18,440 EPITHELIUM AND SHAPING IMMUNE 935 00:34:18,440 --> 00:34:19,040 FUNCTION THERE. 936 00:34:19,040 --> 00:34:20,000 WE'RE BEGINNING TO REALLY 937 00:34:20,000 --> 00:34:21,800 UNDERSTAND A BIRRIER SURFACES, 938 00:34:21,800 --> 00:34:25,680 HOW NEURONS ARE ALSO SHAPING THE 939 00:34:25,680 --> 00:34:26,680 IMMUNE TONE AND IMMUNOLOGIC 940 00:34:26,680 --> 00:34:28,680 RESPONSE IN THE CONTEXT OF 941 00:34:28,680 --> 00:34:31,520 WHETHER IT'S FOOD OR MICROBI OTA 942 00:34:31,520 --> 00:34:32,440 INFECTION OR ALLERGENS AND SO 943 00:34:32,440 --> 00:34:32,640 FORTH. 944 00:34:32,640 --> 00:34:33,720 AND THE HOPE IS THAT THE WORK 945 00:34:33,720 --> 00:34:38,560 THAT YOU WILL HEAR A BIT FROM 946 00:34:38,560 --> 00:34:40,240 GWEN FROM DEBROSKI IS A SAMPLER 947 00:34:40,240 --> 00:34:41,760 ON IN THE PROGRAM, WHERE THIS 948 00:34:41,760 --> 00:34:44,080 GOES NOT ONLY TO OUR OWN 949 00:34:44,080 --> 00:34:45,040 UNDERSTANDING OF MUCOSAL 950 00:34:45,040 --> 00:34:46,360 IMMUNOLOGY BUT TO PERIPHERAL 951 00:34:46,360 --> 00:34:50,640 TISSUES IN THE CONTEXT OF 952 00:34:50,640 --> 00:34:52,400 INFECTION, VACCINATION, CHRONIC 953 00:34:52,400 --> 00:34:54,080 INFLAMMATION, REPAIR, CANCER AND 954 00:34:54,080 --> 00:34:54,880 MORE RECENTLY PRECISION 955 00:34:54,880 --> 00:34:55,880 NUTRITION AS WE REALLY START TO 956 00:34:55,880 --> 00:34:58,960 THINK ABOUT HOW THIS COULD BE 957 00:34:58,960 --> 00:35:01,560 USED IN CONCERT WITH OTHER 958 00:35:01,560 --> 00:35:02,080 INTERVENTION STRATEGIES. 959 00:35:02,080 --> 00:35:04,120 SO I WILL STOP THERE, LET YOU 960 00:35:04,120 --> 00:35:06,320 READ THE ACKNOWLEDGMENTS BUT 961 00:35:06,320 --> 00:35:08,400 ENORMOUS THANKS TO BOTH AID AND 962 00:35:08,400 --> 00:35:10,480 DDK THAT SUPPORT MY LAB AND MIST 963 00:35:10,480 --> 00:35:12,000 OF COURSE, OUR OTHER FUNDERS ARE 964 00:35:12,000 --> 00:35:13,360 LISTED AND ALL OF OUR 965 00:35:13,360 --> 00:35:13,880 COLLABORATORS. 966 00:35:13,880 --> 00:35:15,160 I DON'T KNOW IF THERE'S TIME FOR 967 00:35:15,160 --> 00:35:16,560 QUESTIONS, I WOULD BE HAPPY TO 968 00:35:16,560 --> 00:35:18,480 TAKE A FEW IF ANNETTE ALLOWS, 969 00:35:18,480 --> 00:35:22,200 THAT'S IT AND APOLOGIES FOR MY 970 00:35:22,200 --> 00:35:22,560 CONGESTION. 971 00:35:22,560 --> 00:35:26,920 >> YES, I THINK THERE'S TIME FOR 972 00:35:26,920 --> 00:35:27,600 A COUPLE QUESTIONS. 973 00:35:27,600 --> 00:35:31,720 I WILL START OFF BY JUST ASKING, 974 00:35:31,720 --> 00:35:34,400 DAVID FOR THOSE REALLY ELABORATE 975 00:35:34,400 --> 00:35:35,800 NEURONAL NETWORKS ARE THEY 976 00:35:35,800 --> 00:35:38,440 DEPENDENT ON THE PRESENCE OF 977 00:35:38,440 --> 00:35:40,560 BACTERIA OR MICROBES IN THE HOST 978 00:35:40,560 --> 00:35:43,760 DEVELOPMENT OR ARE THEY SERVE AN 979 00:35:43,760 --> 00:35:45,320 INNATE--OR IS IT KNOWN, IS IT 980 00:35:45,320 --> 00:35:47,880 EVEN KNOWN? 981 00:35:47,880 --> 00:35:49,080 >> SO THAT'S A GOOD QUESTION, I 982 00:35:49,080 --> 00:35:51,720 WAS MOVING THE SCREEN AROUND. 983 00:35:51,720 --> 00:35:53,200 YOU WERE ASKING IF THE 984 00:35:53,200 --> 00:35:55,720 INNOVATION OF GUT OR OTHER 985 00:35:55,720 --> 00:35:58,400 BARRIER TISSUES ARE MIKE ON BI 986 00:35:58,400 --> 00:35:59,600 OTA ARE DEPENDENT? 987 00:35:59,600 --> 00:35:59,960 GREAT QUESTION. 988 00:35:59,960 --> 00:36:01,440 WE HAVEN'T REDERIVED ALL THE 989 00:36:01,440 --> 00:36:03,040 USEFUL REPORTER INTOS A 990 00:36:03,040 --> 00:36:04,480 GERM-FREE SETTING YET BUT IT 991 00:36:04,480 --> 00:36:04,880 WOULD BE VERY NICE. 992 00:36:04,880 --> 00:36:06,400 WE'VE DONE IT FOR A COUPLE AND 993 00:36:06,400 --> 00:36:12,320 WE'RE DOING IT RIGHT NOW, THESE 994 00:36:12,320 --> 00:36:14,480 INENERIVATION FOR PAIN RECEPTORS 995 00:36:14,480 --> 00:36:15,520 AND COLONERGIC NEURONS APPEARS 996 00:36:15,520 --> 00:36:16,960 TO BE INTACT, I THINK BUT THAT'S 997 00:36:16,960 --> 00:36:18,520 A WHOLE SET OF STUDIES THAT 998 00:36:18,520 --> 00:36:19,560 ABSOLUTELY HAS TO BE DONE. 999 00:36:19,560 --> 00:36:22,640 IT'S A GREAT QUESTION. 1000 00:36:22,640 --> 00:36:25,000 >> IF I COULD ASK A QUESTION, 1001 00:36:25,000 --> 00:36:25,480 ANNETTE? 1002 00:36:25,480 --> 00:36:27,720 >> YES, PLEASE DO. 1003 00:36:27,720 --> 00:36:28,640 >> HI, DAVID, WONDERFUL 1004 00:36:28,640 --> 00:36:30,000 PRESENTATION AND OF COURSE YOUR 1005 00:36:30,000 --> 00:36:34,320 WORK, MY QUESTION IS ABOUT HOW 1006 00:36:34,320 --> 00:36:36,640 THE NEUROPEPTIDE THAT'S IN 1007 00:36:36,640 --> 00:36:37,560 NEURO[INDISCERNIBLE] AND THE 1008 00:36:37,560 --> 00:36:40,480 RECEPTOR COME TOGETHER. 1009 00:36:40,480 --> 00:36:42,200 THEY ARE BOTH CONSTITTATIVELY 1010 00:36:42,200 --> 00:36:44,400 EXPRESSED IS IT SOLELY TO THE 1011 00:36:44,400 --> 00:36:48,800 INSULT AND THAT CAUSES SECRETION 1012 00:36:48,800 --> 00:36:52,040 AS A NEUROTRANSMITTER AND THAT 1013 00:36:52,040 --> 00:36:52,960 ENGAGES THE RECEPTOR, OR IS 1014 00:36:52,960 --> 00:36:53,960 THERE MORE TO IT. 1015 00:36:53,960 --> 00:36:55,560 >> HELLO BY THE WAY, HAVEN'T 1016 00:36:55,560 --> 00:36:56,960 SEEN YOU IN AGES. 1017 00:36:56,960 --> 00:36:59,440 WISH WE WERE IN PERSON, SO TO ME 1018 00:36:59,440 --> 00:37:00,920 1 OF THE FUNDAMENTALS OF ALL 1019 00:37:00,920 --> 00:37:04,440 THIS IS A BIT OF A BLACK BOX SO 1020 00:37:04,440 --> 00:37:07,120 HOW IS THE INNERVATION OF THESE 1021 00:37:07,120 --> 00:37:11,120 BARRIER SURFACES IN PARTICULAR 1022 00:37:11,120 --> 00:37:12,880 SENSING ENVIRONMENTAL MICROBI 1023 00:37:12,880 --> 00:37:14,080 OTA INFECTION, WHATEVER STIMULUS 1024 00:37:14,080 --> 00:37:16,840 WE TALK ABOUT, DIET, HOW ARE 1025 00:37:16,840 --> 00:37:20,360 THEY SENSING AND HOW ARE THEY 1026 00:37:20,360 --> 00:37:21,720 ACTIVATED, IS IT DIRECT, 1027 00:37:21,720 --> 00:37:25,400 EPITHELIAL, BUT WHAT WE DO KNOW 1028 00:37:25,400 --> 00:37:27,680 IS THAT NOT ONLY ILCs BUT 1029 00:37:27,680 --> 00:37:31,000 GRANULAR SIGHTS AND A SUBSET OF 1030 00:37:31,000 --> 00:37:32,200 ADAPTIVE LYMPHSIGHTEDS ARE WHAT 1031 00:37:32,200 --> 00:37:34,880 APPEARS BY THE IMAGING SO FAR 1032 00:37:34,880 --> 00:37:35,600 ARE CONSTITTATIVELY, I DON'T 1033 00:37:35,600 --> 00:37:37,680 LIKE TO USE THE TERM CO LOCALIZE 1034 00:37:37,680 --> 00:37:38,760 BECAUSE IT MEANS DIFFERENT 1035 00:37:38,760 --> 00:37:41,240 THINGS TO DIFFERENT PEOPLE, GWEN 1036 00:37:41,240 --> 00:37:44,520 WILL KILL ME IF I GET IT WRONG 1037 00:37:44,520 --> 00:37:46,160 AND ALSO--ALSO, YOU KNOW IF YOU 1038 00:37:46,160 --> 00:37:48,000 SAY CO LOCALIZE TO A 1039 00:37:48,000 --> 00:37:50,320 NEUROSCIENTIST, THEY THINK 1040 00:37:50,320 --> 00:37:51,360 IT'S--YOU'RE TALKING ABOUT 1041 00:37:51,360 --> 00:37:52,360 SYNAPSE WHICH WE'RE NOT. 1042 00:37:52,360 --> 00:37:56,960 I THINK, WHAT I CAN SAY IS 1043 00:37:56,960 --> 00:37:58,440 THEY'RE IN--CONSTITTATIVELY IN 1044 00:37:58,440 --> 00:37:59,400 CLOSE PROXIMITY APPEARS IN THE 1045 00:37:59,400 --> 00:38:01,440 TISSUES SO FAR FROM THE IMAGING 1046 00:38:01,440 --> 00:38:02,720 SO IT MAY FOR WHATEVER REASON 1047 00:38:02,720 --> 00:38:04,400 THERE'S SOMETHING CONTROLLING 1048 00:38:04,400 --> 00:38:06,600 THAT AND REGULATING THAT. 1049 00:38:06,600 --> 00:38:10,000 IT'S NOT COMPLETELY STOCHASTIC 1050 00:38:10,000 --> 00:38:11,280 BUT THEN, THOSE HEMATOPOIETIC 1051 00:38:11,280 --> 00:38:12,600 LINEAGES ARE POISED FOR THE 1052 00:38:12,600 --> 00:38:15,320 IMMEDIATE RELEASE OF PREFORMED 1053 00:38:15,320 --> 00:38:16,760 NEUROPEPTIDES LIKE NEUROMEDIN 1054 00:38:16,760 --> 00:38:17,840 AND CGRP AND ALL THOSE OTHERS 1055 00:38:17,840 --> 00:38:22,280 THAT ARE BEING STUDIED, VIP, SO 1056 00:38:22,280 --> 00:38:24,800 SO I THINK A LOT TO DO WITH 1057 00:38:24,800 --> 00:38:25,400 ANATOMY AS WELL. 1058 00:38:25,400 --> 00:38:28,240 BUT I THINK THERE'S OBVIOUSLY 1059 00:38:28,240 --> 00:38:29,120 SOMETHING CONTROLLING THAT 1060 00:38:29,120 --> 00:38:29,400 PROCESS. 1061 00:38:29,400 --> 00:38:31,920 NOW THERE MAY BE SOME SORT OF 1062 00:38:31,920 --> 00:38:33,360 SYNAPSE FORMATION, I DON'T KNOW 1063 00:38:33,360 --> 00:38:35,520 BUT I DON'T THINK ANYONE KNOWS 1064 00:38:35,520 --> 00:38:36,080 THAT YET. 1065 00:38:36,080 --> 00:38:37,960 >> ESPECIALLY BECAUSE THE 1066 00:38:37,960 --> 00:38:40,120 POSITIVE ACTORS ARE ALSO COUNTER 1067 00:38:40,120 --> 00:38:41,560 BALANCED, YOU RAISED THE POINT 1068 00:38:41,560 --> 00:38:45,600 TO USE THAT, CGRP AND OTHERS VIP 1069 00:38:45,600 --> 00:38:47,360 ARE VERY POSITIVE INHIBITORS 1070 00:38:47,360 --> 00:38:48,080 JUST THE WAY 1071 00:38:48,080 --> 00:38:50,320 NEURO[INDISCERNIBLE] IS A 1072 00:38:50,320 --> 00:38:51,000 POSITIVE ACTIVATOR, AND SOME OF 1073 00:38:51,000 --> 00:38:53,480 THE STUFF WE DID WITH JOHN, THAT 1074 00:38:53,480 --> 00:38:59,160 WE PUBLISHED LIKE AIER OR 2 AGO, 1075 00:38:59,160 --> 00:39:01,480 LIKE UNEXPECTEDLY, CGRP WAS A 1076 00:39:01,480 --> 00:39:03,560 POTENT INHIBITOR AND THAT WAS A 1077 00:39:03,560 --> 00:39:04,720 REGULATOR OF THAT ADAPTIVE 1078 00:39:04,720 --> 00:39:06,120 RESPONSE SO I THINK THERE'S A 1079 00:39:06,120 --> 00:39:07,960 LOT MORE DO THERE FOR SURE. 1080 00:39:07,960 --> 00:39:08,320 >> THANK YOU. 1081 00:39:08,320 --> 00:39:09,200 >> THANK YOU AND I THINK IN THE 1082 00:39:09,200 --> 00:39:11,560 INTEREST OF TIME WE NEED TO MOVE 1083 00:39:11,560 --> 00:39:12,160 ON. 1084 00:39:12,160 --> 00:39:13,680 >> OKAY. 1085 00:39:13,680 --> 00:39:14,640 >> THANK YOU DAVID. 1086 00:39:14,640 --> 00:39:20,480 >> THANKS A98 AND THANKS 1087 00:39:20,480 --> 00:39:20,760 EVERYONE. 1088 00:39:20,760 --> 00:39:21,760 >> OKAY, GREAT, LET ME SHARE 1089 00:39:21,760 --> 00:39:22,840 AGAIN, IT'S GREAT TO BE HERE AND 1090 00:39:22,840 --> 00:39:27,200 IT'S BEEN A PLEASURE TO BE A 1091 00:39:27,200 --> 00:39:28,680 MEMBER OF COUNCIL AND 1092 00:39:28,680 --> 00:39:29,600 OPPORTUNITY TO PRESENT AND END 1093 00:39:29,600 --> 00:39:35,400 THIS ON MY LAST TIME AND REALLY 1094 00:39:35,400 --> 00:39:35,840 FANTASTIC. 1095 00:39:35,840 --> 00:39:37,240 LET ME SEE THE SLIDES IN THE 1096 00:39:37,240 --> 00:39:38,360 APPROPRIATE MODE ONCE I GET THEM 1097 00:39:38,360 --> 00:39:42,600 TO THE RIGHT PLACE. 1098 00:39:42,600 --> 00:39:42,920 >> YEAH. 1099 00:39:42,920 --> 00:39:43,200 >> YEAH. 1100 00:39:43,200 --> 00:39:43,760 >> HERE WE GO. 1101 00:39:43,760 --> 00:39:47,320 SO I'M A NEW MEMBER OF MIST I 1102 00:39:47,320 --> 00:39:50,400 APPLIED AND CAME ON, YOU KNOW IN 1103 00:39:50,400 --> 00:39:51,000 MOST RECENT ROUND. 1104 00:39:51,000 --> 00:39:53,000 SO I WANTED TO SPEND A LITTLE 1105 00:39:53,000 --> 00:39:56,520 TIME SHOWING YOU WHAT WE STRTED 1106 00:39:56,520 --> 00:39:59,200 AND TRY TO REALLY HOW THE MIST 1107 00:39:59,200 --> 00:40:01,080 IS WORKING TO BRING 1108 00:40:01,080 --> 00:40:02,280 INVESTIGATORS TOGETHER SO BY THE 1109 00:40:02,280 --> 00:40:04,160 END, I WILL SHOW YOU A 1110 00:40:04,160 --> 00:40:05,960 COLLABORATION THEY STARTED WITH 1111 00:40:05,960 --> 00:40:10,640 ANOTHER MIST PI JUST IN THIS 50 1112 00:40:10,640 --> 00:40:11,240 YEAR OF FUNDING. 1113 00:40:11,240 --> 00:40:14,440 SO MY INTEREST IS IN THINKING 1114 00:40:14,440 --> 00:40:15,560 ABOUT TRAFFICKING AS ANNETTE 1115 00:40:15,560 --> 00:40:18,200 MENTIONED AND I WANT TO START 1116 00:40:18,200 --> 00:40:23,560 THERE BY SAYING THAT I ACTUALLY 1117 00:40:23,560 --> 00:40:25,840 THINK THAT THE ANATOMY OF OUR 1118 00:40:25,840 --> 00:40:27,240 BODY EVOLVED BENDING TOWARD 1119 00:40:27,240 --> 00:40:29,640 IMMUNOLOGY AND THAT THE 1120 00:40:29,640 --> 00:40:31,120 ANATOMICAL ARRANGEMENT OF 1121 00:40:31,120 --> 00:40:32,080 LYMPHNODE, SPLEEN AND LIVER 1122 00:40:32,080 --> 00:40:33,960 CREATE A FORTRESS THAT IS 1123 00:40:33,960 --> 00:40:35,800 CRITICAL FOR LIMITING ADVERSE 1124 00:40:35,800 --> 00:40:37,680 DISSEMINATION OF MOLECULES AND 1125 00:40:37,680 --> 00:40:40,760 SIGNALS THAT MIGHT FOR EXAMPLE 1126 00:40:40,760 --> 00:40:42,200 DRIVE SEPSIS, OTHERWISE. 1127 00:40:42,200 --> 00:40:45,040 SO WHEN REALLY LOOK AT WHERE 1128 00:40:45,040 --> 00:40:46,200 EVERYTHING'S POSITIONED WE LIKE 1129 00:40:46,200 --> 00:40:48,120 TO THINK ABOUT LYMPHNODES NOT 1130 00:40:48,120 --> 00:40:52,440 JUST AS PLACES THAT INITIATE 1131 00:40:52,440 --> 00:40:53,280 ADAPTIVE IMMUNITY BUT ALSO 1132 00:40:53,280 --> 00:40:55,360 STRUCTURES THAT FILTER TO 1133 00:40:55,360 --> 00:40:56,720 PROTECT THAT CENTRAL BLOOD 1134 00:40:56,720 --> 00:40:58,680 STREAM, YOU KNOW FROM DOWN 1135 00:40:58,680 --> 00:40:59,760 STREAM EVENTS LIEB SEPSIS. 1136 00:40:59,760 --> 00:41:03,880 BUT IN THAT LIGHT, THE INTESTINE 1137 00:41:03,880 --> 00:41:05,680 IS A PARTICULARLY POTENTIALLY 1138 00:41:05,680 --> 00:41:07,480 PRONE TO DISSEMINATION OF 1139 00:41:07,480 --> 00:41:09,720 INFLAMMATORY SIGNALS FROM THE 1140 00:41:09,720 --> 00:41:11,240 MICROBIOME AND THE LIVER IS 1141 00:41:11,240 --> 00:41:14,000 SITTING THERE, REALLY, YOU KNOW 1142 00:41:14,000 --> 00:41:16,040 RECEIVING BLOOD, NOT FROM 1143 00:41:16,040 --> 00:41:18,480 LYMPHATICS BUT FROM THE VENUS 1144 00:41:18,480 --> 00:41:19,200 CIRCULATION ACTING, I WOULD 1145 00:41:19,200 --> 00:41:24,080 ARGUE AS A FILTER. 1146 00:41:24,080 --> 00:41:25,760 AND SO, OUR POSITION IN MIST IS 1147 00:41:25,760 --> 00:41:27,280 TO--1 OF THE STRUCTURES OF MIST 1148 00:41:27,280 --> 00:41:29,200 OF COURSE IS TO THINK ABOUT 1149 00:41:29,200 --> 00:41:30,440 BASIC SCIENCE BUT WE WANT TO 1150 00:41:30,440 --> 00:41:36,920 THINK ABOUT IT FROM THE CONTEXT 1151 00:41:36,920 --> 00:41:39,320 OF UNDERSTANDING HOW REMIGHT 1152 00:41:39,320 --> 00:41:41,160 BETTER UNDERSTAND DISEASES OF 1153 00:41:41,160 --> 00:41:45,040 CHRONIC INFLAMMATION BY AND 1154 00:41:45,040 --> 00:41:47,840 IMPROVING BASIC SCIENCE AND 1155 00:41:47,840 --> 00:41:49,240 UNDERSTANDING. 1156 00:41:49,240 --> 00:41:53,360 SO THIS VENUS OUTFLOW TO THE 1157 00:41:53,360 --> 00:41:54,840 LIVER HAS REALLY CAPTIVATED OUR 1158 00:41:54,840 --> 00:41:55,720 ATTENTION ON MULTIPLE FRONTS AND 1159 00:41:55,720 --> 00:41:57,520 YOU CAN SEE HERE A MORE DETAILED 1160 00:41:57,520 --> 00:41:59,280 CARTOON OF THE SMALL INTESTINE 1161 00:41:59,280 --> 00:42:02,000 AND THE COLON AND VENUS SUPPLY 1162 00:42:02,000 --> 00:42:04,880 COMING AS THE MAJOR BLOOD SUPPLY 1163 00:42:04,880 --> 00:42:05,520 OF THE LIVER. 1164 00:42:05,520 --> 00:42:07,200 SO, YOU KNOW IN THE BE CONTEXT 1165 00:42:07,200 --> 00:42:08,800 OF THINKING ABOUT CHRONIC 1166 00:42:08,800 --> 00:42:12,000 INFLAMMATORY DISEASES, WE KNOW 1167 00:42:12,000 --> 00:42:13,640 THAT ANTITNF THERAPEUTICS ARE 1168 00:42:13,640 --> 00:42:15,120 HUGELY BENEFICIAL FOR NOT ALL 1169 00:42:15,120 --> 00:42:18,480 BUT MANY PATIENTS WHO HAVE 1170 00:42:18,480 --> 00:42:19,920 INFLAMMATORY BOWEL DISEASE SO 1171 00:42:19,920 --> 00:42:21,680 IT'S RATHER IRONIC AND WE 1172 00:42:21,680 --> 00:42:23,360 THOUGHT POTENTIALLY WORTH 1173 00:42:23,360 --> 00:42:26,360 EXPLORING BASIC SCIENCE AROUND 1174 00:42:26,360 --> 00:42:28,800 WHY ANTITUMOR OR ANTITNF 1175 00:42:28,800 --> 00:42:31,240 THERAPIES CAN ACTUALLY IN SOME 1176 00:42:31,240 --> 00:42:31,840 CASES INDUCE LIVER INJURY IN 1177 00:42:31,840 --> 00:42:34,160 PATIENT WHO IS ARE TAKING THEM 1178 00:42:34,160 --> 00:42:38,480 AND RECEIVING BENEFIT AT THE GUT 1179 00:42:38,480 --> 00:42:39,680 LEVEL FROM THIS SAME DRUG. 1180 00:42:39,680 --> 00:42:42,440 SO IT SEEMS A BIT COUNTER 1181 00:42:42,440 --> 00:42:45,000 INTUITIVE AND IT'S THAT KIND OF 1182 00:42:45,000 --> 00:42:45,800 COUNTER INATURATIVE SCENARIO WHY 1183 00:42:45,800 --> 00:42:47,640 WE THINK WE HAVE PLOAR TO LEARN 1184 00:42:47,640 --> 00:42:48,480 ABOUT BASIC SCIENCE. 1185 00:42:48,480 --> 00:42:50,720 SO IN THIS CONTEXT AND THE IN 1186 00:42:50,720 --> 00:42:53,280 THE CONTEXT OF OUR MIST GRANT 1187 00:42:53,280 --> 00:42:55,240 THAT WE'RE IN THE MIDST OF 1188 00:42:55,240 --> 00:42:59,080 LAWNCHLING 1 OF THE THINGS THAT 1189 00:42:59,080 --> 00:43:02,760 WE DID WAS USE MOUSE MODELS OF 1190 00:43:02,760 --> 00:43:03,600 INFLAMMATORY BOWEL DISEASE THAT 1191 00:43:03,600 --> 00:43:06,080 ARE DRIVEN BY TNF, 1 OF THOSE 1192 00:43:06,080 --> 00:43:08,200 ARE THE TNF ALTASDA ARE MOUSE 1193 00:43:08,200 --> 00:43:10,520 THAT'S BEEN IN THE LITERATURE OF 1194 00:43:10,520 --> 00:43:12,760 THE MOUSE MODEL FOR A COUPLE OF 1195 00:43:12,760 --> 00:43:14,840 DECADES, AND ALSO SMALL BOWEL 1196 00:43:14,840 --> 00:43:15,800 RESECTION, SO RADICAL SMALL 1197 00:43:15,800 --> 00:43:18,680 BOWEL RESECTION IN MICE IS 1198 00:43:18,680 --> 00:43:20,200 MIMICKED TO--IS MEANT TO MIMIC 1199 00:43:20,200 --> 00:43:21,840 THAT TYPE OF RESECTION THAT 1200 00:43:21,840 --> 00:43:26,320 OCCURS SOMETIME IN KIDS AFTER 1201 00:43:26,320 --> 00:43:27,720 NECK ROUGH ATOMITIZING ENTERIC 1202 00:43:27,720 --> 00:43:29,600 COLITIS AND IN THAT CONTEXT WE 1203 00:43:29,600 --> 00:43:31,080 KNOW THAT 1 OF THE MOST DOWN 1204 00:43:31,080 --> 00:43:32,800 STREAM PROBLEMS OF KIDS HAVE 1205 00:43:32,800 --> 00:43:34,240 MASSIVE SMALL BOWEL RESECTION IS 1206 00:43:34,240 --> 00:43:36,160 ACTUALLY LIVER FAILURE SO WHAT 1207 00:43:36,160 --> 00:43:38,800 INTERESTED US IS THAT ANTITNF 1208 00:43:38,800 --> 00:43:41,360 THERAPEUTICS, SO THESE ARE MOUSE 1209 00:43:41,360 --> 00:43:44,720 MONOCLONAL ANTIBODIES TARGETING 1210 00:43:44,720 --> 00:43:45,920 TNF, ACTUALLY INCREASED THE 1211 00:43:45,920 --> 00:43:47,560 PRESENCE OF BACTERIA THAT WE 1212 00:43:47,560 --> 00:43:50,280 COULD RECOVER, FROM THE LIVER 1213 00:43:50,280 --> 00:43:52,080 EITHER IN THE ILIATIC MODEL OR 1214 00:43:52,080 --> 00:43:54,880 IN THE SMALL BOWEL RESECTION 1215 00:43:54,880 --> 00:43:57,720 MODEL AND CONSEQUENTLY WE ALSO 1216 00:43:57,720 --> 00:43:59,920 SEE ELEVATED CYTOKINE RNA, SO 1217 00:43:59,920 --> 00:44:02,320 THIS WAS JUST, YOU KNOW BACTERIA 1218 00:44:02,320 --> 00:44:04,840 AS IT STOOD IN THE MOMENT THAT 1219 00:44:04,840 --> 00:44:07,360 WE SACRIFICED THE ANIMAL SO WE 1220 00:44:07,360 --> 00:44:09,560 ALSO TRIED AN ORAL LAUGHERAGE 1221 00:44:09,560 --> 00:44:11,600 THAT WE COULD TRACK USING 1222 00:44:11,600 --> 00:44:15,360 RESTRICTION ELEMENTS AND INDEED 1223 00:44:15,360 --> 00:44:19,080 AFTER GIVING A LAVAGE OF 1224 00:44:19,080 --> 00:44:23,760 CLEBSIELLA, WE WOULD FIND THAT 1225 00:44:23,760 --> 00:44:25,160 ANTITNX THERAPY WOULD INCREASE 1226 00:44:25,160 --> 00:44:28,400 THIS LIVER TRANSLOCATION OF 1227 00:44:28,400 --> 00:44:30,400 KLEBSIELLA, SO WE GOT INTERESTED 1228 00:44:30,400 --> 00:44:32,000 IN WHAT'S GOING ON UPTREME AND 1229 00:44:32,000 --> 00:44:34,120 HOW COULD THEY RESPOND 1230 00:44:34,120 --> 00:44:35,640 DIFFERENTLY FROM THE LIVER AND 1 1231 00:44:35,640 --> 00:44:42,560 THING WE NOTICED THAT VENUS 1232 00:44:42,560 --> 00:44:44,640 OUTFLOW I'VE BEEN DISCUSSING BY 1233 00:44:44,640 --> 00:44:47,320 THE LIVER GOING BY THE PORTAL 1234 00:44:47,320 --> 00:44:47,520 VAIN. 1235 00:44:47,520 --> 00:44:49,200 NORMALLY, THIS REALLY SURPRISED 1236 00:44:49,200 --> 00:44:51,560 US BUT LEUKOCYTE COUNTS IN THE 1237 00:44:51,560 --> 00:44:54,080 PORTAL VEIN APREVIATED HERE AS 1238 00:44:54,080 --> 00:44:57,520 PV, ARE ACTUALLY 2 OR 3 OR 4 1239 00:44:57,520 --> 00:44:59,800 FOLD ELEVATED COMPARED WITH 1240 00:44:59,800 --> 00:45:02,160 OTHER SYSTEMIC VENUS VESSELS AND 1241 00:45:02,160 --> 00:45:03,880 THIS INCLUDES, NUTRIFILLS AND 1242 00:45:03,880 --> 00:45:05,320 MONOCYTES AND ALSO LYMPHOCYTES, 1243 00:45:05,320 --> 00:45:09,520 AND SO HERE YOU CAN SEE THAT 1244 00:45:09,520 --> 00:45:11,960 ELEVATED INCREASE AND IT'S 1245 00:45:11,960 --> 00:45:14,520 BLUNTED BY ANTITNF SO IT LOOKS 1246 00:45:14,520 --> 00:45:15,760 LIKE IT'S INHIBITING 1247 00:45:15,760 --> 00:45:17,040 INFLAMMATION BUT WE'RE CURIOUS 1248 00:45:17,040 --> 00:45:19,880 IF IT MAY BE HOW COULD IT BE 1249 00:45:19,880 --> 00:45:20,800 DRIVING LIVER FAILURE, 1 OF THE 1250 00:45:20,800 --> 00:45:22,320 THINGS OR LIVER INFLAMMATION, 1 1251 00:45:22,320 --> 00:45:24,760 OF THE THINGS THAT WE WERE 1252 00:45:24,760 --> 00:45:26,640 WONDERING IS COULD IT BE THAT 1253 00:45:26,640 --> 00:45:29,200 THIS ENHANCED LEUKOCYTE COUNTS, 1254 00:45:29,200 --> 00:45:31,520 YOU KNOW IS IT MAYBE ROLLING OF 1255 00:45:31,520 --> 00:45:32,960 LEUKOCYTES ON THE ENDOTHELIUM. 1256 00:45:32,960 --> 00:45:34,280 AND SO, 1 OF THE THINGS THAT 1257 00:45:34,280 --> 00:45:38,720 WE'VE DONE IS WE'VE PUT TNF 1258 00:45:38,720 --> 00:45:43,440 RECEPTOR KNOCKOUT MICE, WE PUT 1259 00:45:43,440 --> 00:45:44,760 WILD-TYPE MARROW BACK INTO 1260 00:45:44,760 --> 00:45:46,160 DIFFERENT RECIPIENTS SO WE'RE 1261 00:45:46,160 --> 00:45:47,960 TRYING HERE IN TNF RECEPTOR 1262 00:45:47,960 --> 00:45:50,840 KNOCKOUT MICE TO GET 1263 00:45:50,840 --> 00:45:52,160 NONHEMATOPOIETIC CELLS LIKE 1264 00:45:52,160 --> 00:45:53,800 CELLS DELETED OF TNF RECEPTOR 1265 00:45:53,800 --> 00:45:55,000 AND WHAT YOU CAN SEE IS THAT YOU 1266 00:45:55,000 --> 00:45:59,600 DO NOT GET A COMPLETE REVERSAL 1267 00:45:59,600 --> 00:46:01,760 OF THIS ELEVATED PORTAL VENUS 1268 00:46:01,760 --> 00:46:05,000 ACCOUNT BUT WE GOT A PARTIAL 1269 00:46:05,000 --> 00:46:06,000 REVERSAL, ESPECIALLY WHEN 1270 00:46:06,000 --> 00:46:07,840 THEY'RE BOTH MISSING AND FOR 1271 00:46:07,840 --> 00:46:09,480 MONOCYTES IT'S QUITE IMPRESSIVE 1272 00:46:09,480 --> 00:46:11,320 REVERSAL OF THAT ELEVATION, SO 1273 00:46:11,320 --> 00:46:13,920 THIS IS ALSO A THING THAT WE 1274 00:46:13,920 --> 00:46:17,120 SEE, IF WE BLOCK CLASSICAL 1275 00:46:17,120 --> 00:46:19,200 ADHESION MOLECULES THAT WOULD BE 1276 00:46:19,200 --> 00:46:20,760 INVOLVED IN LEUKOCYTES AND 1277 00:46:20,760 --> 00:46:22,160 INTERACTIONS ON HE'S VESICLES, 1278 00:46:22,160 --> 00:46:25,960 SO IF WE CLOCK BETA 1 AND 2 1279 00:46:25,960 --> 00:46:26,720 INVOLVED LEUKOCYTE TRAFFICKING 1280 00:46:26,720 --> 00:46:29,080 WE CAN SEE THAT NUTRIFILLS AND 1281 00:46:29,080 --> 00:46:31,080 MONOCYTES COUNTS ARE REDUCED IN 1282 00:46:31,080 --> 00:46:35,400 THE MORTAL VEIN AND THIS RESULTS 1283 00:46:35,400 --> 00:46:37,680 IN MORE OF THE GAFFAGE BACTERIA 1284 00:46:37,680 --> 00:46:38,280 REACHING THE LIVER. 1285 00:46:38,280 --> 00:46:41,360 SO OUR MODEL IS WHAT WE'RE IN 1286 00:46:41,360 --> 00:46:43,560 THE MIDDLE OF TESTING USING 1287 00:46:43,560 --> 00:46:45,280 INTRA VILAL IMAGES IS THAT TNF 1288 00:46:45,280 --> 00:46:48,600 THAT'S MADE FROM THE INTESTINE 1289 00:46:48,600 --> 00:46:51,240 IS NOT ALWAYS JUST DRIVING 1290 00:46:51,240 --> 00:46:52,920 INFLAMMATORY DISEASE BUT IT 1291 00:46:52,920 --> 00:46:55,960 ACTUALLY ALSO ACTIVATES THE 1292 00:46:55,960 --> 00:46:58,240 MESENTERIC OUTFLOW DEEP VAIN IN 1293 00:46:58,240 --> 00:47:02,800 A MANNER THAT FACILITATES A BIT 1294 00:47:02,800 --> 00:47:03,880 OF LEUKOCYTE ROLLING WHICH YOU 1295 00:47:03,880 --> 00:47:06,040 CAN SEE HERE IN OUR INTERVITAL 1296 00:47:06,040 --> 00:47:09,120 IMAGES IN THE LOWER PANEL WE PUT 1297 00:47:09,120 --> 00:47:10,880 20 PANELS TOGETHER TO SHOW YOU 1298 00:47:10,880 --> 00:47:12,840 THE TRACKINGS THAT LEUKOCYTES 1299 00:47:12,840 --> 00:47:15,520 MAKE AND THAT THAT ROLLING 1300 00:47:15,520 --> 00:47:19,320 ACTUALLY ALLOWS FOR PHAGOCYTES 1301 00:47:19,320 --> 00:47:20,840 BETWEEN THE INTESTINE AND THE 1302 00:47:20,840 --> 00:47:23,520 LIVER TO PICK UP PHAGOCYTIC 1303 00:47:23,520 --> 00:47:24,720 CARGO AND CONSUME IT BEFORE IT 1304 00:47:24,720 --> 00:47:27,000 ARRIVES TO THE LIVER AND IN THAT 1305 00:47:27,000 --> 00:47:31,440 WAY, YOU KNOW TNF DOES HAVE A 1306 00:47:31,440 --> 00:47:33,560 ROLE PROTECTING THE LIVER SO AIM 1307 00:47:33,560 --> 00:47:35,200 1 OF OUR GRANT IS TO DIVE INTO 1308 00:47:35,200 --> 00:47:38,520 THAT IN A DEEPER WAY AND REALLY 1309 00:47:38,520 --> 00:47:40,160 TEST THIS CONCEPT THAT 1310 00:47:40,160 --> 00:47:41,320 PHAGOCYTES THAT DON'T EVEN LEAVE 1311 00:47:41,320 --> 00:47:44,800 THE BLOOD STREAM BUT SIMPLY ROLL 1312 00:47:44,800 --> 00:47:46,480 ALONG THE BLOOD VESSELS MAY HAVE 1313 00:47:46,480 --> 00:47:48,960 A ROLE OF LIMITING DISSEMINATION 1314 00:47:48,960 --> 00:47:50,040 OF MICROBES FROM THE GUT TO THE 1315 00:47:50,040 --> 00:47:51,480 LIVER AND WE THINK THIS MIGHT 1316 00:47:51,480 --> 00:47:56,040 HELP US UNDERSTAND SOME OF THE 1317 00:47:56,040 --> 00:47:57,840 48URES OF ANTI[INDISCERNIBLE] 1318 00:47:57,840 --> 00:47:59,280 THERAPEUTICS THAT ARE PUZZLING. 1319 00:47:59,280 --> 00:48:01,480 SO NORMALLY WE THINKING ABOUT 1320 00:48:01,480 --> 00:48:04,200 THE LYMPHATIC OUTFLOW FROM THE 1321 00:48:04,200 --> 00:48:05,880 INY TESTINE AND OURY 1322 00:48:05,880 --> 00:48:07,120 SOPHISTICATED OUR MOVE TO THINK 1323 00:48:07,120 --> 00:48:08,520 ABOUT THE BLOOD VASCULATURE IS 1324 00:48:08,520 --> 00:48:11,040 NEW, SO HERE I SHOW YOU THE 1325 00:48:11,040 --> 00:48:11,720 MESSENTERIEN TARY, ACTUALLY 1326 00:48:11,720 --> 00:48:15,720 DAVID BROUGHT UP THE MESOTHELIAL 1327 00:48:15,720 --> 00:48:18,280 CELLS SO MESENTERIC THATCH LINED 1328 00:48:18,280 --> 00:48:21,200 BY THE CELLS AND HOUSING ALL THE 1329 00:48:21,200 --> 00:48:23,080 LYMPHNODES IN THE GUT AND ARE IN 1330 00:48:23,080 --> 00:48:24,520 THE GUT AND WE'VE BEEN 1331 00:48:24,520 --> 00:48:27,200 INTERESTED IN THOSE AND IN THE 1332 00:48:27,200 --> 00:48:29,960 CONTEXT OF CROHN'S DISEASE, WE 1333 00:48:29,960 --> 00:48:31,040 KNOW THESE LYMPHATICS THAT ARE 1334 00:48:31,040 --> 00:48:33,720 FOUND IN FAT NOT ONLY EXPAND 1335 00:48:33,720 --> 00:48:36,440 THEMSELVES BUT THAT TERTIARY 1336 00:48:36,440 --> 00:48:38,400 LYMPHOID ORGANS DEVELOP ALONG 1337 00:48:38,400 --> 00:48:42,000 THE LYMPHATIC TRACKS THAT FEED 1338 00:48:42,000 --> 00:48:43,600 DOWN TO DRAINING LYMPHNODES AND 1339 00:48:43,600 --> 00:48:45,360 IN MOUSE MODELS WHAT WE HAVE 1340 00:48:45,360 --> 00:48:48,800 BEEN ABLE TO SEE IS THAT YOU 1341 00:48:48,800 --> 00:48:51,880 HAVE THE TNF DELTA ARE MOUSE 1342 00:48:51,880 --> 00:48:54,440 DEVELOPS THOSE STAIN TYPES WITH 1343 00:48:54,440 --> 00:48:56,520 TLOs ALONG WITH LYMPHATIC AND 1344 00:48:56,520 --> 00:48:59,920 WE END UP CONVERTS WHAT IN A 1345 00:48:59,920 --> 00:49:01,320 WILD-TYPE SCENARIO WOULD BE 1346 00:49:01,320 --> 00:49:03,280 MOVEMENT OF TRACER THAT HERE WE 1347 00:49:03,280 --> 00:49:05,200 INJECT THE PATCH DOWN TO THE 1348 00:49:05,200 --> 00:49:06,560 DRAINING LYMPHNODE THIS, IS A 1349 00:49:06,560 --> 00:49:07,720 VERY NORMAL PROCESS THAT TAKES 1350 00:49:07,720 --> 00:49:12,320 JUST A FEW MINUTES. 1351 00:49:12,320 --> 00:49:14,160 IF THESE TLOs DEVELOP FROM THE 1352 00:49:14,160 --> 00:49:17,960 CONTEXT OF CROHN'S LIKE ILEITIS, 1353 00:49:17,960 --> 00:49:20,040 THE TRACER COOPERATE PASS 1354 00:49:20,040 --> 00:49:21,640 THROUGH THE TLO, NEVER MAKE ITS 1355 00:49:21,640 --> 00:49:24,920 TO THE LYMPHNODE AND ACTUALLY 1356 00:49:24,920 --> 00:49:27,640 THE CARGO INSIDE THAT ENDS UP 1357 00:49:27,640 --> 00:49:29,040 LEAKS OUT AND WE EVEN HAVE BACK 1358 00:49:29,040 --> 00:49:32,480 FLOW AND WE THINK THAT SOME OF 1359 00:49:32,480 --> 00:49:34,760 THESE FEATURES MAY DRIVE SOME OF 1360 00:49:34,760 --> 00:49:37,080 THE PATHOLOGY BUT ON THE OTHER 1361 00:49:37,080 --> 00:49:38,800 HAND THEY PREVENT DISTEMNATION. 1362 00:49:38,800 --> 00:49:41,680 SO BACK TO THAT DISSEMINATION 1363 00:49:41,680 --> 00:49:42,320 CONCEPT. 1364 00:49:42,320 --> 00:49:44,160 SO I WANT TO SWITCH GEARS JUST A 1365 00:49:44,160 --> 00:49:47,800 LITTLE HERE AND SAY THAT AS WE 1366 00:49:47,800 --> 00:49:48,560 WERE THINKING ABOUT OUTFLOW FROM 1367 00:49:48,560 --> 00:49:51,240 THE GUT IN THE CONTEXT OF 1368 00:49:51,240 --> 00:49:54,160 CROHN'S DISEASE, I PAPER THAT 1369 00:49:54,160 --> 00:49:56,080 REALLY STRUCK US AS REALLY 1370 00:49:56,080 --> 00:50:00,480 INTERESTING WAS THAT OF A STUDY 1371 00:50:00,480 --> 00:50:02,280 CONDUCTED BY LEE VINCENT FROM 1372 00:50:02,280 --> 00:50:04,400 CINCINNATI WHERE HE WAS STUDYING 1373 00:50:04,400 --> 00:50:13,080 THE PEDIATRIC IBD SO CALLED RISK 1374 00:50:13,080 --> 00:50:13,520 COHORT. 1375 00:50:13,520 --> 00:50:15,480 AND YOU CAN SEE FROM THIS 1376 00:50:15,480 --> 00:50:16,360 PUBLICATION FROM 2014 A NUMBER 1377 00:50:16,360 --> 00:50:18,600 OF GENES THAT ARE ELEVATED AS 1378 00:50:18,600 --> 00:50:21,200 DISEASE BECOMES MORE SEVERE, SO 1379 00:50:21,200 --> 00:50:26,760 CD STANDS FOR CROHN'S DISEASE 1380 00:50:26,760 --> 00:50:28,760 AND DI FOR ULCERING FOR SEVERE 1381 00:50:28,760 --> 00:50:30,000 CONVERSION BUT WE CAN ALSO SEE 1382 00:50:30,000 --> 00:50:32,280 IS SOME OF THE MOST DOWN 1383 00:50:32,280 --> 00:50:35,200 REGULATED GENES ARE ASSOCIATED 1384 00:50:35,200 --> 00:50:36,640 WITH LIP O METABOLISM. 1385 00:50:36,640 --> 00:50:38,040 SO BEFORE JOINING OTHER 1386 00:50:38,040 --> 00:50:39,200 YAIRPINGS OF CHRONIC 1387 00:50:39,200 --> 00:50:41,200 INFLAMMATION THAT WE HAVE 1388 00:50:41,200 --> 00:50:41,920 STUDIED HAVE INVOLVED 1389 00:50:41,920 --> 00:50:44,160 CARDIOVASCULAR DISEASE AND 1390 00:50:44,160 --> 00:50:45,240 THINKING ABOUT FLIEK O PROTEINS 1391 00:50:45,240 --> 00:50:46,360 AND WE WERE INTRIGUE BODY THIS. 1392 00:50:46,360 --> 00:50:47,880 THE FIRST THING YOU THINK ABOUT 1393 00:50:47,880 --> 00:50:49,960 IS WELL, OKAY, GUT IS 1394 00:50:49,960 --> 00:50:51,160 TRANSPORTING FAT THROUGH THE 1395 00:50:51,160 --> 00:50:52,440 LYMPHATICS AND A LOT OF THESE 1396 00:50:52,440 --> 00:50:54,440 PROTEINS THAT GET DOWN REGULATED 1397 00:50:54,440 --> 00:50:56,920 IN CROHN'S DISEASE ARE 1398 00:50:56,920 --> 00:50:58,640 ASSOCIATED WITH FAT ABSORPTION 1399 00:50:58,640 --> 00:50:59,120 OF NUTRIENTS. 1400 00:50:59,120 --> 00:51:01,960 SO HERE'S A PICTURE OF THE 1401 00:51:01,960 --> 00:51:02,920 TRIGLYCERIDES AND CHOLESTEROL 1402 00:51:02,920 --> 00:51:05,280 THAT YOU BRING INTO THE ENTERO 1403 00:51:05,280 --> 00:51:08,880 SIGHT AND APO B AND APOAC1 ALL 1404 00:51:08,880 --> 00:51:10,840 CONVERGE ON THIS MICRON TO 1405 00:51:10,840 --> 00:51:12,800 ASSEMBLE THE FAT SO THAT THEY 1406 00:51:12,800 --> 00:51:19,640 CAN COME AS THIS PARTICLE INTO 1407 00:51:19,640 --> 00:51:20,920 THE ABNORMALITIES LIMINAL SPACE 1408 00:51:20,920 --> 00:51:24,400 SO THIS IS HOW YOU ABSORB FAT. 1409 00:51:24,400 --> 00:51:25,440 SOPHISTICATED WE THOUGHT MAYBE 1410 00:51:25,440 --> 00:51:27,000 THE MEANING OF THESE DATA ARE 1411 00:51:27,000 --> 00:51:28,760 THAT YOU CAN'T TRANSPORT FATS 1412 00:51:28,760 --> 00:51:30,000 NORMALLY IN CROHN'S DISEASE BUT 1413 00:51:30,000 --> 00:51:31,720 WE ACTUALLY CARRIED OUT A STUDY 1414 00:51:31,720 --> 00:51:35,440 IN HUMAN CROHN'S PATIENTS USING 1415 00:51:35,440 --> 00:51:37,120 STABLE TRACERS WHERE WE COULD 1416 00:51:37,120 --> 00:51:39,520 ATTRACT THE APPEARANCE OF THE 1417 00:51:39,520 --> 00:51:41,480 TRIGLYCERIDES INTO THE PLASMA 1418 00:51:41,480 --> 00:51:42,680 AFTER IT GOES THROUGH LYMPHATICS 1419 00:51:42,680 --> 00:51:44,400 AND GOES THROUGH THE EMILY NODES 1420 00:51:44,400 --> 00:51:46,160 AND HITS PLASMA AND WE FOUND 1421 00:51:46,160 --> 00:51:47,240 THIS IS NORMAL IN CROHN'S 1422 00:51:47,240 --> 00:51:50,760 DISEASE AND THAT MAKES SENSE 1423 00:51:50,760 --> 00:51:53,160 BECAUSE ABSORPTION OF MICRONS 1424 00:51:53,160 --> 00:51:54,560 HAPPENS REALLY PROXIMAL IN THE 1425 00:51:54,560 --> 00:51:58,800 GUT TO THE ILIUM BUT IT WAS AN 1426 00:51:58,800 --> 00:52:00,000 IMPORTANT THING THAT TO RULE OUT 1427 00:52:00,000 --> 00:52:02,000 AND IT CAUSED US TO THINK THAT 1428 00:52:02,000 --> 00:52:04,320 THESE GENES MIGHT BE MORE ABOUT 1429 00:52:04,320 --> 00:52:05,880 OTHER GLYCOPROTEINS SO WE DO 1430 00:52:05,880 --> 00:52:07,920 KNOW THAT CROHN'S PATIENTS HAVE 1431 00:52:07,920 --> 00:52:10,120 A DECREASE IN HDL CHOLESTEROL, A 1432 00:52:10,120 --> 00:52:11,880 DIFFERENT TYPE OF PROTEIN, A 1433 00:52:11,880 --> 00:52:13,640 TYPE OF PROTEIN HAVE YOU 1434 00:52:13,640 --> 00:52:16,160 MEASURED BY YOUR DOCTOR WHEN YOU 1435 00:52:16,160 --> 00:52:17,360 MEASURE YOUR CARDIOVASCULAR 1436 00:52:17,360 --> 00:52:17,600 HEALTH. 1437 00:52:17,600 --> 00:52:18,760 AND INTERESTINGLY THIS IS KNOWN 1438 00:52:18,760 --> 00:52:20,760 TO BE DECREASED IN CROHN'S 1439 00:52:20,760 --> 00:52:21,160 PATIENTS. 1440 00:52:21,160 --> 00:52:22,920 SO HDL AGAIN IS NORMALLY--HOLD 1441 00:52:22,920 --> 00:52:26,080 ON HERE, I DIDN'T MEAN TO DO 1442 00:52:26,080 --> 00:52:33,280 THAT. 1443 00:52:33,280 --> 00:52:33,720 I'M SORRY. 1444 00:52:33,720 --> 00:52:34,800 I NEED TO MOVE THIS OVER AND I 1445 00:52:34,800 --> 00:52:37,600 DON'T KNOW WHAT I DID HERE HERE, 1446 00:52:37,600 --> 00:52:39,160 HERE WE GO, IS NORMALLY MADE BY 1447 00:52:39,160 --> 00:52:41,000 THE LIVER AND ENTERS THE BLOOD 1448 00:52:41,000 --> 00:52:45,320 STREAM AND WHAT WE KNOW THE 1449 00:52:45,320 --> 00:52:46,680 TISSUE INTERACTS WITH THE TISSUE 1450 00:52:46,680 --> 00:52:48,040 CELLS TO OTHERWISE BE TOXIC AND 1451 00:52:48,040 --> 00:52:50,880 IT PICKS UP IT THROUGH ABCAC1 1452 00:52:50,880 --> 00:52:52,600 TRANSPORTER THAT DONATES 1453 00:52:52,600 --> 00:52:53,920 CLEFTERAL 2 HDL PARTICLES. 1454 00:52:53,920 --> 00:52:55,440 AND IN MOST TISSUES AND WE 1455 00:52:55,440 --> 00:52:58,320 WORKED ON THIS MANY OTHER 1456 00:52:58,320 --> 00:52:59,280 TISSUES, LIKE SKIN, ARTERY WALL 1457 00:52:59,280 --> 00:53:02,920 IN THE PAST, THIS HDL WILL CARRY 1458 00:53:02,920 --> 00:53:04,120 THAT CHOLESTEROL OUT AND 1459 00:53:04,120 --> 00:53:06,880 DISSEMESTER NAT OUT OF THE ORGAN 1460 00:53:06,880 --> 00:53:08,040 VIA THE LYMPHATICS AND 1461 00:53:08,040 --> 00:53:08,880 EVENTUALLY WILL BRING THIS BACK 1462 00:53:08,880 --> 00:53:14,720 TO THE LIVER FOR PRODUCTION OF 1463 00:53:14,720 --> 00:53:16,360 BIOACIDS BUT WHATIA NOT SHOWN ON 1464 00:53:16,360 --> 00:53:18,680 THIS CARTOON IS THAT WE'VE KNOWN 1465 00:53:18,680 --> 00:53:19,880 SINCE THE 1970S THAT THE 1466 00:53:19,880 --> 00:53:22,440 TRANSPORTER AND KEY PROTEIN 1467 00:53:22,440 --> 00:53:24,200 APOA-1 THAT FORMS AT NASCENT HDL 1468 00:53:24,200 --> 00:53:26,160 IS MADE BY THE SMALL INTESTINE. 1469 00:53:26,160 --> 00:53:27,840 AND SO YOU WOULD THINK BASED ON 1470 00:53:27,840 --> 00:53:30,800 THE FACT THAT YOU KNOW YOU HAVE 1471 00:53:30,800 --> 00:53:32,680 THIS BEAUTIFUL LYMPHATIC IN 1472 00:53:32,680 --> 00:53:35,120 EVERY VILLUS THAT THE HDL OF THE 1473 00:53:35,120 --> 00:53:36,960 INTESTINE WOULD GO OUT THROUGH 1474 00:53:36,960 --> 00:53:39,080 THE LYMPHATIC AND IN FACT IN THE 1475 00:53:39,080 --> 00:53:40,000 LITERATURE LIKE THIS REALLY NICE 1476 00:53:40,000 --> 00:53:42,120 ARTICLE THAT WAS PUBLISHED 1477 00:53:42,120 --> 00:53:45,280 SEVERAL YEARS AGO ASSUMED THAT 1478 00:53:45,280 --> 00:53:48,880 ALL DPLIEK O PROTEINS NOT JUST 1479 00:53:48,880 --> 00:53:50,480 [INDISCERNIBLE], BUT HDL MADE BY 1480 00:53:50,480 --> 00:53:51,800 THE INTESTINE GOES INTO THE 1481 00:53:51,800 --> 00:53:52,120 LIMP. 1482 00:53:52,120 --> 00:53:53,800 BUT IT COULD BE DIFFERENT IN THE 1483 00:53:53,800 --> 00:53:54,680 SMALL INTESTINE SO THINKING 1484 00:53:54,680 --> 00:53:56,720 ABOUT AGAIN ABOUT THE 1485 00:53:56,720 --> 00:53:57,920 SPECIALIZED FEATURES OF 1486 00:53:57,920 --> 00:54:04,600 DIFFERENT REGIONS OF THE GUT, WE 1487 00:54:04,600 --> 00:54:11,880 KNOW THIS HAS THE VASCULATURE 1488 00:54:11,880 --> 00:54:14,040 THAT OVERLIES THE AREA, SO IT 1489 00:54:14,040 --> 00:54:15,640 COULD BE THAT HDL DON'T FOLLOW 1490 00:54:15,640 --> 00:54:17,280 THE RULE OF GOING INTO 1491 00:54:17,280 --> 00:54:17,560 LYMPHATIC. 1492 00:54:17,560 --> 00:54:20,040 SO TO LOOK AT THIS WE ACTUALLY 1493 00:54:20,040 --> 00:54:21,640 MADE A MOUSE SEVERAL YEARS AGO 1494 00:54:21,640 --> 00:54:25,080 WHERE WE CAN PHOTO TAG HDL 1495 00:54:25,080 --> 00:54:27,480 WITHIN TISSUES BECAUSE THE HDL 1496 00:54:27,480 --> 00:54:31,280 THAT MADE HAS A PHOTO 1497 00:54:31,280 --> 00:54:32,320 ACTIVATABLE GFP DOMAINOT END 1498 00:54:32,320 --> 00:54:34,040 TERMINUS SO WE CAN SHINE THE 1499 00:54:34,040 --> 00:54:35,360 LIGHT ON DIFFERENT ORGANS AND 1500 00:54:35,360 --> 00:54:36,640 FOR EXAMPLE, WITH WHEN WE SHINE 1501 00:54:36,640 --> 00:54:37,720 LIGHT ON THE SKIN AND PAST, WE 1502 00:54:37,720 --> 00:54:39,360 WOULD TAKE THE FLUID OUT OF THE 1503 00:54:39,360 --> 00:54:41,440 SKIN AND SEE THIS FLUORESCENT 1504 00:54:41,440 --> 00:54:43,760 HDL BUT IF TIME PASSED WE WOULD 1505 00:54:43,760 --> 00:54:46,120 SEE THAT THAT FLUORESCENT HDL 1506 00:54:46,120 --> 00:54:47,840 WOULD MOVE OUT INTO THE SKIN OUT 1507 00:54:47,840 --> 00:54:48,960 OF THE SKIN AND INTO PLASMA. 1508 00:54:48,960 --> 00:54:50,360 YOU CAN SEE THAT TIME COURSE 1509 00:54:50,360 --> 00:54:52,600 HERE AND IN THIS CASE, THIS IS 1510 00:54:52,600 --> 00:54:53,560 LYMPHATIC DEPENDENT WHICH I'M 1511 00:54:53,560 --> 00:54:58,320 NOT SHOWING YOU BUT IN THE GUT, 1512 00:54:58,320 --> 00:55:01,200 WE FOUND--WE USE THE SAME TOOL. 1513 00:55:01,200 --> 00:55:04,160 WE LIT UP, WE CUT A LITTLE SLIT 1514 00:55:04,160 --> 00:55:05,600 INTO THE LUMEN OF THE INTESTINE 1515 00:55:05,600 --> 00:55:09,800 SO WE COULD LIGHT UP THE 1516 00:55:09,800 --> 00:55:11,560 INTESTINAL PRODUCED HDL AND WE 1517 00:55:11,560 --> 00:55:12,960 FOWBD THAT THE FLUORESCENCE 1518 00:55:12,960 --> 00:55:15,200 ENDED UP IN THE PORTAL VEINS AND 1519 00:55:15,200 --> 00:55:16,840 NOT THE LYMPHATICS IN THE FIRST 1520 00:55:16,840 --> 00:55:19,280 FEW MINUTES AND IT WAS NOT UNTIL 1521 00:55:19,280 --> 00:55:22,400 30 MINUTES WENT BY WHEN THE 1522 00:55:22,400 --> 00:55:23,640 WHOLE BODY COULD EQUILIBRATE 1523 00:55:23,640 --> 00:55:26,240 THAT WE WOULD SEE THAT THE HDL 1524 00:55:26,240 --> 00:55:28,480 WAS IN EVERY COMPARTMENT SO WE 1525 00:55:28,480 --> 00:55:30,840 CONCLUDED THAT THE INTESTINE 1526 00:55:30,840 --> 00:55:33,560 MAKES HDL AND PUTS IT DIRECTLY 1527 00:55:33,560 --> 00:55:35,520 INTO THE VENUS VASCULATURE TO 1528 00:55:35,520 --> 00:55:38,160 THE LIVER, NOT AT THE LYMPHATIC 1529 00:55:38,160 --> 00:55:39,720 AND IT ACTUALLY ONLY GOES INTO 1530 00:55:39,720 --> 00:55:41,360 THE LYMPHATIC WHEN IT LATER 1531 00:55:41,360 --> 00:55:42,760 ARRIVES FROM THE INTESTINE FROM 1532 00:55:42,760 --> 00:55:44,760 A LOCATION, SAY AS IT COMES IN 1533 00:55:44,760 --> 00:55:47,360 FROM THE MUSCLE SIDE. 1534 00:55:47,360 --> 00:55:49,080 NOW, WE ALSO WOULD FIND THAT THE 1535 00:55:49,080 --> 00:55:51,520 MAIN PRODUCTION OF HDL WAS AT 1536 00:55:51,520 --> 00:55:55,760 THE ILIUM, SO IT SEEMS AS THOUGH 1537 00:55:55,760 --> 00:55:58,560 HDL IS GOING TO THE PORTAL VEIN, 1538 00:55:58,560 --> 00:55:59,960 NOT THE LYMPHATICS AND MAYBE 1539 00:55:59,960 --> 00:56:00,960 IT'S REALLY BEING GENERATED IN A 1540 00:56:00,960 --> 00:56:03,040 PLACE WHERE YOU START TO SEE A 1541 00:56:03,040 --> 00:56:04,240 RICHER MICROBIOME LIKE THE ILIUM 1542 00:56:04,240 --> 00:56:06,080 SO IS THERE A ROLE IN HOST 1543 00:56:06,080 --> 00:56:08,880 DEFENSE FOR THIS HDL AND 1544 00:56:08,880 --> 00:56:09,800 PARTICULARLY PERHAPS HOST 1545 00:56:09,800 --> 00:56:11,320 DEFENSE OF THE LIVER SINCE IT 1546 00:56:11,320 --> 00:56:15,320 ENDS UP IN THIS PORTAL VENUS 1547 00:56:15,320 --> 00:56:15,600 VASCULATURE. 1548 00:56:15,600 --> 00:56:19,560 AND SO WHAT WE ENDED UP FINDING 1549 00:56:19,560 --> 00:56:21,880 BY SPECIFIC DELETION OF HDL FROM 1550 00:56:21,880 --> 00:56:22,760 THE INTESTINE, ET CETERA IN 1551 00:56:22,760 --> 00:56:24,320 ADDITION TO THE MODEL OF PHOTO 1552 00:56:24,320 --> 00:56:25,640 ACTIVATION THAT I JUST SHOWED 1553 00:56:25,640 --> 00:56:28,520 YOU, IS THAT HDL THAT'S MADE BY 1554 00:56:28,520 --> 00:56:31,840 THE SMALL INTESTINE IS ENTERING 1555 00:56:31,840 --> 00:56:33,480 THE PORTAL VAIN AND IT'S 1556 00:56:33,480 --> 00:56:34,400 ASSOCIATING WITH SPECIFIC CARGO 1557 00:56:34,400 --> 00:56:39,360 AND 1 OF THOSE IS LPS BINDING 1558 00:56:39,360 --> 00:56:40,840 PROBETWEEN OR LBP AND INSTEAD OF 1559 00:56:40,840 --> 00:56:44,040 WHEN IT ARRIVES TO THE LIVER, 1560 00:56:44,040 --> 00:56:46,840 INSTEAD OF THE LBP PRESENTING 1561 00:56:46,840 --> 00:56:48,560 LPS TO TLR4 TO DRIVE 1562 00:56:48,560 --> 00:56:49,960 INFLAMMATION THAT YOU MIGHT 1563 00:56:49,960 --> 00:56:52,880 EXPECT, IN FACT, IT'S HIDING THE 1564 00:56:52,880 --> 00:56:54,840 LPS, SO SOMEHOW ON THIS PARTICLE 1565 00:56:54,840 --> 00:56:56,600 AND WE'RE VERY INTERESTED IN THE 1566 00:56:56,600 --> 00:56:59,000 STRUCTURE OF THIS, THE LPS GETS 1567 00:56:59,000 --> 00:57:02,480 HIDDEN BY HDL AND THIS ACTUALLY 1568 00:57:02,480 --> 00:57:04,320 PREVEBTS FLAMMATION AND WE CAN 1569 00:57:04,320 --> 00:57:05,280 SO THIS DRAMATICALLY PROTECTS 1570 00:57:05,280 --> 00:57:06,440 THE LIVER IN THE SMALL SECTION 1571 00:57:06,440 --> 00:57:08,080 MODEL BUT IT LEAVES THIS BIG 1572 00:57:08,080 --> 00:57:10,280 QUESTION, WHICH IS OKAY, THE 1573 00:57:10,280 --> 00:57:11,720 INTESTINE IS MAKING AND THE 1574 00:57:11,720 --> 00:57:16,080 ILIUM IS MAKING HDL TO 1575 00:57:16,080 --> 00:57:17,920 NEUTRALIZE LPS, AND PROTECT DOWN 1576 00:57:17,920 --> 00:57:19,280 STREAM TISSUES, YOU MIGHT THINK 1577 00:57:19,280 --> 00:57:23,760 PLACES LIKE THE COLON WHICH HAVE 1578 00:57:23,760 --> 00:57:25,760 LOTS OF LPS WOULD MAKE EACH MORE 1579 00:57:25,760 --> 00:57:28,480 HDL, BUT IF YOU LOOK AT SINGLE 1580 00:57:28,480 --> 00:57:29,760 CELL SEQUENCING DAT THAT'S NOT 1581 00:57:29,760 --> 00:57:32,720 WHAT YOU SEE, THE COMPONENTS 1582 00:57:32,720 --> 00:57:34,800 LIKE APO1, ARE SEEN WELL IN THE 1583 00:57:34,800 --> 00:57:36,640 ILIUM BUT NOT THE COLON. 1584 00:57:36,640 --> 00:57:39,760 SO WE WERE ALSO CURIOUS ABOUT 1585 00:57:39,760 --> 00:57:42,360 THIS CONUNDRUM AND INCORPORATED 1586 00:57:42,360 --> 00:57:46,680 SOME PLANS TO DO BASIC RESEARCH 1587 00:57:46,680 --> 00:57:48,960 TO BETTER UNDERSTAND WHY COLON O 1588 00:57:48,960 --> 00:57:50,520 SIGHTS DON'T MAKE IT AND JUST TO 1589 00:57:50,520 --> 00:57:53,040 REVIEW, YOU KNOW WE TALKED ABOUT 1590 00:57:53,040 --> 00:57:55,280 THE FACT THAT EVERY VILLUS IN 1591 00:57:55,280 --> 00:57:57,200 THE SMALL INTESTINE HAS THIS 1592 00:57:57,200 --> 00:57:58,640 LYMPHATIC SO IT'S INTIMATE, NEAR 1593 00:57:58,640 --> 00:58:00,080 THE SURFACE AND THEN THERE'S 1594 00:58:00,080 --> 00:58:01,120 ALSO A POETIC TEBTIAL FOR 1595 00:58:01,120 --> 00:58:02,760 ABSORPTION IN THE SMALL 1596 00:58:02,760 --> 00:58:04,040 INTESTINE SO THE COLON OF COURSE 1597 00:58:04,040 --> 00:58:05,160 IS DIFFERENT AND THE STRUCTURE 1598 00:58:05,160 --> 00:58:08,200 OF THE COLON, YOU KNOW DOESN'T 1599 00:58:08,200 --> 00:58:10,640 NECESSARILY HAVE A LYMPHATIC IN 1600 00:58:10,640 --> 00:58:12,520 EVERY, YOU KNOW SCRIPT SPACE OR 1601 00:58:12,520 --> 00:58:12,760 DOES IT. 1602 00:58:12,760 --> 00:58:14,400 AND THIS IS WHAT WE ALSO BEGAN 1603 00:58:14,400 --> 00:58:16,840 TO REALIZE IS THAT WE DON'T 1604 00:58:16,840 --> 00:58:19,000 REALLY UNDERSTAND THE 3 1605 00:58:19,000 --> 00:58:20,760 DIMENSIONAL ORGANIZATION OF THE 1606 00:58:20,760 --> 00:58:25,400 COLON WITH RESPECT TO OUTFLOW 1607 00:58:25,400 --> 00:58:26,040 VESSELS LIKE LYMPHATICS. 1608 00:58:26,040 --> 00:58:28,360 SO THIS CARTOON HERE ON THE LEFT 1609 00:58:28,360 --> 00:58:30,040 DOES NOT DEPICT ANOTHER MAJOR 1610 00:58:30,040 --> 00:58:33,880 FEATURE OF THE COLON WHICH ARE 1611 00:58:33,880 --> 00:58:36,840 THESE KIND OF, THESE FOLDS, 1612 00:58:36,840 --> 00:58:38,000 WHICH ARE KNOWN IMPORTANT 1613 00:58:38,000 --> 00:58:48,360 FEATURES OF THE COLON, SO WE'VE 1614 00:58:48,360 --> 00:58:50,920 UNDERTAKEN A CLEARED APPEAR TO 1615 00:58:50,920 --> 00:58:53,120 LOOK AT 3 DIMENSIONAL STRUCTURES 1616 00:58:53,120 --> 00:58:54,480 OF THE LYMPHATICS, THEY'RE IN 1617 00:58:54,480 --> 00:58:55,920 GREEN, THE BLOOD VESSELS ARE IN 1618 00:58:55,920 --> 00:58:58,160 RED SO WHEY WANT YOU TO NOTICE, 1619 00:58:58,160 --> 00:59:00,480 I'M GOING FASTER THAN I WAS 1620 00:59:00,480 --> 00:59:03,880 THINKING IT WOULD, IS THAT IN 1621 00:59:03,880 --> 00:59:05,280 FACT THE RED GOES VERY CLOSE TO 1622 00:59:05,280 --> 00:59:07,880 THE SURFACE BUT MOST OF THE 1623 00:59:07,880 --> 00:59:11,920 LYMPHATICS ARE DOWN BELOW THE 1624 00:59:11,920 --> 00:59:13,840 KREBS, THEIR ONLY EXPRESSION TO 1625 00:59:13,840 --> 00:59:15,840 THIS IS THERE ARE A FEW LITTLE 1626 00:59:15,840 --> 00:59:17,520 TRANDS, SO THIS IS CLOSER TO THE 1627 00:59:17,520 --> 00:59:18,640 MUSCLES DOWN HERE, AS SOON AS WE 1628 00:59:18,640 --> 00:59:21,440 GET BACK TO THE EPITHELIAL, 1629 00:59:21,440 --> 00:59:23,840 THESE FEW STRANDS, THERE ARE A 1630 00:59:23,840 --> 00:59:26,320 FEW SPACES IN THOSE FOLDS, WHERE 1631 00:59:26,320 --> 00:59:28,680 THE LYMPHATICS WILL COME CLOSER 1632 00:59:28,680 --> 00:59:30,320 TO THE SURFACE. 1633 00:59:30,320 --> 00:59:31,440 SO, WE'RE CURIOUS ABOUT THOSE 1634 00:59:31,440 --> 00:59:33,520 AND THERE'S LOTS MORE TO LEARN 1635 00:59:33,520 --> 00:59:35,120 BUT OVERALL, WE CAN DEFINITELY 1636 00:59:35,120 --> 00:59:38,560 SAY THAT THE COLON IS DESIGNED 1637 00:59:38,560 --> 00:59:40,160 TO PUT AT A DISTANCE, YOU KNOW 1638 00:59:40,160 --> 00:59:42,320 THE VESSELS THAT WILL BE 1639 00:59:42,320 --> 00:59:42,800 INVOLVED IN ABSORPTION. 1640 00:59:42,800 --> 00:59:44,160 SO WE'RE TRYING TO FIGURE OUT IF 1641 00:59:44,160 --> 00:59:45,760 THAT, PLUS THE FACT THAT THE 1642 00:59:45,760 --> 00:59:48,560 COLON IS NOT ABSORBED AND THE 1643 00:59:48,560 --> 00:59:50,600 EXTRA MUCUS MIGHT REALLY CHANGE 1644 00:59:50,600 --> 00:59:53,280 HOW LPS AND OTHER CARGO ARE 1645 00:59:53,280 --> 00:59:54,640 TRANSPORTED FROM DIFFERENT 1646 00:59:54,640 --> 00:59:56,120 REGIONS OF THE GUT BUT I JUST 1647 00:59:56,120 --> 00:59:58,640 WANT TO END HERE BY SHOWING YOU 1648 00:59:58,640 --> 01:00:00,280 AN EVOLVING VIEW AND POINTING TO 1649 01:00:00,280 --> 01:00:01,760 THIS COLLABORATION THAT WE JUST 1650 01:00:01,760 --> 01:00:02,480 START BIDE INTERACTING WITH 1651 01:00:02,480 --> 01:00:04,520 GROUPS IN THE MIST ANDOOSE 1652 01:00:04,520 --> 01:00:05,920 REALLY AN EVOLVING VIEW AROUND 1653 01:00:05,920 --> 01:00:08,120 THE QUESTION OF WHAT ELSE IS 1654 01:00:08,120 --> 01:00:09,200 UNIQUE ABOUT THE ILIUM THAT 1655 01:00:09,200 --> 01:00:12,440 MIGHT BE LINKED TO HDL 1656 01:00:12,440 --> 01:00:13,720 BIOGENESIS SPECIFICALLY THERE, 1657 01:00:13,720 --> 01:00:15,560 AND YOU KNOW DISTINCTLY IN THE 1658 01:00:15,560 --> 01:00:15,880 COLON. 1659 01:00:15,880 --> 01:00:17,760 SO WE WENT BACK TO SOME OF OUR 1660 01:00:17,760 --> 01:00:20,160 DATA, IN THE GUT, YOU KNOW, THE 1661 01:00:20,160 --> 01:00:22,480 DATA WE LOOKED AT IN HDL WAS 1662 01:00:22,480 --> 01:00:24,920 REALLY MOSTLY IN THE LIVER AND 1663 01:00:24,920 --> 01:00:26,680 IN THE SMALL BALB RESECTION, WE 1664 01:00:26,680 --> 01:00:28,240 REALIZED WHEN THE INTESTINE 1665 01:00:28,240 --> 01:00:30,760 CANNOT MAKE HDL, THE GUT WAS 1666 01:00:30,760 --> 01:00:32,840 DOWN REGULATING INTERESTING 1667 01:00:32,840 --> 01:00:35,200 GENES IN CELLS AND ENTERO 1668 01:00:35,200 --> 01:00:36,000 ENDOCRINE CELLS, ET CETERA, ET 1669 01:00:36,000 --> 01:00:37,400 CETERA THAT ARE LISTED HERE SO 1670 01:00:37,400 --> 01:00:39,880 WE DO THINK THAT HDL AT THE 1671 01:00:39,880 --> 01:00:41,200 ILIUM PLAYS A ROLE AT LEAST IN 1672 01:00:41,200 --> 01:00:42,800 THE CONTEXT OF INFLAMMATION AND 1673 01:00:42,800 --> 01:00:44,320 I WOULD SAY SMALL BOWEL 1674 01:00:44,320 --> 01:00:47,360 RESECTION, INJURY TO THE 1675 01:00:47,360 --> 01:00:47,920 INTESTINE. 1676 01:00:47,920 --> 01:00:49,200 IN REGULATING OUTCOMES THERE. 1677 01:00:49,200 --> 01:00:53,000 I WANT TO POINT OUT THAT, YOU 1678 01:00:53,000 --> 01:00:55,600 KNOW THE BIOACID TRANSPORTERS 1679 01:00:55,600 --> 01:00:56,160 WERE NOT CHANGED. 1680 01:00:56,160 --> 01:00:57,600 HOWEVER, WHEN WE SET OUR SIGHTS 1681 01:00:57,600 --> 01:01:00,080 ON DOING 3 DIMENSIONAL 1682 01:01:00,080 --> 01:01:01,160 RECONSTRUCTION BY IMAGING OF 1683 01:01:01,160 --> 01:01:03,600 SOME OF THESE MEDIATORS AND 1684 01:01:03,600 --> 01:01:06,080 DIFFERENT TYPES OF EPITHELIAL 1685 01:01:06,080 --> 01:01:07,160 CELLS, [INDISCERNIBLE] WHO WAS 1686 01:01:07,160 --> 01:01:09,040 DOING THIS IN THE LAB SAID WE 1687 01:01:09,040 --> 01:01:11,800 CAN'T DO IT BECAUSE THE TISSUES 1688 01:01:11,800 --> 01:01:12,080 DISSOLVE. 1689 01:01:12,080 --> 01:01:14,800 ONLY THE KNOCK OUT, THE HDL 1690 01:01:14,800 --> 01:01:17,320 DEFICIENCY IN THE IMIUM TUMLY 1691 01:01:17,320 --> 01:01:17,600 DISSOLVED. 1692 01:01:17,600 --> 01:01:22,480 SO WHEN WE DISCOVERED THAT THE 1693 01:01:22,480 --> 01:01:24,360 TISSUE WAS DISSOLVING WE 1694 01:01:24,360 --> 01:01:27,000 IMMEDIATELY THOUGHT, OH, WOW, 1695 01:01:27,000 --> 01:01:28,720 THOSE ACIDS MIGHT BE REALLY 1696 01:01:28,720 --> 01:01:29,000 DIFFERENT. 1697 01:01:29,000 --> 01:01:32,040 SO ANOTHER COLLEAGUE IN MIST IS 1698 01:01:32,040 --> 01:01:35,200 [INDISCERNIBLE] WHO JUST MOVED 1699 01:01:35,200 --> 01:01:38,080 TO DARTMOUTH AND HE'S BEEN 1700 01:01:38,080 --> 01:01:39,280 WORKING ON ILEITIS AND HERE'S 1 1701 01:01:39,280 --> 01:01:41,400 OF HIS CORTOONS THAT REVIEWS FOR 1702 01:01:41,400 --> 01:01:43,080 YOU, WHEN THE LIVER MAKES 1703 01:01:43,080 --> 01:01:44,680 BIOACIDS THEY GET MOVED THROUGH 1704 01:01:44,680 --> 01:01:48,080 THE BILE DUCT AND IN THE ILIUM, 1705 01:01:48,080 --> 01:01:49,360 THEY'RE ACTIVELY REABSORBED AND 1706 01:01:49,360 --> 01:01:50,480 ONLY A SMALL PROPORTION ENDS UP 1707 01:01:50,480 --> 01:01:56,440 IN THE COLON AND OF COURSE 1708 01:01:56,440 --> 01:01:59,120 THEY'RE UNDERGOING ALL KIEFNEDS 1709 01:01:59,120 --> 01:01:59,840 OF MODIFICATIONS, HYDROXALATION 1710 01:01:59,840 --> 01:02:02,040 AND OTHERS IN THE MIC ROW BIOME 1711 01:02:02,040 --> 01:02:04,080 BUT HE HAS POINTED OUT THAT 1712 01:02:04,080 --> 01:02:05,840 BIOACID TOXICITY IS A REAL 1713 01:02:05,840 --> 01:02:09,160 POETIC TEBTIAL PROBLEM AT THE 1714 01:02:09,160 --> 01:02:10,320 ILIUM, THEY DISSOLVE, TISSUES 1715 01:02:10,320 --> 01:02:14,360 FOR EXAMPLE AND THEY CREATE A 1716 01:02:14,360 --> 01:02:15,280 NUMBER OF [INDISCERNIBLE] 1717 01:02:15,280 --> 01:02:15,480 STRESS. 1718 01:02:15,480 --> 01:02:17,560 SO ANOTHER FIGURE FROM HIS 1719 01:02:17,560 --> 01:02:20,600 REVIEW SHOWS T-CELLS HERE, 1720 01:02:20,600 --> 01:02:23,680 EXPRESSING THIS TRANSPORTER MDR 1721 01:02:23,680 --> 01:02:26,320 1 WHICH ACTUALLY PROGRAMS 1722 01:02:26,320 --> 01:02:27,960 T-CELLS TO RESIST BIOACID 1723 01:02:27,960 --> 01:02:30,520 TOXICITY AND IT TOO IS IN THE 1724 01:02:30,520 --> 01:02:32,640 ABC FAMILY, IN THE ABC FAMILY 1725 01:02:32,640 --> 01:02:36,320 MEMBER, BUT IT'S NOT ABCAC1, THE 1726 01:02:36,320 --> 01:02:37,440 CHOLESTEROL TRANSPORTER BUT 1727 01:02:37,440 --> 01:02:41,000 HERE'S A PICTURE OF HIS PAPER 1728 01:02:41,000 --> 01:02:45,520 WHERE HE REVEALED THAT NDR 1 OR 1729 01:02:45,520 --> 01:02:47,800 ABC 1 EXPRESSION BY T-CELLS 1730 01:02:47,800 --> 01:02:50,920 ACTUALLY IS CRITICAL FOR 1731 01:02:50,920 --> 01:02:51,680 REDUCINGOXIDATIVE STRESS, TNF 1732 01:02:51,680 --> 01:02:53,640 INDUCTION IN THE CONTEXT OF 1733 01:02:53,640 --> 01:02:54,800 ILLUMINATE YIETIS. 1734 01:02:54,800 --> 01:02:55,720 IT'S POTENTIALLY A REALLY 1735 01:02:55,720 --> 01:02:56,720 IMPORTANT FEATURE OF CROHNS 1736 01:02:56,720 --> 01:03:01,160 DISEASE SO WE HAVE NOW GONE INTO 1737 01:03:01,160 --> 01:03:04,320 THE MOUSE THAT CANNOT EXPRESS 1738 01:03:04,320 --> 01:03:06,400 INTESTINAL HDL BECAUSE IT LOOKS 1739 01:03:06,400 --> 01:03:08,360 ADCA 1 AND BLOCKS ACROSS THE 1740 01:03:08,360 --> 01:03:11,800 CREE AND WE'VE PROFILED DEEPLY 1741 01:03:11,800 --> 01:03:13,440 PROFILED BIOACID AND I JUST WANT 1742 01:03:13,440 --> 01:03:15,200 TO SHOW YOU A LITTLE SNIPIT OF 1743 01:03:15,200 --> 01:03:16,400 THIS DATA HERE. 1744 01:03:16,400 --> 01:03:18,480 AT THE ILIUM, NOT AT THE LIVER, 1745 01:03:18,480 --> 01:03:22,080 BUT AT THE ILIAL TISSUE, YOU CAN 1746 01:03:22,080 --> 01:03:24,840 SEE THAT PRIMARY BIOACIDS ARE 1747 01:03:24,840 --> 01:03:27,040 REALLY STUCK THERE IN THE 1748 01:03:27,040 --> 01:03:29,320 TISSUE, COMPARED WITH THE LITTER 1749 01:03:29,320 --> 01:03:29,560 MATE. 1750 01:03:29,560 --> 01:03:31,640 AND INDEED, IF WE LOOK AT A 1751 01:03:31,640 --> 01:03:35,440 BUNCH OF DIFFERENT COMPARTMENTS 1752 01:03:35,440 --> 01:03:38,000 FROM THE ILERAL CONTENTS TO THE 1753 01:03:38,000 --> 01:03:40,280 FECAL CONTENTS AND OTHER PLACES 1754 01:03:40,280 --> 01:03:42,640 LIKE PORTAL PLASMA AND SYSTEMIC 1755 01:03:42,640 --> 01:03:44,240 PLASMA IT APPEARS QUITE CLEARLY 1756 01:03:44,240 --> 01:03:48,160 THAT IF THE EPITHELIAL CELLS ARE 1757 01:03:48,160 --> 01:03:51,040 ABC1 NEGATIVE THAT THE TISSUE 1758 01:03:51,040 --> 01:03:52,440 EPITHELIAL CELLS JUST REALLY 1759 01:03:52,440 --> 01:03:55,240 HOLD ON TO THESE PRIMARY 1760 01:03:55,240 --> 01:03:56,960 BIOACIDS AND THAT'S CLEARLY WHAT 1761 01:03:56,960 --> 01:03:58,240 CAUSED OUR TISSUE TO DISSOLVE 1762 01:03:58,240 --> 01:04:00,840 AND WE THINK THIS WILL BE REALLY 1763 01:04:00,840 --> 01:04:03,760 IMPORTANT IN THINKING ABOUT THIS 1764 01:04:03,760 --> 01:04:06,560 CONNECTION OF DPLIEK O PROTEIN 1765 01:04:06,560 --> 01:04:07,960 MEDIATORS TO CROHN'S DISEASE SO 1766 01:04:07,960 --> 01:04:09,120 KIND OF BACK TO THIS. 1767 01:04:09,120 --> 01:04:11,160 SO THE BIG QUESTION FOR US AT 1768 01:04:11,160 --> 01:04:14,840 THE MOMENT IS IF ILIAL HDL IS 1769 01:04:14,840 --> 01:04:16,000 LINKED TO BIOACID HANDLING. 1770 01:04:16,000 --> 01:04:19,200 IF LOOKS LIKE IT FROM THE ADA 1 1771 01:04:19,200 --> 01:04:22,160 STANDPOINT, WE'RE IN THE MIDST 1772 01:04:22,160 --> 01:04:23,720 OF THIS, THERE'S NOTHING IN THE 1773 01:04:23,720 --> 01:04:26,720 LITERATURE ON THIS, WE HAVE AN 1774 01:04:26,720 --> 01:04:28,480 APOAC1 FLOCKS MOUSE, WHERE WE 1775 01:04:28,480 --> 01:04:31,600 CAN SEPARATE IS THIS HDL OR IS 1776 01:04:31,600 --> 01:04:32,400 THIS TRANSPORTER DOING SOMETHING 1777 01:04:32,400 --> 01:04:33,080 INDEPENDENT. 1778 01:04:33,080 --> 01:04:34,520 ALL OF IT IS INTERESTING AND 1779 01:04:34,520 --> 01:04:34,920 WOULD BE SURPRISING. 1780 01:04:34,920 --> 01:04:37,320 SO JUST TO END, YOU KNOW OUR 1781 01:04:37,320 --> 01:04:39,920 SECOND AIM, AS WE LAUNCHED THIS 1782 01:04:39,920 --> 01:04:41,280 INTERACTION WITH THE MIST GROUP 1783 01:04:41,280 --> 01:04:43,880 IS TO THINK ABOUT DISTEMNATION 1784 01:04:43,880 --> 01:04:45,200 OF MOLECULAR MEDIATORS WHERE OUR 1785 01:04:45,200 --> 01:04:47,160 FIRST THING WAS MORE ABOUT 1786 01:04:47,160 --> 01:04:49,560 LEUKOCYTE TRAFFICKING FROM THE 1787 01:04:49,560 --> 01:04:49,800 GUT. 1788 01:04:49,800 --> 01:04:50,760 SO, HAPPY TO END THERE. 1789 01:04:50,760 --> 01:04:52,840 I THINK I USED UP PRETTY MUCH 1790 01:04:52,840 --> 01:04:55,480 THE WHOLE 30 MINUTES OF MY TIME. 1791 01:04:55,480 --> 01:04:57,800 PERHAPS THERE'S TIME FOR A FEW 1792 01:04:57,800 --> 01:04:58,040 QUESTIONS. 1793 01:04:58,040 --> 01:05:01,120 SO, I JUST WANT TO HIGHLIGHT KEY 1794 01:05:01,120 --> 01:05:02,520 PEOPLE IN THIS WORK BECAUSE 1795 01:05:02,520 --> 01:05:06,120 THERE'S SEVERAL KEY PEOPLE TO 1796 01:05:06,120 --> 01:05:06,440 POINT OUT. 1797 01:05:06,440 --> 01:05:07,560 [INDISCERNIBLE] IS THE PERSON 1798 01:05:07,560 --> 01:05:10,120 WHO WORK ARED ON HDL FROM THE 1799 01:05:10,120 --> 01:05:11,680 GUT INITIALLY HE'S IN SOUTH 1800 01:05:11,680 --> 01:05:13,320 KOREA RUNNING HIS OWN LAB RAARE 1801 01:05:13,320 --> 01:05:14,240 TOY. 1802 01:05:14,240 --> 01:05:17,560 THE KEY IMAGING INDIVIDUALS IN 1803 01:05:17,560 --> 01:05:20,920 THE GROUP ARE BARON AND RAFAEL 1804 01:05:20,920 --> 01:05:23,480 AND HE ALSO WORKS ON TNF DELTAA, 1805 01:05:23,480 --> 01:05:26,280 AND THE CONTEXT OF TLOs AND 1806 01:05:26,280 --> 01:05:27,720 LYMPHATIC TRANSPORT AND 1807 01:05:27,720 --> 01:05:30,640 [INDISCERNIBLE] HAS BEEN WORKING 1808 01:05:30,640 --> 01:05:32,680 ON THE BIOASIGNIFYS RESEARCH 1809 01:05:32,680 --> 01:05:33,320 THAT I SHOWED. 1810 01:05:33,320 --> 01:05:35,160 SO THANKS A LOT. 1811 01:05:35,160 --> 01:05:35,920 >> THANK YOU VERY MUCH GWEN. 1812 01:05:35,920 --> 01:05:39,000 I THINK WE HAVE TIME FOR A 1813 01:05:39,000 --> 01:05:39,920 QUESTION OR 2. 1814 01:05:39,920 --> 01:05:41,560 EITHER SPEAK UP OR RAISE YOUR 1815 01:05:41,560 --> 01:05:52,120 HAND, I'LL LOOK FOR YOU AND CALL 1816 01:05:56,400 --> 01:05:56,560 ON YOU. 1817 01:05:56,560 --> 01:05:57,080 >> THANK YOU. 1818 01:05:57,080 --> 01:05:59,360 THAT WAS BEAUTIFUL, I SAW THE 1819 01:05:59,360 --> 01:06:01,480 UNUSUAL LYMPHATICS THAT ARE 1820 01:06:01,480 --> 01:06:05,120 DRAINING INTO THE CECUM AND 1821 01:06:05,120 --> 01:06:06,520 COLON, DO YOU KNOW ANYTHING 1822 01:06:06,520 --> 01:06:09,080 FURTHER ABOUT THEM AND WHAT 1823 01:06:09,080 --> 01:06:10,680 DISTINGUISHES THEM GIVEN THEY'RE 1824 01:06:10,680 --> 01:06:12,480 SOMEWHAT RARE? 1825 01:06:12,480 --> 01:06:14,960 >> YOU ARE TALKING ABOUT THOSE 1826 01:06:14,960 --> 01:06:15,320 LITTLE SPINS? 1827 01:06:15,320 --> 01:06:17,000 >> SO WE'RE TRYING TO, THERE'S A 1828 01:06:17,000 --> 01:06:19,000 WHOLE STORY BEHIND THAT THAT I 1829 01:06:19,000 --> 01:06:20,600 DIDN'T INCLUDE, SO WE'VE BEEN 1830 01:06:20,600 --> 01:06:25,720 PUTTING TRACERS INTO THE COLON, 1831 01:06:25,720 --> 01:06:28,200 AND THE BEHAVIOR AND TOTAL 1832 01:06:28,200 --> 01:06:30,040 DIFFERENT THAN THE SOLID, SO 1833 01:06:30,040 --> 01:06:31,640 SOME OF THEM ARE LUMINAL 1834 01:06:31,640 --> 01:06:31,880 TRACERS. 1835 01:06:31,880 --> 01:06:33,680 SO WE ARE TRYING TO FIGURE OUT 1836 01:06:33,680 --> 01:06:35,600 IF WE CAN GET THEM LABELED IN A 1837 01:06:35,600 --> 01:06:38,720 SPECIFIC WAY SO THIS WAY WE CAN 1838 01:06:38,720 --> 01:06:40,840 EXACERBATE THE TISSUE AND WE CAN 1839 01:06:40,840 --> 01:06:47,440 ASK WHEN WHAT YOU JUST ASKED SO 1840 01:06:47,440 --> 01:06:50,000 AT THE MOMENT WE DON'T KNOW IF 1841 01:06:50,000 --> 01:06:51,680 THOSE TAGS HAVE SPECIAL FEATURES 1842 01:06:51,680 --> 01:06:53,080 OR WHAT THEY'RE ABOUT, BUT WE 1843 01:06:53,080 --> 01:06:55,160 CAN SAY THAT ALWAYS HAPPENS IN 1844 01:06:55,160 --> 01:06:58,840 THOSE SPECIALIZED FOLDS OF THE 1845 01:06:58,840 --> 01:06:59,040 COLON. 1846 01:06:59,040 --> 01:07:02,920 AND WE--IT'S VERY CLEAR THAT OUR 1847 01:07:02,920 --> 01:07:06,400 OUTFLOW TRACERS WILL ACCUMULATE 1848 01:07:06,400 --> 01:07:07,600 IN THAT LITTLE SPACE IN THOSE 1849 01:07:07,600 --> 01:07:10,400 FOLDS SO WE THINK THIS IS A 1850 01:07:10,400 --> 01:07:11,960 CRITICAL MEDIATOR OF OUTFLOW AND 1851 01:07:11,960 --> 01:07:13,720 WHAT WE'RE FINDING THAT'S SO 1852 01:07:13,720 --> 01:07:15,800 DIFFERENT IN THE SMALL INTESTINE 1853 01:07:15,800 --> 01:07:18,720 IS THAT AS THAT MATERIAL 1854 01:07:18,720 --> 01:07:20,520 ACCUMULATES, SOME OF IT DRAINING 1855 01:07:20,520 --> 01:07:26,920 OUT IN A PERIVENUS ROOT WHICH IS 1856 01:07:26,920 --> 01:07:29,560 VERY SIMILAR TO THE MENENG ESE, 1857 01:07:29,560 --> 01:07:31,560 AND 0 DIFFERENT THAN THE SMALL 1858 01:07:31,560 --> 01:07:31,840 INTESTINE. 1859 01:07:31,840 --> 01:07:34,240 BUT IT'S ALL DIFFERENT IF WE TIE 1860 01:07:34,240 --> 01:07:35,680 OUT THE LYMPHATICS IT ALL PUSHES 1861 01:07:35,680 --> 01:07:35,880 BACK. 1862 01:07:35,880 --> 01:07:40,240 SO I DON'T KNOW WHY, THESE 1863 01:07:40,240 --> 01:07:41,520 LITTLE THINGS STICK OUT. 1864 01:07:41,520 --> 01:07:45,280 ONE IDEA I HAVE ABOUT THE FOLD 1865 01:07:45,280 --> 01:07:46,680 IS THAT, YOU KNOW 1866 01:07:46,680 --> 01:07:48,280 [INDISCERNIBLE] HAS ARGUED THAT 1867 01:07:48,280 --> 01:07:51,280 THESE ARE PLACES WHERE 1868 01:07:51,280 --> 01:07:52,720 PARTICULAR MICROBIOME MIGHT BE 1869 01:07:52,720 --> 01:07:54,720 ENRICHED SO THAT MIGHT BE AREAS 1870 01:07:54,720 --> 01:07:56,120 WHERE LYMPHATIC OUTPUT WAS 1871 01:07:56,120 --> 01:07:57,320 REALLY, REALLY IMPORTANT BUT YOU 1872 01:07:57,320 --> 01:08:00,760 KNOW AT THE MOMENT, I'M TOTALLY 1873 01:08:00,760 --> 01:08:01,480 OPEN TO IDEAS. 1874 01:08:01,480 --> 01:08:06,000 WE ARE TRYING TO, YOU KNOW 1875 01:08:06,000 --> 01:08:06,600 DETERMINE DISTINGUISHING 1876 01:08:06,600 --> 01:08:08,440 FEATURES AND CAN WE JUST GET RID 1877 01:08:08,440 --> 01:08:09,120 OF THOSE. 1878 01:08:09,120 --> 01:08:11,880 I WILL JUST TAKE 1 QUICK COMMENT 1879 01:08:11,880 --> 01:08:13,280 AS A TEASER, EVERGHT THING I WAS 1880 01:08:13,280 --> 01:08:14,840 GOING TO PRESENT TODAY BUT 1881 01:08:14,840 --> 01:08:16,240 DIDN'T, WAS A PAPER WE HAD 1882 01:08:16,240 --> 01:08:20,400 ACCEPTED ON FRIDAY, WHICH IS ALL 1883 01:08:20,400 --> 01:08:21,880 ABOUT BIOELASTIC COALIC ACID 1884 01:08:21,880 --> 01:08:22,800 CONTROLLING IMMUNE FUNCTION IN 1885 01:08:22,800 --> 01:08:24,200 THE GUT AND AS PERIPHERAL 1886 01:08:24,200 --> 01:08:25,440 TISSUES IN THE GUT SO I THINK 1887 01:08:25,440 --> 01:08:26,760 YOU AND MARK HAVE SOMETHING TO 1888 01:08:26,760 --> 01:08:27,800 TALK ABOUT THE END OF THE 1889 01:08:27,800 --> 01:08:28,520 MEETING FOR SURE. 1890 01:08:28,520 --> 01:08:30,360 >> YEAH, WE HAVE LOTS TO TALK 1891 01:08:30,360 --> 01:08:30,680 ABOUT, TOO. 1892 01:08:30,680 --> 01:08:31,680 >> I KNOW, I KNOW. 1893 01:08:31,680 --> 01:08:32,760 I'M LOOKING FORWARD TO IT. 1894 01:08:32,760 --> 01:08:34,400 >> SO JUST TO SAY WE'VE ONLY HAD 1895 01:08:34,400 --> 01:08:37,400 1 MEETING SO FAR AND IT'S BEEN 1896 01:08:37,400 --> 01:08:37,680 ON SCROOM. 1897 01:08:37,680 --> 01:08:41,720 SO, LOOKING FORWARD TO MORE. 1898 01:08:41,720 --> 01:08:43,480 REAL LIEOF THE MIST INTERACTION. 1899 01:08:43,480 --> 01:08:44,960 >> THANK YOU, BEAUTIFUL TALK. 1900 01:08:44,960 --> 01:08:46,680 >> GWEN I HAVE A QUESTION IF 1901 01:08:46,680 --> 01:08:49,320 ANNETTE IS THERE TIME FOR 1902 01:08:49,320 --> 01:08:51,040 ANOTHER QUESTION. 1903 01:08:51,040 --> 01:08:52,280 >> WE'RE RIGHT AT 2:10 SO IT'S 1904 01:08:52,280 --> 01:08:53,560 UP TO YOU. 1905 01:08:53,560 --> 01:08:58,160 >> YES, PLEASE, PLEASE! 1906 01:08:58,160 --> 01:08:58,720 >> PLEASE, PLEASE! 1907 01:08:58,720 --> 01:09:02,160 >> WELL IT'S A REALLY LOVELY 1908 01:09:02,160 --> 01:09:03,040 PRESENTATION, THE KIND OF WORK 1909 01:09:03,040 --> 01:09:05,000 YOU CAN DO IN THE MOUSE BUT 1910 01:09:05,000 --> 01:09:07,760 WOULD BE EXTRAORDINARILY HARD TO 1911 01:09:07,760 --> 01:09:11,960 DO IN HUMANS BUT THEN YOU 1912 01:09:11,960 --> 01:09:15,080 ALLUDED TO THE PUZZLING 1913 01:09:15,080 --> 01:09:17,200 QUESTIONS ABOUT ANTITNF THERAPY 1914 01:09:17,200 --> 01:09:18,560 AND LIVER BIOLOGY THAT YOU WANT 1915 01:09:18,560 --> 01:09:20,720 TO PURSUE, AND I WAS HOPING YOU 1916 01:09:20,720 --> 01:09:22,960 COULD ELABORATE A LITTLE BIT ON 1917 01:09:22,960 --> 01:09:24,880 WHAT THOSE APPROACHES MIGHT BE 1918 01:09:24,880 --> 01:09:29,240 AND WHERE YOU MIGHT BE STYMIED 1919 01:09:29,240 --> 01:09:32,920 BY THIS WORKING IN HUMANS? 1920 01:09:32,920 --> 01:09:35,960 >> YEAH, SO, A BIG COMPONENT OF 1921 01:09:35,960 --> 01:09:37,840 OUR GRANT THAT WE'RE, YOU KNOW 1922 01:09:37,840 --> 01:09:40,480 WE'RE REALLY LAUNCHING NOW, WE 1923 01:09:40,480 --> 01:09:42,360 LET A BUNCH OF BATCHES CATCH UP 1924 01:09:42,360 --> 01:09:44,160 OF TISSUE BUT WE'RE TRYING TO 1925 01:09:44,160 --> 01:09:47,200 PROFILE ACROSS THE GUT DIFFERENT 1926 01:09:47,200 --> 01:09:49,080 VENUS COMPARTMENTS, AND WE CAN'T 1927 01:09:49,080 --> 01:09:50,600 REALLY DO THIS IN THE MOUSE SO 1928 01:09:50,600 --> 01:09:51,680 WELL BECAUSE THE MOUSE IS SO 1929 01:09:51,680 --> 01:09:52,880 TINY AND OF COURSE WE WOULD LIKE 1930 01:09:52,880 --> 01:09:55,000 FOR IT TO BE RELEVANT IN YOU HAD 1931 01:09:55,000 --> 01:09:56,360 PLAN SO WE'RE SAMPLING PIGLETS 1932 01:09:56,360 --> 01:10:00,280 AND WE HAVE A CONTRACT WITH AN 1933 01:10:00,280 --> 01:10:01,000 INVESTIGATOR NAMED KD--SALLY 1934 01:10:01,000 --> 01:10:03,320 WHERE WE CAN GO IN, IN THE 1935 01:10:03,320 --> 01:10:04,720 BIGLET MODEL IN THE LIVER INJURY 1936 01:10:04,720 --> 01:10:06,080 THERE'S A NUMBER OF REALLY NICE 1937 01:10:06,080 --> 01:10:09,640 MODELS ABOUT YOU HOO AS A SMALL 1938 01:10:09,640 --> 01:10:10,560 BOWEL RESECTION MODEL WHICH IS 1939 01:10:10,560 --> 01:10:11,960 NOT PART OF OUR GRANT AND OUR 1940 01:10:11,960 --> 01:10:13,640 GRANT WE'RE TRYING TO DO THE 1941 01:10:13,640 --> 01:10:14,720 BASIC SCIENCE PROFILING OF 1942 01:10:14,720 --> 01:10:20,680 DIFFERENT REGIONS BUT WHAT WE'RE 1943 01:10:20,680 --> 01:10:22,680 THINKING IS THAT IN FACT, 1944 01:10:22,680 --> 01:10:23,840 CHANGING LEUKOCYTES ABILITY TO 1945 01:10:23,840 --> 01:10:25,360 SAMPLE AND ROLL ALONG THE 1946 01:10:25,360 --> 01:10:26,600 VESSELS IS YOU KNOW AT HEART OF 1947 01:10:26,600 --> 01:10:28,600 SOME OF THE PROBLEMS IT CAN 1948 01:10:28,600 --> 01:10:31,360 DEVELOP IN THE LIVER, AREA WHERE 1949 01:10:31,360 --> 01:10:35,480 WE'RE STYMIED, IS THAT SURGICAL 1950 01:10:35,480 --> 01:10:37,120 MANIPULATION EFFECTS ACTUALLY 1951 01:10:37,120 --> 01:10:38,720 LIKE MONOCYTES AND NUTRIFILLS 1952 01:10:38,720 --> 01:10:40,000 MASSIVELY GO BACK TO THE BONE 1953 01:10:40,000 --> 01:10:43,720 MARROW AND SEE WE LOSE SOME OF 1954 01:10:43,720 --> 01:10:46,960 THE SENSITIVITY OF THE DATA IN 1955 01:10:46,960 --> 01:10:48,920 SOME OF OUR IMAGING PROTOCOLS, 1956 01:10:48,920 --> 01:10:51,560 SO THAT ALSO MEANS THAT IN A 1957 01:10:51,560 --> 01:10:53,760 HUMAN SCENARIO WHERE SURGERY IS 1958 01:10:53,760 --> 01:10:55,240 HAPPENING WE DON'T GET THE SAME 1959 01:10:55,240 --> 01:10:57,800 RESULT AS IF THERE ISN'T A 1960 01:10:57,800 --> 01:10:58,400 SURGERY. 1961 01:10:58,400 --> 01:11:00,640 SO THERE ARE SOME OBSTACLES TO 1962 01:11:00,640 --> 01:11:01,920 TRANSLATING IT TO HUMANS, WE'RE 1963 01:11:01,920 --> 01:11:03,360 HOPING THAT THE PIGLET MODEL 1964 01:11:03,360 --> 01:11:05,120 WILL BE SOMETHING THAT CAN BE 1965 01:11:05,120 --> 01:11:07,040 REALLY, REALLY HELPFUL AND THE 1966 01:11:07,040 --> 01:11:07,640 BEAUTY--THE BEAUTY OF THE 1967 01:11:07,640 --> 01:11:10,840 PICTURE IS THAT IT HAS A NORMAL 1968 01:11:10,840 --> 01:11:11,160 PROFILE. 1969 01:11:11,160 --> 01:11:15,120 THE MOUSE IS VERY SKEWED TO HDL 1970 01:11:15,120 --> 01:11:16,160 IN A NONCARDIOVASCULAR DISEASE 1971 01:11:16,160 --> 01:11:19,160 SETTING BUT THE BIGLET REALLY 1972 01:11:19,160 --> 01:11:20,800 HAS--THE PIGLET HAS THE OPTION 1973 01:11:20,800 --> 01:11:23,800 FOR PARENTAL NUTRITION AND YOU 1974 01:11:23,800 --> 01:11:25,160 KNOW VARIOUS OTHERS--SO THIS IS 1975 01:11:25,160 --> 01:11:26,000 WHERE WE LANDING. 1976 01:11:26,000 --> 01:11:29,080 IT SHOULD BE MORE TRANSLATIONAL 1977 01:11:29,080 --> 01:11:31,600 IN THAT WAY. 1978 01:11:31,600 --> 01:11:36,160 >> GREAT. 1979 01:11:36,160 --> 01:11:37,480 THANK YOU. 1980 01:11:37,480 --> 01:11:42,600 >> THANK YOU GWEN, AND NOW 1981 01:11:42,600 --> 01:11:53,160 DR. DEBROSKI, YOU CAN SHARE YOUR 1982 01:11:55,400 --> 01:11:55,560 SLIDES. 1983 01:11:55,560 --> 01:11:56,680 >> CAN YOU SEE THAT? 1984 01:11:56,680 --> 01:11:57,600 >> YES, IT LOOKS GOOD. 1985 01:11:57,600 --> 01:12:00,800 >> SO THANK YOU ANNETTE AND 1986 01:12:00,800 --> 01:12:02,240 NIAID STAFF FOR INVITING ME 1987 01:12:02,240 --> 01:12:04,440 TODAY AND BEING PART OF THIS 1988 01:12:04,440 --> 01:12:05,840 TRIO OF INVESTIGATORS IN THE 1989 01:12:05,840 --> 01:12:08,800 MIST THAT ARE GOING TO KIND OF 1990 01:12:08,800 --> 01:12:11,480 DESCRIBE TO YOU OUR EFFORTS. 1991 01:12:11,480 --> 01:12:12,680 I JUST--TO TELL YOU ABOUT 1992 01:12:12,680 --> 01:12:14,400 MYSELF, I LIKE TO START OFF WITH 1993 01:12:14,400 --> 01:12:15,240 A SLIDE AS SUCH. 1994 01:12:15,240 --> 01:12:17,880 THIS IS A GREAT TEACHING SLIDE 1995 01:12:17,880 --> 01:12:20,800 FOR THE VET OPPORTUNITIES AT 1996 01:12:20,800 --> 01:12:22,880 PENNVET, I SPENT MY ENTIRE 1997 01:12:22,880 --> 01:12:25,400 CAREER THINK BEING THIS CLASS OF 1998 01:12:25,400 --> 01:12:27,160 ORGANISMS, YOU KNOW HOOK WARMS 1999 01:12:27,160 --> 01:12:28,760 AND THEY'RE ALWAYS GREAT FOR 2000 01:12:28,760 --> 01:12:31,120 FEAR PACT FACTOR OR WOW FACTOR 2001 01:12:31,120 --> 01:12:33,400 IN THEIR BIOLOGY WITH EITHER 2002 01:12:33,400 --> 01:12:35,200 THEIR CUTTING PLATES OR TEETH 2003 01:12:35,200 --> 01:12:37,200 DEPENDING ON THE HOOK WORM 2004 01:12:37,200 --> 01:12:37,560 SPECIES. 2005 01:12:37,560 --> 01:12:43,040 BUT THE REASON WHY I THINK THAT 2006 01:12:43,040 --> 01:12:44,000 MUCOSAL IMMUNOLOGY HAS BEEN AT 2007 01:12:44,000 --> 01:12:47,880 THE CENTER OF MY ENTIRE CAREER 2008 01:12:47,880 --> 01:12:49,480 IN BIOMEDICAL RESEARCH IS MOSTLY 2009 01:12:49,480 --> 01:12:50,960 CAPTURED BY THIS IMAGE ON THE 2010 01:12:50,960 --> 01:12:53,080 FAR LEFT. 2011 01:12:53,080 --> 01:12:55,880 YOU CAN SEE HERE SOME ADULT 2012 01:12:55,880 --> 01:12:58,560 PARASITE REALLY LATCHED ON TO 2013 01:12:58,560 --> 01:13:00,520 THE GASTROINTESTINAL MUCOSA AND 2014 01:13:00,520 --> 01:13:02,880 THESE ORGANISMS CAN SURVIVE UP 2015 01:13:02,880 --> 01:13:05,880 TO A DECADE IN THEIR HOST BEFORE 2016 01:13:05,880 --> 01:13:09,640 THEY'RE OFTEN REPLACED BY NEW 2017 01:13:09,640 --> 01:13:11,840 PARASITES THAT ARE ESTABLISHED 2018 01:13:11,840 --> 01:13:14,880 THIS NICHE. 2019 01:13:14,880 --> 01:13:16,840 THERE'S A VARIETY OF ISSUES 2020 01:13:16,840 --> 01:13:18,560 AROUND THAT FORM DISEASE THAT 2021 01:13:18,560 --> 01:13:19,440 UNFORTUNATELY STILL EXIST IN THE 2022 01:13:19,440 --> 01:13:22,000 U.S. AS WELL AS PLACES ACROSS 2023 01:13:22,000 --> 01:13:24,480 THE GLOBE AND IN THE DEVELOPING 2024 01:13:24,480 --> 01:13:26,080 WORLD AND 1 MOST NOTABLY IS THAT 2025 01:13:26,080 --> 01:13:28,920 THERE ARE NO VACCINES, 2026 01:13:28,920 --> 01:13:31,040 REINFECTION RATES ARE HIGH 2027 01:13:31,040 --> 01:13:32,680 AND--BUT WHAT WE LOOK AT IN THE 2028 01:13:32,680 --> 01:13:35,760 LAB IS HOW THESE ORGANISMS BY 2029 01:13:35,760 --> 01:13:36,720 FOLLOWING THEIR UNIQUE BIOLOGY 2030 01:13:36,720 --> 01:13:43,600 HOW MUCH WE CAN LEARN ABOUT THE 2031 01:13:43,600 --> 01:13:45,560 BASIC TENNANTs OF THE MUCOSAL 2032 01:13:45,560 --> 01:13:46,080 SYSTEM. 2033 01:13:46,080 --> 01:13:47,800 BECAUSE THESE PARASITES FOR A 2034 01:13:47,800 --> 01:13:49,080 CERTAIN DECADE IF THEY'RE IN THE 2035 01:13:49,080 --> 01:13:50,520 HOST NEED TO,A VOID THE IMMUNE 2036 01:13:50,520 --> 01:13:52,480 SYSTEM AND THEY DO THAT BY A 2037 01:13:52,480 --> 01:13:56,760 VARIETY OF DIFFERENT MECHANISMS, 2038 01:13:56,760 --> 01:13:59,320 MANY OF WHICH WHOLE LOT THE 2039 01:13:59,320 --> 01:14:00,880 INVESTIGATORS HAVE INVESTIGATED 2040 01:14:00,880 --> 01:14:06,080 AND TODAY WE ARE DEFER - 2041 01:14:06,080 --> 01:14:06,880 -DEFINITELY USING MORE 2042 01:14:06,880 --> 01:14:08,760 INFORMATION ABOUT THE HOOK WORM 2043 01:14:08,760 --> 01:14:09,840 AND IMMUNE SYSTEMS AND I WILL 2044 01:14:09,840 --> 01:14:12,160 TELL YOU A BRIEF STORY BY 2045 01:14:12,160 --> 01:14:12,800 STUDYING THEIR BIOLOGY. 2046 01:14:12,800 --> 01:14:14,120 BUT BRINGING THIS BACK, I THINK 2047 01:14:14,120 --> 01:14:15,400 THE LAST PRESENTER, I WANTED TO 2048 01:14:15,400 --> 01:14:17,200 BRING THIS BACK TO SOME OF THE 2049 01:14:17,200 --> 01:14:19,440 COMMENTS THAT DR. FAUCI MADE 2050 01:14:19,440 --> 01:14:23,200 WITH THE OVERARCHING GOAL OF 2051 01:14:23,200 --> 01:14:24,160 NIAID AND PARTICULARLY OF MIST 2052 01:14:24,160 --> 01:14:28,400 IS TO REALLY COME UP WITH WAYS 2053 01:14:28,400 --> 01:14:30,800 TO SAVE LIVES, RIGHT? 2054 01:14:30,800 --> 01:14:32,560 WE'RE IN THE PANDEMIC AND 2055 01:14:32,560 --> 01:14:34,920 THERE'S A WHOLE HOST OF VIRUSES 2056 01:14:34,920 --> 01:14:37,520 BUT ALSO MANY OTHER PATHOGENS 2057 01:14:37,520 --> 01:14:39,360 WHICH WE JUST REALLY DO HAVE AN 2058 01:14:39,360 --> 01:14:41,920 UNMET NEED FOR VACCINE COVERAGE 2059 01:14:41,920 --> 01:14:45,520 AND SO I KIND OF GRABBED THIS 2060 01:14:45,520 --> 01:14:48,440 RECENT REVIEW AND JUST GOING 2061 01:14:48,440 --> 01:14:51,280 OVER, HERE'S--YOU KNOW SARS 2062 01:14:51,280 --> 01:14:55,360 COV-2 DUCKED INTO THESE OTHER 2063 01:14:55,360 --> 01:15:00,880 BACTERIAL PATHOGENS LIKE STREP, 2064 01:15:00,880 --> 01:15:01,960 THERE'S RSV, AND CERTAINLY IN 2065 01:15:01,960 --> 01:15:05,280 THE GI TRACT THERE ARE A WHOLE 2066 01:15:05,280 --> 01:15:08,240 HOST OF PATHOGENIC BACTERIA THAT 2067 01:15:08,240 --> 01:15:12,680 WE NEED VACCINES FOR AS WELL AS 2068 01:15:12,680 --> 01:15:14,160 IN THE GENITAL/URINARY TRACT. 2069 01:15:14,160 --> 01:15:18,080 WE HEARD ABOUT HIV, THE TOOL BOX 2070 01:15:18,080 --> 01:15:20,560 THAT WE HAVE BUT CERTAINLY WE 2071 01:15:20,560 --> 01:15:22,520 STILL NEED BONA FIDE VACCINES 2072 01:15:22,520 --> 01:15:29,320 THERE AND HEPATITIS HEPATITIS O 2073 01:15:29,320 --> 01:15:31,040 THERE'S A HUGE NEED FOR THE MIST 2074 01:15:31,040 --> 01:15:33,280 PROGRAM I THINK IT REALLY 2075 01:15:33,280 --> 01:15:34,680 CAPTURES SOME OF THE MOST 2076 01:15:34,680 --> 01:15:35,480 PREEMINENT SCIENTISTS IN THE 2077 01:15:35,480 --> 01:15:38,000 FIELD AS YOU JUST HEARD FROM 2078 01:15:38,000 --> 01:15:39,440 DAVID AND GWEN IN THE ELEGANT 2079 01:15:39,440 --> 01:15:41,080 WORK THAT THEY'RE DOING TO TRY 2080 01:15:41,080 --> 01:15:42,600 TO UNDERSTAND MORE ABOUT THESE 2081 01:15:42,600 --> 01:15:44,920 MUCOSAL SERVICES SO KEY CAN 2082 01:15:44,920 --> 01:15:48,080 DEVELOP VACCINES TO PREVENT THE 2083 01:15:48,080 --> 01:15:49,800 NEXT FOR SURE HAPPENING 2084 01:15:49,800 --> 01:15:50,320 BIOLOGICAL THREAT. 2085 01:15:50,320 --> 01:15:51,880 SO WHAT'S THE PROBLEM? 2086 01:15:51,880 --> 01:15:52,120 , RIGHT? 2087 01:15:52,120 --> 01:15:54,960 THERE ARE A NUMBER OF ISSUES 2088 01:15:54,960 --> 01:15:59,440 WHEN 1 NEEDS TO--1 DESIRES TO 2089 01:15:59,440 --> 01:16:01,200 VACCINATE AT THE MUCOSAL SURFACE 2090 01:16:01,200 --> 01:16:03,040 SO THIS SLIDE IS DESIGNED TO 2091 01:16:03,040 --> 01:16:06,960 CAPTURE SOME OF THOSE CHALLENGES 2092 01:16:06,960 --> 01:16:09,280 TO TO VACCINATION. 2093 01:16:09,280 --> 01:16:11,200 YOU KNOW, YOU MAY THINK OF THIS 2094 01:16:11,200 --> 01:16:14,320 AS THE GI TRACT JUST AS WELL AS 2095 01:16:14,320 --> 01:16:15,800 THE RESTIER REVIEWATTORY TRACT 2096 01:16:15,800 --> 01:16:19,400 BUT ANY GIIVE ACSEEN WOULD NEED 2097 01:16:19,400 --> 01:16:20,400 TO WITHSTAND THE CLINICAL 2098 01:16:20,400 --> 01:16:22,040 GENETICS DODGE NOWS MUCUS LAYER 2099 01:16:22,040 --> 01:16:25,240 OR ALL THE PROTEASE ACTIVITY 2100 01:16:25,240 --> 01:16:27,080 THAT IS OFTEN PRESENT. 2101 01:16:27,080 --> 01:16:30,080 CERTAINLY THERE ARE SPECIALIZED 2102 01:16:30,080 --> 01:16:31,480 DEPOTS FOR ANTIGEN ACQUISITION 2103 01:16:31,480 --> 01:16:32,680 AND TO GET ANTIGENS TO THE RIELT 2104 01:16:32,680 --> 01:16:37,120 PLACE AND TO THE RIGHT CELLS, IS 2105 01:16:37,120 --> 01:16:39,200 STILL A VERY MUCH A CHALLENGE. 2106 01:16:39,200 --> 01:16:45,760 I'M GOING TO TELL YOU A BIT 2107 01:16:45,760 --> 01:16:47,080 ABOUT DENDRITIC CELLS, DENDRITIC 2108 01:16:47,080 --> 01:16:49,480 CELLS TODAY THAT WE'VE UNCOVERED 2109 01:16:49,480 --> 01:16:51,760 BUT, MOVING ALONG, YOU KNOW, 2110 01:16:51,760 --> 01:16:54,440 THEN YOU NEED TO GET THE ANTIGEN 2111 01:16:54,440 --> 01:16:57,200 PASSED THIS MUCOSAL SURFACE OR 2112 01:16:57,200 --> 01:16:58,840 PAST EPITHELIUM, WHETHER IT'S 2113 01:16:58,840 --> 01:17:00,000 TIGHT JUNCTIONS AND YOU KNOW 2114 01:17:00,000 --> 01:17:01,880 THERE'S BEEN A LARGE BODY OF 2115 01:17:01,880 --> 01:17:04,080 WORK INDICATING HOW DENDRITIC 2116 01:17:04,080 --> 01:17:05,840 CELLS COME IN MANY DIFFERENT 2117 01:17:05,840 --> 01:17:07,880 FLAVORS AND DISTINCT SUBSETS, 2118 01:17:07,880 --> 01:17:09,040 MANY OF THEM ARE TOLL-LIKE 2119 01:17:09,040 --> 01:17:11,000 RECEPTORRER GENIC IN THE GI 2120 01:17:11,000 --> 01:17:12,880 TRACT SO EVEN VACCINATION COULD 2121 01:17:12,880 --> 01:17:15,960 LEAD TO HITTING THE ROLE DC 2122 01:17:15,960 --> 01:17:17,040 SUBSET, NOT TO THE TYPE OF 2123 01:17:17,040 --> 01:17:22,520 RESPONSE THAT WOULD LEAD TO HOST 2124 01:17:22,520 --> 01:17:23,800 PROTECTIVE IMMUNITY. 2125 01:17:23,800 --> 01:17:25,320 AND SO TARGETING HAS BEEN A 2126 01:17:25,320 --> 01:17:26,840 LONG-TERM INTEREST OF MINE AND 2127 01:17:26,840 --> 01:17:28,960 IT STILL STANDS TO BE A BIRRIER 2128 01:17:28,960 --> 01:17:29,720 SURFACESSIER BUT REALLY WHAT I 2129 01:17:29,720 --> 01:17:33,800 WANT TO GET TO TODAY IS 2130 01:17:33,800 --> 01:17:36,480 WHEN--AND SO NICELY INTRODUCED 2131 01:17:36,480 --> 01:17:41,400 BY GWEN, WE WANT TO GET THE 2132 01:17:41,400 --> 01:17:44,000 RIGHT LYMPHOID TISSUE PRIMED 2133 01:17:44,000 --> 01:17:47,680 WITH OUR VACCINE OF INTEREST, 2134 01:17:47,680 --> 01:17:47,880 RIGHT? 2135 01:17:47,880 --> 01:17:49,880 SO NOT ONLY DO WE NEED THE RIGHT 2136 01:17:49,880 --> 01:17:51,480 ANTIGEN BUT WE WILL GET TO THE 2137 01:17:51,480 --> 01:17:52,280 RIGHT LYMPHOCYTES AND THE RIGHT 2138 01:17:52,280 --> 01:17:54,120 PLACE AND THE RIGHT TIME TO 2139 01:17:54,120 --> 01:17:58,000 AVOITD THE WRONG IMMUNE 2140 01:17:58,000 --> 01:17:58,360 PHENOTYPE. 2141 01:17:58,360 --> 01:17:59,960 AND WHAT I WANT TO ARGUE TODAY 2142 01:17:59,960 --> 01:18:01,680 IS THAT CYTOKINES MAY BE PART 2143 01:18:01,680 --> 01:18:02,760 AND PARCEL TO ANSWER HOW TO 2144 01:18:02,760 --> 01:18:06,280 DIRECT SOME OF THIS. 2145 01:18:06,280 --> 01:18:06,560 RIGHT? 2146 01:18:06,560 --> 01:18:11,320 SO, IT'S REALLY CATCHING ON THAT 2147 01:18:11,320 --> 01:18:12,520 INCLUDING CYTOKINES, AS 2148 01:18:12,520 --> 01:18:14,200 ADJUVANTS TO HELP TO DIRECT THE 2149 01:18:14,200 --> 01:18:17,440 TYPES OF IMMUNE RESPONSES NEEDED 2150 01:18:17,440 --> 01:18:18,360 FOR PROTECTIVE IMMUNITY MIGHT 2151 01:18:18,360 --> 01:18:19,760 REALLY HOLD SOME OF THE PROMISE 2152 01:18:19,760 --> 01:18:21,280 THAT WE NEED IN MOVING FORWARD 2153 01:18:21,280 --> 01:18:23,640 BECAUSE A LOT OF INSTANCES, WE 2154 01:18:23,640 --> 01:18:24,920 HAVE THE RIGHT ANTIJEVENS BUT 2155 01:18:24,920 --> 01:18:26,880 WE'RE NOT LISTENING IN THE RIGHT 2156 01:18:26,880 --> 01:18:28,840 IMMUNE RESPONSES, AND PERHAPS 2157 01:18:28,840 --> 01:18:30,040 BOTH CYTOKINES, WE COULD DO 2158 01:18:30,040 --> 01:18:37,160 THIS, YOU KNOW, MY COLLEAGUES 2159 01:18:37,160 --> 01:18:40,520 HERE AND OTHER MEMBERS OF THE 2160 01:18:40,520 --> 01:18:42,960 MIFULT, BORIS AND CHRIS WE ARE 2161 01:18:42,960 --> 01:18:46,480 PART OF THE PENN INSTITUTE FOR 2162 01:18:46,480 --> 01:18:48,320 INFECT YOWZ DECEASES AND SWRO 2163 01:18:48,320 --> 01:18:49,600 NOTTIC DISEASES. 2164 01:18:49,600 --> 01:18:53,000 SOPHISTICATED AND WE'RE USING 2165 01:18:53,000 --> 01:18:55,720 IMEULOGIOLOGY TO FORCE A MODEL 2166 01:18:55,720 --> 01:18:58,520 AND IL7 IS THE LAB THAT IS 2167 01:18:58,520 --> 01:19:01,080 NEEDED TO HELP AUGMENT MRNA 2168 01:19:01,080 --> 01:19:02,520 ACNATION IN THE ANIMAL MODEL. 2169 01:19:02,520 --> 01:19:03,720 SO KIND OF WATCH THAT SPACE AND 2170 01:19:03,720 --> 01:19:06,640 WE ARE DOING A LOT OF THINGS 2171 01:19:06,640 --> 01:19:07,040 HERE AT PEIN, N. 2172 01:19:07,040 --> 01:19:09,120 BUT LAWEDDER DALE I WANT TO GET 2173 01:19:09,120 --> 01:19:10,920 TO IS THE CYTOKINE THAT IS NEAR 2174 01:19:10,920 --> 01:19:13,160 AND DEAR TO MY HEART AND 1 THAT 2175 01:19:13,160 --> 01:19:15,320 DAVID INTRODUCED AND THAT IS 2176 01:19:15,320 --> 01:19:17,600 METAAT THAT TIMIC IL1 SUPER 2177 01:19:17,600 --> 01:19:19,440 FAMILY AND IL1S CYTOKINE VS LONG 2178 01:19:19,440 --> 01:19:22,680 BEEN RECOGNIZED THAT THEY COULD 2179 01:19:22,680 --> 01:19:24,520 AUGMENT VACCINE INDUCED IMMUNE 2180 01:19:24,520 --> 01:19:25,800 RESPONSES AND THAT'S PERHAPS 2181 01:19:25,800 --> 01:19:27,840 BECAUSE THE NATURAL BIOLOGY OF 2182 01:19:27,840 --> 01:19:29,000 THE IL1 FAMILY CYTOKINE CANS 2183 01:19:29,000 --> 01:19:31,280 THAT OF BEING RELEASED AT SIGHTS 2184 01:19:31,280 --> 01:19:32,680 OF TISSUE INJURY AND DEATH. 2185 01:19:32,680 --> 01:19:36,320 WE NOW KNOW THERE ARE A VARIETY 2186 01:19:36,320 --> 01:19:39,960 OF DIFFERENT FLAVORS OF DEATH 2187 01:19:39,960 --> 01:19:44,160 AND POPITOSEIS, ON AND LET ALONE 2188 01:19:44,160 --> 01:19:46,280 PROCESSING AND APOPTOSIS BUT 2189 01:19:46,280 --> 01:19:49,160 THESE PROCESSES OFTEN LEAD TO 2190 01:19:49,160 --> 01:19:51,600 ELABORATION IL1 FAMILY 2191 01:19:51,600 --> 01:19:52,000 CYTOKINES. 2192 01:19:52,000 --> 01:19:53,480 IL1 BETA, IL18 AND I'M GOING TO 2193 01:19:53,480 --> 01:19:57,080 TALK TO YOU TODAY A LOT ABOUT 2194 01:19:57,080 --> 01:19:57,560 IL13. 2195 01:19:57,560 --> 01:20:00,800 SO, THIS IS MODEL CAPTURES THE 2196 01:20:00,800 --> 01:20:04,360 IDEA THAT PERHAPS IN LOOKING AT 2197 01:20:04,360 --> 01:20:05,880 HOW CYTOKINES AND ENDOGENOUS 2198 01:20:05,880 --> 01:20:08,000 REGULATORS OF THE ADAPTIVE 2199 01:20:08,000 --> 01:20:11,200 IMMUNITY, INNATE AND ADAPTIVE 2200 01:20:11,200 --> 01:20:14,520 IMMUNITY THAT BY LEARNING MORE 2201 01:20:14,520 --> 01:20:16,040 ABOUT THEIR SOURCES AND THE 2202 01:20:16,040 --> 01:20:18,960 DIFFERENT CONTEXT IN WHICH THEY 2203 01:20:18,960 --> 01:20:21,400 AUGMENT OR MODULATE THESE 2204 01:20:21,400 --> 01:20:25,000 RESPONSES, WE CAN DEVELOP BETTER 2205 01:20:25,000 --> 01:20:26,840 VACCINES, THAT'S REALLY THE MAIN 2206 01:20:26,840 --> 01:20:27,160 STATEMENT. 2207 01:20:27,160 --> 01:20:28,440 SO TAKE SOMETHING THE BODY 2208 01:20:28,440 --> 01:20:30,240 NORMALLY MAKES THAT HAS A SIGN 2209 01:20:30,240 --> 01:20:32,000 OF INJURY OR DAMAGE AND WAKES UP 2210 01:20:32,000 --> 01:20:34,640 THE IMMUNE SYSTEM AND 2211 01:20:34,640 --> 01:20:35,880 INCORPORATE THAT INTO VACCINES 2212 01:20:35,880 --> 01:20:38,000 THAT ARE GOING TO BE ROBUST AND 2213 01:20:38,000 --> 01:20:40,120 HOPEFULLY LONG LIVE VACCINE 2214 01:20:40,120 --> 01:20:42,520 RESPONSES AND IT'S NOT A NEW 2215 01:20:42,520 --> 01:20:44,600 IDEA REALLY, THERE'S IDEAS THAT 2216 01:20:44,600 --> 01:20:47,000 ARE AROUND FOR A LITTLE WHILE. 2217 01:20:47,000 --> 01:20:48,560 HERE'S AN EXCERPT FROM--THIS IS 2218 01:20:48,560 --> 01:20:51,000 AS FAR AS IN 2010 SO ABOUT, YOU 2219 01:20:51,000 --> 01:20:53,680 KNOW 12 YEARS AGO, BUT INCLUDING 2220 01:20:53,680 --> 01:20:57,960 THE IL1 FAMILY OF CYTOKINES INTO 2221 01:20:57,960 --> 01:21:01,240 HA SUBUNIT VACCINES AGAINST FLU, 2222 01:21:01,240 --> 01:21:03,240 IS LISTED VERY PROFOUND ANTIBODY 2223 01:21:03,240 --> 01:21:04,800 RESPONSE IN SALIVA AND THERE'S A 2224 01:21:04,800 --> 01:21:07,560 WASH FLUID WHICH IS REALLY WHERE 2225 01:21:07,560 --> 01:21:09,360 WE WANT THOSE ANTIBODY TITERS, 2226 01:21:09,360 --> 01:21:09,560 RIGHT? 2227 01:21:09,560 --> 01:21:10,720 THAT'S WHAT'S ROUGH ATOM TECTING 2228 01:21:10,720 --> 01:21:11,320 PEOPLE RIGHT NOW. 2229 01:21:11,320 --> 01:21:17,880 SO LOOK AT THIS, IL1 ALPHA, IL1 2230 01:21:17,880 --> 01:21:19,520 BETA, IL18 AND HERE'S MY 2231 01:21:19,520 --> 01:21:20,760 FAVORITE IL33 AND SO I WAS 2232 01:21:20,760 --> 01:21:24,040 TRYING TO HIGHLIGHT FOR YOU 2233 01:21:24,040 --> 01:21:30,800 THAT, YOU KNOW THERE IS AN 2234 01:21:30,800 --> 01:21:32,760 APPRECIATION FOR USING ALARMINS 2235 01:21:32,760 --> 01:21:35,080 AND UNDERSTANDING THE BIOLOGY OF 2236 01:21:35,080 --> 01:21:37,920 ALARMINS IS KEY TO THIS PROCESS. 2237 01:21:37,920 --> 01:21:39,760 O IL33, IL33 AS ALREADY 2238 01:21:39,760 --> 01:21:42,680 MENTIONED IS A MEMBER OF THE 2239 01:21:42,680 --> 01:21:45,920 SUPERFAMILY, IT SIGNALS THROUGH 2240 01:21:45,920 --> 01:21:48,920 HETERODYNAMMIC RECEPTOR AND 2241 01:21:48,920 --> 01:21:50,360 ACCESSORY PROTEIN AND ST2, AND 2242 01:21:50,360 --> 01:21:52,320 THESE ARE LARGELY ATTRACTED TO 2243 01:21:52,320 --> 01:21:59,600 THE IL33 RESPONSE OF THE CELLS 2244 01:21:59,600 --> 01:22:01,800 AND ONCE ENGAGED IT CIRCLES 2245 01:22:01,800 --> 01:22:07,840 THROUGH THE RECEPTOR SIGNALS AND 2246 01:22:07,840 --> 01:22:10,440 INVOLVING NF-KAPPAB SIGNALING. 2247 01:22:10,440 --> 01:22:12,640 IL33 HAS LONG BEEN APPRECIATED 2248 01:22:12,640 --> 01:22:15,280 TO BE CONSTITTATIVELY EXPRESSED 2249 01:22:15,280 --> 01:22:17,880 CYTOKINE AT BARRIER SURFACES, 2250 01:22:17,880 --> 01:22:20,400 INVESTIGATORS LIKE GERARD AND 2251 01:22:20,400 --> 01:22:21,160 COLLEAGUES WHO ORIGEALLY 2252 01:22:21,160 --> 01:22:22,120 IDENTIFIED THIS MOLECULE IN 2253 01:22:22,120 --> 01:22:26,160 PLACES LIKE THE SKIN, AND THE 2254 01:22:26,160 --> 01:22:27,480 INTESTINE AND THE, HERE, IT'S 2255 01:22:27,480 --> 01:22:29,360 KIND OF A CROSS SECTION THROUGH 2256 01:22:29,360 --> 01:22:36,040 THE VILLI AND THE AIR WAY 2257 01:22:36,040 --> 01:22:37,480 EPITHELIUM, HAVE REALLY KIND OF 2258 01:22:37,480 --> 01:22:39,000 STIMULATED INTENSE INTEREST AND 2259 01:22:39,000 --> 01:22:41,440 HOW THE CYTOKINE WANTS ITS 2260 01:22:41,440 --> 01:22:43,040 RELEASE FROM DAMAGED CELLS CAN 2261 01:22:43,040 --> 01:22:44,960 LEAD TO ROBUST IMMUNE RESPONSES 2262 01:22:44,960 --> 01:22:48,440 BUT THOSE IMMUNE RESPONSES THAT 2263 01:22:48,440 --> 01:22:49,680 IL33 ILLICITS HAVE BECOME MORE 2264 01:22:49,680 --> 01:22:51,000 AND MORE COMPLEX THE MORE 2265 01:22:51,000 --> 01:22:52,600 THEY'VE BEEN STUDIED AND IT 2266 01:22:52,600 --> 01:22:55,080 FIRST STARTED OUT AS IL33 TYPE 2 2267 01:22:55,080 --> 01:22:58,560 RESPONSES AND NOW, I DARE SAY 2268 01:22:58,560 --> 01:23:00,440 THERE'S NOT 1 TYPE OF CONONICLE 2269 01:23:00,440 --> 01:23:02,960 RESPONSE THAT WE UNDERSTAND IN 2270 01:23:02,960 --> 01:23:04,200 T-CELL ADAPTIVE IMMUNITY THAT 2271 01:23:04,200 --> 01:23:05,880 IL33 DOESN'T HAVE SOME KIND OF A 2272 01:23:05,880 --> 01:23:07,080 ROLE. 2273 01:23:07,080 --> 01:23:09,200 AND ALSO IN CHRONIC DISEASE, WE 2274 01:23:09,200 --> 01:23:13,000 HEARD ABOUT SOME OF THE NIAID 2275 01:23:13,000 --> 01:23:16,760 PRIORITIES IN FOOD ALLERGY, 2276 01:23:16,760 --> 01:23:20,960 THESE ARE EXCERPTS FROM--THESE 2277 01:23:20,960 --> 01:23:23,760 ARE IMAGES FROM ESOPHAGEAL 2278 01:23:23,760 --> 01:23:27,840 BIOPSIES OF PATIENTS WITH EOE OR 2279 01:23:27,840 --> 01:23:28,760 EOCENOPHILIC ESOF GIETIS. 2280 01:23:28,760 --> 01:23:34,920 YOU CAN SEE THE BASAL CELLS HERE 2281 01:23:34,920 --> 01:23:37,760 AND THE ESOPHAGUS ARE FULL OF 2282 01:23:37,760 --> 01:23:41,400 IL33 AND IT'S ENVISIONED THAT 2283 01:23:41,400 --> 01:23:43,760 UPON AN INJURYIOUS EVENT THE 2284 01:23:43,760 --> 01:23:45,600 IL33 AND ELABORATED AND HELPS 2285 01:23:45,600 --> 01:23:47,000 DRIVE THE PATHOPHYSIOLOGY OF 2286 01:23:47,000 --> 01:23:47,320 THIS DISEASE. 2287 01:23:47,320 --> 01:23:50,120 CAN YOU SEE HERE THE NUMBER OF 2288 01:23:50,120 --> 01:23:53,280 IL33 POSITIVE BASAL CELLS AND 2289 01:23:53,280 --> 01:23:56,240 ACTIVE EOE PATIENTS 2290 01:23:56,240 --> 01:23:57,440 SIGNIFICANTLY HIRE THAN THAT 2291 01:23:57,440 --> 01:24:00,120 THAN THOSE INACTIVE PATIENTS WHO 2292 01:24:00,120 --> 01:24:00,520 ARE INITIATIVE. 2293 01:24:00,520 --> 01:24:02,680 SO, YOU KNOW WHAT WE'VE BEEN 2294 01:24:02,680 --> 01:24:05,520 INTERESTED IN 33, FOR QUITE A 2295 01:24:05,520 --> 01:24:08,160 FEW YEARS, AND YOU KNOW WHAT 2296 01:24:08,160 --> 01:24:10,320 REALLY PERTURBED ME HOW IMAGES 2297 01:24:10,320 --> 01:24:11,680 SUCH AS THIS, PARTICULARLY 2298 01:24:11,680 --> 01:24:12,640 BECOMING DOGMA AND I THINK SOME 2299 01:24:12,640 --> 01:24:14,520 OF THE WORK THAT I'M GOING TO 2300 01:24:14,520 --> 01:24:16,600 SHOW YOU TODAY HELPS TO 2301 01:24:16,600 --> 01:24:18,200 CHALLENGE THAT OR AT LEAST 2302 01:24:18,200 --> 01:24:22,720 EXPAND THE VIEW AS WAS POINTED 2303 01:24:22,720 --> 01:24:22,960 OUT. 2304 01:24:22,960 --> 01:24:26,040 IT HAS LONG BEEN THOUGHT THAT 2305 01:24:26,040 --> 01:24:28,720 IL33 WAS SOLELY A DAMAGE 2306 01:24:28,720 --> 01:24:30,720 RELEASED PRODUCT OF, YOU KNOW 2307 01:24:30,720 --> 01:24:33,360 INJURED CELLS, WE RELEASE THIS 2308 01:24:33,360 --> 01:24:34,440 AND GOING--ONCE IL33 MADE IT OUT 2309 01:24:34,440 --> 01:24:37,480 TO THE EXTRA CELLULAR SPACE, IT 2310 01:24:37,480 --> 01:24:38,760 WAS ENGAGE RECEPTOR EXPRESS ON A 2311 01:24:38,760 --> 01:24:43,080 VARIETY OF DIFFERENT CELL TYPES. 2312 01:24:43,080 --> 01:24:45,760 AND HIGHLIGHTED FOR YOU HOW 2313 01:24:45,760 --> 01:24:48,520 ILC2s, USE IL33 AS A MAJOR 2314 01:24:48,520 --> 01:24:50,560 STIMULUS BUT ALSO IT WAS 2315 01:24:50,560 --> 01:24:52,320 ORIGINALLY IDENTIFIED AS A MASS 2316 01:24:52,320 --> 01:24:58,640 CELL AND ACTIVATING CYTOKINE. 2317 01:24:58,640 --> 01:25:00,680 AND RECENTLY POWERING AND OTHERS 2318 01:25:00,680 --> 01:25:02,800 HAVE DEMONSTRATED 33, HAS THE 2319 01:25:02,800 --> 01:25:05,880 ANTIINFLAMMATORY ROLE IN BEING A 2320 01:25:05,880 --> 01:25:06,920 GREAT ACTIVATOR TREG EXPANSION 2321 01:25:06,920 --> 01:25:12,520 IN THE GUT AND ACTUALLY 2322 01:25:12,520 --> 01:25:13,640 ENFORCING THE IMMUNOSUPPRESSIVE 2323 01:25:13,640 --> 01:25:16,160 CHARACTER OF CERTAIN T-CELLS, 2324 01:25:16,160 --> 01:25:18,320 TREG SUBSETS, SO YOU KNOW WHAT 2325 01:25:18,320 --> 01:25:20,080 PERTURBED ME ABOUT THIS ENTIRE 2326 01:25:20,080 --> 01:25:26,240 MODEL WAS THAT A CELL INJURY 2327 01:25:26,240 --> 01:25:27,840 EVENT COULD MEDIATE SUCH 2328 01:25:27,840 --> 01:25:28,400 DESPERATE OUTCOMES. 2329 01:25:28,400 --> 01:25:29,800 IT JUST SEEMED LIKE THERE WAS 2330 01:25:29,800 --> 01:25:31,080 SOMETHING MISSING THAT WE NEEDED 2331 01:25:31,080 --> 01:25:38,360 TO UNDERSTAND ABOUT THE BIOLOGY 2332 01:25:38,360 --> 01:25:38,760 OF THE CYTOKINE. 2333 01:25:38,760 --> 01:25:40,880 AND WE HAD A BIT OF A INSIGHT IN 2334 01:25:40,880 --> 01:25:43,480 THIS WORK, WHERE MY GROUP WAS IN 2335 01:25:43,480 --> 01:25:44,640 CINCINNATI WHERE FOR VARIOUS 2336 01:25:44,640 --> 01:25:47,160 REASONS WE DECIDED TO SORT CELLS 2337 01:25:47,160 --> 01:25:48,480 THAT WERE THE EPITHELIAL CELLS 2338 01:25:48,480 --> 01:25:50,360 OR IN THE MYELOID COMPARTMENT, 2339 01:25:50,360 --> 01:25:52,040 AND YOU KNOW I'M NOT TALKING 2340 01:25:52,040 --> 01:25:53,560 ABOUT TRIPLE FACTORS TODAY, IT 2341 01:25:53,560 --> 01:25:55,200 WAS ANOTHER KIND OF DAMAGE 2342 01:25:55,200 --> 01:25:57,240 INDUCED MOLECULE OF THE AREA 2343 01:25:57,240 --> 01:25:58,680 SURFACES BUT WE WE FOUND WAS 2344 01:25:58,680 --> 01:26:00,840 THAT IL33 AT LEAST AT THE 2345 01:26:00,840 --> 01:26:02,200 TRANSCRIPT LEVEL COULD BE 2346 01:26:02,200 --> 01:26:04,080 EXPRESSED IN BOTH EPITHELIALS 2347 01:26:04,080 --> 01:26:06,680 COMPARTMENT AS WELL AS A MYELOID 2348 01:26:06,680 --> 01:26:09,680 COMPARTMENT, 11 C AND CONONICLE 2349 01:26:09,680 --> 01:26:11,440 FEATURE AT LEAST IN THE LUNG FOR 2350 01:26:11,440 --> 01:26:14,320 THE MACROPHAGES AND AS WELL AS 2351 01:26:14,320 --> 01:26:17,040 DENDRITIC CELLS. 2352 01:26:17,040 --> 01:26:20,280 NOW, MOST INVESTIGATORS WOULD 2353 01:26:20,280 --> 01:26:20,960 HAVE COMPLETELY--LOOKEDDA THE 2354 01:26:20,960 --> 01:26:23,800 DIFFERENCE IN SCALE AND IGNORED 2355 01:26:23,800 --> 01:26:24,720 THIS, RIGHT? 2356 01:26:24,720 --> 01:26:27,640 BECAUSE CLEARLY EPITHELIAL 2357 01:26:27,640 --> 01:26:29,880 CELLS, THE ORDER OF MAGNITUDE 2358 01:26:29,880 --> 01:26:31,160 GREATER SOURCE OF IL33 THAN 2359 01:26:31,160 --> 01:26:33,040 ANYTHING IN THE MYELOID 2360 01:26:33,040 --> 01:26:33,840 COMPARTMENT COULD EXPRESS AND I 2361 01:26:33,840 --> 01:26:35,480 THINK THIS IS WHY MANY 2362 01:26:35,480 --> 01:26:37,680 INVESTIGATORS EVEN USING IL33 2363 01:26:37,680 --> 01:26:39,080 REPORTER MICE HAVE MISSED THIS 2364 01:26:39,080 --> 01:26:40,720 BECAUSE THEY'RE LOOKING AT MAJOR 2365 01:26:40,720 --> 01:26:41,960 SOURCES AND NOT MINOR SOURCES 2366 01:26:41,960 --> 01:26:43,320 BUT I'M HERE TO TELL YOU THAT 2367 01:26:43,320 --> 01:26:45,280 JUST BECAUSE YOU'RE A SMALL 2368 01:26:45,280 --> 01:26:49,120 PERSON DOESN'T MEAN YOUR NOT AN 2369 01:26:49,120 --> 01:26:50,280 IMPORTANT PERSON, SPEAKING 2370 01:26:50,280 --> 01:26:51,000 METAFOREVERICALLY BUT ANYWAY, WE 2371 01:26:51,000 --> 01:26:52,880 WENT ON TO LOOK AT MUCOSAL 2372 01:26:52,880 --> 01:26:54,720 SURFACES IN A VARIETY OF 2373 01:26:54,720 --> 01:26:59,400 DIFFERENT PLACES AND I HAVE A 2374 01:26:59,400 --> 01:27:02,880 VERY CLOSE COLLEAGUE WHO STUDIES 2375 01:27:02,880 --> 01:27:04,960 CHRONIC SIGNUEICITIS FROM NAISAL 2376 01:27:04,960 --> 01:27:06,720 POLYPS SO WHAT YOU'RE LOOKING AT 2377 01:27:06,720 --> 01:27:07,800 WITH THE PUBLISHED WORK THAT 2378 01:27:07,800 --> 01:27:10,560 WE'RE LOOKING AT FROM THE COHEN 2379 01:27:10,560 --> 01:27:12,600 LAB AND BRANCHRATORY TO LOOK AT 2380 01:27:12,600 --> 01:27:13,960 HUMAN NAISAL POLYPS DISEASE AND 2381 01:27:13,960 --> 01:27:16,160 YOU CAN SEE THAT SURPRISE, 2382 01:27:16,160 --> 01:27:17,560 SURPRISE IL33 AS EXPECTED WHILE 2383 01:27:17,560 --> 01:27:20,480 IT WAS IN THE NUCLEI OF 2384 01:27:20,480 --> 01:27:21,880 EPITHELLIAL CELLSIAL CELLS 2385 01:27:21,880 --> 01:27:24,880 BORDERING THIS, POLYP, HERE IN 2386 01:27:24,880 --> 01:27:26,320 THE LAMINA PROARP RIA AREA WE 2387 01:27:26,320 --> 01:27:28,760 CAN SEER CLEAR EVIDENCE THAT 2388 01:27:28,760 --> 01:27:30,400 THERE WERE--WHAT LOOK LIKE 2389 01:27:30,400 --> 01:27:35,160 ANTIGEN PRESENTING CELLS BY 2390 01:27:35,160 --> 01:27:38,240 VIRTUE OF EXPRESSING HLA-DR AND 2391 01:27:38,240 --> 01:27:39,560 THEN ALSO OOH LIERKS 33. 2392 01:27:39,560 --> 01:27:41,720 THERE WERE INSTANCES WHERE THERE 2393 01:27:41,720 --> 01:27:43,960 WERE MYELOID INIAGE CELLS THAT 2394 01:27:43,960 --> 01:27:45,240 WERE NOT ANTIGEN PRESENTING 2395 01:27:45,240 --> 01:27:48,840 CELLS BY NOT HAVING HLA-DR BUT 2396 01:27:48,840 --> 01:27:50,320 STILL HAD IL33 AND I HOPE CAN 2397 01:27:50,320 --> 01:27:51,960 YOU ALREADY APPRECIATE THAT THIS 2398 01:27:51,960 --> 01:27:53,920 IL33 WAS IN THE CYTOPLASM OF 2399 01:27:53,920 --> 01:27:56,160 MANY OF THESE CELL TYPES, NOT IN 2400 01:27:56,160 --> 01:27:58,000 THE NUCLEI WITH THE EPITHELIAL 2401 01:27:58,000 --> 01:27:58,680 CELLS. 2402 01:27:58,680 --> 01:28:01,160 SIMILARLY IN MICE, WE FOUND 2403 01:28:01,160 --> 01:28:02,720 ALMOST THE EXACT FINDING NOW 2404 01:28:02,720 --> 01:28:04,360 NOTE THAT IS CHRONIC 2405 01:28:04,360 --> 01:28:05,760 INFLAMMATORY STATE AND THIS HERE 2406 01:28:05,760 --> 01:28:07,960 IS A QUIESCENT STATE WHERE MICE 2407 01:28:07,960 --> 01:28:10,280 THAT ARE IN SPF CONDITION SO 2408 01:28:10,280 --> 01:28:11,320 THEY CERTAINLY HAVE A MIRROR 2409 01:28:11,320 --> 01:28:13,960 IMAGE ROUGH ATOM BIOME, DIDN'T 2410 01:28:13,960 --> 01:28:15,640 DRIVE THAT FEATURE BUT IL33 2411 01:28:15,640 --> 01:28:18,240 AGAIN WAS IN THE YOU THIS CLE I 2412 01:28:18,240 --> 01:28:20,400 OF EPITHELIAL CELLS BUT WE COULD 2413 01:28:20,400 --> 01:28:23,200 FIND THESE RARE APCs THAT ARE 2414 01:28:23,200 --> 01:28:24,720 CONSTITTATIVELY FOUND IN THE GI 2415 01:28:24,720 --> 01:28:26,880 TRACT AND EXPRESS IL33 IN THE 2416 01:28:26,880 --> 01:28:27,760 CYTOPLASM. 2417 01:28:27,760 --> 01:28:31,680 SO YOU KNOW, PART OF NOT OUR 2418 01:28:31,680 --> 01:28:41,040 MIST WORK BUT NIAID FUNDED WORK 2419 01:28:41,040 --> 01:28:43,920 IS TO DEFINE WHETHER THERE'S A 2420 01:28:43,920 --> 01:28:45,000 PARTICULAR LANDSCAPE IN THE 2421 01:28:45,000 --> 01:28:46,200 MODEL VERSUS THOSE THAT DO NOT. 2422 01:28:46,200 --> 01:28:47,440 BUT I WON'T BE TALKING ABOUT 2423 01:28:47,440 --> 01:28:47,920 THAT TODAY. 2424 01:28:47,920 --> 01:28:49,400 BUT I WILL BE TALKING ABOUT 2425 01:28:49,400 --> 01:28:52,960 HOWEVER, IS AGAIN, MY LOVE FOR A 2426 01:28:52,960 --> 01:28:54,280 PARASETTIC HELMETS AND HOW 2427 01:28:54,280 --> 01:28:55,640 IMPORTANT THEY ARE FOR BOTH 2428 01:28:55,640 --> 01:28:57,080 HUMAN AND ANIMAL HEGHT AND WE 2429 01:28:57,080 --> 01:29:01,240 FIGURED THAT TO PARSE OUT THIS 2430 01:29:01,240 --> 01:29:02,720 POETIC TEBTIAL DIFFERENT 2431 01:29:02,720 --> 01:29:07,120 BIOLOGICAL ROLE FOR IL33, IN THE 2432 01:29:07,120 --> 01:29:08,600 EPITHELIAL COMPARTMENT VERSUS 2433 01:29:08,600 --> 01:29:10,760 THE MYELOID COMPARTMENT IS 2434 01:29:10,760 --> 01:29:12,280 WORKED OUT USING THE MOUSE 2435 01:29:12,280 --> 01:29:13,360 INFECTION MODEL. 2436 01:29:13,360 --> 01:29:19,200 SO THE RESILIENCE IS THE WORK 2437 01:29:19,200 --> 01:29:20,240 HORSE OF THE PARASITE LIKE 2438 01:29:20,240 --> 01:29:22,400 MYSELF AND TO BECOME QUITE A 2439 01:29:22,400 --> 01:29:23,160 POPULAR MODEL EVEN FOR 2440 01:29:23,160 --> 01:29:24,560 INDIVIDUAL WHO IS DON'T LOVE 2441 01:29:24,560 --> 01:29:30,560 WORMS AS MUCH AS I DO, AND 2442 01:29:30,560 --> 01:29:31,520 INFECTIOUS STAGE LARVA AND 2443 01:29:31,520 --> 01:29:32,680 MIGRATE THROUGH THE LUNG IN THE 2444 01:29:32,680 --> 01:29:34,560 FIRST 3 DAYS OF INFECTION, 2445 01:29:34,560 --> 01:29:36,000 THEY'RE COUGHED UP AND SWALLOWED 2446 01:29:36,000 --> 01:29:38,920 TO ENTER THE GI TRACT AND HERE'S 2447 01:29:38,920 --> 01:29:40,520 WHERE PIPE 2 IMMUNE 2448 01:29:40,520 --> 01:29:41,360 DYSFUNCTIONUNITY ELIMINATES 2449 01:29:41,360 --> 01:29:43,920 THOSE PARASITES FROM THE GI 2450 01:29:43,920 --> 01:29:45,800 LUMEN OF IMMUNO COMPETENT 2451 01:29:45,800 --> 01:29:46,040 ANIMALS. 2452 01:29:46,040 --> 01:29:48,760 SO WHAT WE DECIDED TO DO WAS TO 2453 01:29:48,760 --> 01:29:50,040 SELECTIVELY DELETE AL33 AND 2454 01:29:50,040 --> 01:29:51,000 EITHER THE EPITHELIAL 2455 01:29:51,000 --> 01:29:52,520 COMPARTMENT OR THE MYELOID 2456 01:29:52,520 --> 01:29:57,440 COMPARTMENT, OKAY IN AND ASK 2457 01:29:57,440 --> 01:29:58,160 DOES IT MATTER? 2458 01:29:58,160 --> 01:29:59,840 AND WHOA, IT REALLY MATTERS, SO 2459 01:29:59,840 --> 01:30:03,000 LOSS OF 33 IN THE INTESTINAL 2460 01:30:03,000 --> 01:30:04,480 EPITHELIAL COMPARTMENT AS WOULD 2461 01:30:04,480 --> 01:30:05,680 BE EXPECTED AND WHAT HAPPENS IN 2462 01:30:05,680 --> 01:30:09,280 A MOUSE THAT LACKS IL33 AND ALSO 2463 01:30:09,280 --> 01:30:11,280 ALL CELLS IT GREATLY IMPAIRS 2464 01:30:11,280 --> 01:30:11,920 HOST IMMUNITY. 2465 01:30:11,920 --> 01:30:12,280 RIGHT? 2466 01:30:12,280 --> 01:30:13,400 SO HERE'S NUMBER OF WORMS THAT 2467 01:30:13,400 --> 01:30:16,600 ARE IN THE BOWEL, IN THE 2468 01:30:16,600 --> 01:30:17,760 INTESTINAL LUMEN, NUMBER OF EGGS 2469 01:30:17,760 --> 01:30:24,480 COMES OUT IN THE STOOL BUT 2470 01:30:24,480 --> 01:30:26,840 SURPRISINGLY LACK OF 33 IN THE 2471 01:30:26,840 --> 01:30:28,040 MYELOID COMPARTMENT GAVE A VERY 2472 01:30:28,040 --> 01:30:35,040 ROBUST OPERATING OPPOSITE RESP. 2473 01:30:35,040 --> 01:30:37,880 AND WE KNOW THAT WHEN THE 2474 01:30:37,880 --> 01:30:39,480 MYELOID CELLS LACK 33, WAS 2475 01:30:39,480 --> 01:30:40,840 MANIFEST VERY EARLY IN 2476 01:30:40,840 --> 01:30:42,440 INFECTION, ACTUALLY WE NOW THINK 2477 01:30:42,440 --> 01:30:48,360 IT'S TOTALLY A BASAL DEFECT THAT 2478 01:30:48,360 --> 01:30:57,640 THE BASAL CONDITIONS BEFORE WARM 2479 01:30:57,640 --> 01:30:59,920 INFECTION IS INITIATED, AND IN 2480 01:30:59,920 --> 01:31:01,360 THE SMALL INTESTINE 92 THE 2481 01:31:01,360 --> 01:31:02,200 INFLAMMATORY ENVIRONMENT AND SO 2482 01:31:02,200 --> 01:31:03,960 WHEN WE LOOKED AT IN MORE KIND 2483 01:31:03,960 --> 01:31:07,280 OF NUTS AND BOLTS IMMUNOLOGICAL 2484 01:31:07,280 --> 01:31:10,160 APPROACHES FOR THE IMPORTANCE OF 2485 01:31:10,160 --> 01:31:11,840 MYELOID 33, SORTING OUT 2486 01:31:11,840 --> 01:31:14,400 DENDRITIC CELLS EITHER LACKED OR 2487 01:31:14,400 --> 01:31:18,080 POSSESSED THE CYTOKINE AND POST 2488 01:31:18,080 --> 01:31:19,560 AND STIMULATING NAIVE T-CELLS WE 2489 01:31:19,560 --> 01:31:21,000 FOUND THAT SURPRISE, SURPRISE, 2490 01:31:21,000 --> 01:31:23,640 LACK OF MYELOID 33 HAD NO IMPACT 2491 01:31:23,640 --> 01:31:27,560 ON KIND OF CONVENTIONAL TH2 2492 01:31:27,560 --> 01:31:27,800 CELLS. 2493 01:31:27,800 --> 01:31:30,000 VERY MODERATE EFFECT ON TH1 2494 01:31:30,000 --> 01:31:31,560 CELLS OR TH17 CELLS BUT WHAT 2495 01:31:31,560 --> 01:31:33,600 HAPPENED WAS THAT IT REALLY 2496 01:31:33,600 --> 01:31:35,840 IMPAIRED THE FULL EXPANSION OF 2497 01:31:35,840 --> 01:31:37,840 THE T-REGS APART SO THIS STARTED 2498 01:31:37,840 --> 01:31:39,720 TO SMELL LIKE THE FEELING OF 2499 01:31:39,720 --> 01:31:40,880 [INDISCERNIBLE] WORK THAT HAD 2500 01:31:40,880 --> 01:31:42,640 BEEN PUBLISHED A FEW YEARS PRIOR 2501 01:31:42,640 --> 01:31:47,120 AND IT MADE US THINK THAT 2502 01:31:47,120 --> 01:31:51,120 PERHAPS 33 WAS A VERY IMPORTANT 2503 01:31:51,120 --> 01:31:54,120 ROLE IN DRIVE FOR MYELOID CELLS 2504 01:31:54,120 --> 01:31:56,320 IN VIVO WAS IMPORTANT FOR 2505 01:31:56,320 --> 01:31:57,720 EXPANTEDDING TREGS IN THE GUT. 2506 01:31:57,720 --> 01:31:59,920 SO TURNS OUT THAT DAN CAMP WILL 2507 01:31:59,920 --> 01:32:02,800 BELL AND OTHERS THAT--DAN 2508 01:32:02,800 --> 01:32:03,800 CAMPBELL AND OTHERS THAT WORKED 2509 01:32:03,800 --> 01:32:05,960 ON THIS THEY ARE SUITED TO 2510 01:32:05,960 --> 01:32:07,120 EFFECTIVELY EXPRESS THE 2511 01:32:07,120 --> 01:32:09,600 POPULATIONS THAT EXPRESS THEIR 2512 01:32:09,600 --> 01:32:10,280 TRANSCRIPTION FACTORS. 2513 01:32:10,280 --> 01:32:12,000 SO THERE'S THELPER 2 CELLS 2514 01:32:12,000 --> 01:32:15,160 EXPRESS GATTA 3 AND THERE'S TREG 2515 01:32:15,160 --> 01:32:17,440 THAT EXPRESS GATTA 3 AND THEY 2516 01:32:17,440 --> 01:32:18,720 CROSS REGULATE 1 ANOTHER AND ON 2517 01:32:18,720 --> 01:32:22,120 DOWN THE LINE AND TFRs AND TFH 2518 01:32:22,120 --> 01:32:24,120 AND DBET EXPRESSING AND TREGS 2519 01:32:24,120 --> 01:32:25,760 AND WORKING IN THE TREGS AND 2520 01:32:25,760 --> 01:32:29,960 THERE'S A LOT, LOT OF INTEREST 2521 01:32:29,960 --> 01:32:31,040 IN THIS PARTICULAR EXPOSURE BUT 2522 01:32:31,040 --> 01:32:32,800 FOR US FOR WORMS WE THOUGHT 2523 01:32:32,800 --> 01:32:34,520 ABOUT THE GATTA 3 EXPRESSING 2524 01:32:34,520 --> 01:32:36,120 TREG SUBSET AND LOW AND BEHIND 2525 01:32:36,120 --> 01:32:38,800 WHEN WE GENERATED ANIMALS THAT 2526 01:32:38,800 --> 01:32:40,880 SPRVEGLY LACK GATE KEEPER THEA 3 2527 01:32:40,880 --> 01:32:42,440 IN THE TREG COMPARTMENT THOSE 2528 01:32:42,440 --> 01:32:44,320 ANIMALS JUST LIKE THE ANIMALS 2529 01:32:44,320 --> 01:32:46,640 THAT LACKED MYELOID 33, HAD 2530 01:32:46,640 --> 01:32:47,080 ENHANCED IMMUNITY. 2531 01:32:47,080 --> 01:32:48,440 SO WE STARTED TO THINK THAT 2532 01:32:48,440 --> 01:32:51,360 THERE WAS A CIRCUIT THAT WE HAD 2533 01:32:51,360 --> 01:32:53,000 UNCOVERED WHERE, MYELOID 33--SO, 2534 01:32:53,000 --> 01:32:54,520 YOU KNOW, AGAIN THERE'S THE 2535 01:32:54,520 --> 01:32:56,720 ADULT WORM EXPS EGGS AND WE LOSE 2536 01:32:56,720 --> 01:32:58,360 THESE ST2 EXPRESSIONOT SAME TREG 2537 01:32:58,360 --> 01:32:59,320 SUBSET. 2538 01:32:59,320 --> 01:33:00,840 SOPHISTICATEDY WE STARTED TO 2539 01:33:00,840 --> 01:33:02,600 THINK THAT PERHAPS THE MYELOID 2540 01:33:02,600 --> 01:33:07,160 DERIVED 33 WAS TALKING TO THE 2541 01:33:07,160 --> 01:33:08,080 GATTA 3 EXPRESSING SUBSET. 2542 01:33:08,080 --> 01:33:09,400 AND WHEN YOU THINK ABOUT CELLS 2543 01:33:09,400 --> 01:33:12,040 TALKING TO 1 ANOTHER, ISN'T THAT 2544 01:33:12,040 --> 01:33:14,040 REALLY THE BASIC TENANTS OF WHAT 2545 01:33:14,040 --> 01:33:15,440 WE WANT DURING VACCINATION, 2546 01:33:15,440 --> 01:33:15,680 RIGHT? 2547 01:33:15,680 --> 01:33:18,440 WE WANT A SELL THAT AS HASN'T 2548 01:33:18,440 --> 01:33:22,880 GEN, IN ORDER TO PRIME AND 2549 01:33:22,880 --> 01:33:23,920 PROGRAM ADAPTIVE LYMPHOCYTES SO 2550 01:33:23,920 --> 01:33:27,720 WE CAN HAVE LONG-TERM BOF-CELL 2551 01:33:27,720 --> 01:33:28,720 AND T-CELL IMMUNITY SO WE THINK 2552 01:33:28,720 --> 01:33:30,320 THAT WHEN THESE CELLS COME 2553 01:33:30,320 --> 01:33:33,280 TOGETHER, PERHAPS THERE WAS SOME 2554 01:33:33,280 --> 01:33:34,880 UNKNOWN--AS YET UNKNOWN 2555 01:33:34,880 --> 01:33:37,080 MECHANISM WHEREBY THIS EABT 2556 01:33:37,080 --> 01:33:39,760 ANTIGEN PRESENTING CELL, THE 2557 01:33:39,760 --> 01:33:41,960 LARGER CELL, DELIVERS 33 2558 01:33:41,960 --> 01:33:43,920 EXQUISITELY DELIBERATELY TO A 2559 01:33:43,920 --> 01:33:44,160 T-CELL. 2560 01:33:44,160 --> 01:33:46,480 AND WE TOOK A TOTALLY AGNOSTIC 2561 01:33:46,480 --> 01:33:48,640 APPROACH AND PERFORM RNA 2562 01:33:48,640 --> 01:33:50,720 SEQUENCING, TO LOOK AT DENDRITIC 2563 01:33:50,720 --> 01:33:53,440 CELLS THAT WERE CD103 POSITIVE 2564 01:33:53,440 --> 01:33:56,120 AND MUCOSAL DCs AND MESENTERIC 2565 01:33:56,120 --> 01:33:57,280 LYMPHNODE, AND ASKED, DID IT 2566 01:33:57,280 --> 01:34:02,160 MATTER, IF THEY LACKED IL33 OR 2567 01:34:02,160 --> 01:34:02,800 PROCESSED IL33. 2568 01:34:02,800 --> 01:34:05,000 I AND TELL YOU THIS WAS A RARE 2569 01:34:05,000 --> 01:34:06,880 EXCITING MOMENT WHERE WHEN THE 2570 01:34:06,880 --> 01:34:10,520 DATA CAME OUT, THERE WAS THIS 2571 01:34:10,520 --> 01:34:13,600 TEAM THAT WAS A PART FROM ALL 2572 01:34:13,600 --> 01:34:15,400 OTHERS THAT WAS MODERATELY DOWN 2573 01:34:15,400 --> 01:34:16,800 REGULATED AND WASN'T QUITE 2 2574 01:34:16,800 --> 01:34:21,520 FOLD DOWN REGULATED BUT IT WAS 2575 01:34:21,520 --> 01:34:23,040 IL33 DEPENDENT, INTRINSICALLY IN 2576 01:34:23,040 --> 01:34:24,840 THE COMPARTMENT AND YOU CAN SEE 2577 01:34:24,840 --> 01:34:27,120 AGAIN, YOU KNOW THE HERBERT LAB 2578 01:34:27,120 --> 01:34:28,880 DOES, WE GO AFTER THE SMALL 2579 01:34:28,880 --> 01:34:31,920 PERSON, THE LESS LIKELY 2580 01:34:31,920 --> 01:34:32,240 CANDIDATE. 2581 01:34:32,240 --> 01:34:34,960 SO THIS IS THE LOWEST CHANGE OUT 2582 01:34:34,960 --> 01:34:38,080 OF THE ENTIRE GENE SET BUT THIS 2583 01:34:38,080 --> 01:34:42,320 GENE WAS ENCODED, CALLED MPEG 1 2584 01:34:42,320 --> 01:34:43,800 FOR MACROPHAGE EXPRESS GENE 1 2585 01:34:43,800 --> 01:34:46,400 AND CODED A PROTEIN FOR PERFORIN 2586 01:34:46,400 --> 01:34:48,840 2, AND THOSE WHO ARE FAMILIAR 2587 01:34:48,840 --> 01:34:50,440 WITH THE EXPLOSION OF INTEREST 2588 01:34:50,440 --> 01:34:53,400 IN POOR FORMING PROTEINS AND THE 2589 01:34:53,400 --> 01:34:55,440 [INDISCERNIBLE] FAMILY AS 2590 01:34:55,440 --> 01:34:57,040 DELIVERING IL1 BETA FROM LIVE 2591 01:34:57,040 --> 01:35:00,280 SALES AND THE VACCINE ADJUSTICE 2592 01:35:00,280 --> 01:35:02,480 ACCESS VEPTS YOU'VE SEEN CAN BE 2593 01:35:02,480 --> 01:35:05,800 AUGMENTED THROUGH THE IL1 BETA 2594 01:35:05,800 --> 01:35:06,600 [INDISCERNIBLE] PATHWAY AND SO 2595 01:35:06,600 --> 01:35:09,160 THAT TYPE OF LITERATURE REALLY 2596 01:35:09,160 --> 01:35:13,200 GOT US EXCITED ABOUT IL33 AND 2597 01:35:13,200 --> 01:35:13,520 PERFORIN 2. 2598 01:35:13,520 --> 01:35:14,760 AND PERFORIN 2 IS EXPRESSED ON A 2599 01:35:14,760 --> 01:35:17,480 VARIETY OF DIFFERENT INNATE LIKE 2600 01:35:17,480 --> 01:35:18,600 CELLS, IT'S EVOLUTIONARY 2601 01:35:18,600 --> 01:35:21,400 CONSERVED IS VERY SIMILAR TO 2602 01:35:21,400 --> 01:35:23,120 PERFORIN 1 BUT WHAT MAKES 2603 01:35:23,120 --> 01:35:25,520 PERFORIN 2 UNIQUE IS THAT IT HAS 2604 01:35:25,520 --> 01:35:28,840 THE TRANSMEMBRANE TETHER AND 2605 01:35:28,840 --> 01:35:31,640 THAT ALLOWS PERFORIN 2 TO BE 2606 01:35:31,640 --> 01:35:32,240 CONSTITTATIVELY EXPRESSED INTO 2607 01:35:32,240 --> 01:35:33,040 ENDOSTUDIES OF MULTIPLE 2608 01:35:33,040 --> 01:35:34,800 ENDOCRINES IN APCs, MOSTLY THE 2609 01:35:34,800 --> 01:35:36,840 WORK HAS FOCUSED ON TISSUE 2610 01:35:36,840 --> 01:35:37,880 MACROPHAGES, IT WAS LITERALLY 2611 01:35:37,880 --> 01:35:41,760 NOTHING KNOWN ABOUT DENDRITIC 2612 01:35:41,760 --> 01:35:43,080 CELLS BEFORE WOR PERFORIN 2 2613 01:35:43,080 --> 01:35:44,240 EXPRESSION BEFORE WE STARTED 2614 01:35:44,240 --> 01:35:45,880 WORKING ON THIS. 2615 01:35:45,880 --> 01:35:49,760 MECHANISTICALLY IT HAD BEEN 2616 01:35:49,760 --> 01:35:50,520 RECOGNIZED BY [INDISCERNIBLE] 2617 01:35:50,520 --> 01:35:52,440 AND OTHERS IN FLORIDA AT 2618 01:35:52,440 --> 01:35:54,240 UNIVERSITY OF MIAMI THAT 2619 01:35:54,240 --> 01:35:56,280 MICROBIAL EXPOSURE TO APCs 2620 01:35:56,280 --> 01:35:58,560 LIKE TISSUE MACROFAJS, CAUSES A 2621 01:35:58,560 --> 01:36:03,560 RAPID RELO XAIGZ AND A EFFUSION 2622 01:36:03,560 --> 01:36:05,800 OF CONTAINING ENDOSEEMS WITH 2623 01:36:05,800 --> 01:36:08,040 LYSOSOMES SO THE PH AGO-LIES 2624 01:36:08,040 --> 01:36:09,920 STUDIES OF MULTIPLE ENDOCRINAL 2625 01:36:09,920 --> 01:36:12,120 THAT OCCURS ONCE THE BACTERIUM 2626 01:36:12,120 --> 01:36:13,440 WAS PART OF THE EFFECTOR 2627 01:36:13,440 --> 01:36:16,120 RESPONSE SO NOW WHEN THAT OCCURS 2628 01:36:16,120 --> 01:36:18,240 WHEN THAT FUSION OCCURS WHEN YOU 2629 01:36:18,240 --> 01:36:19,440 HAVE A BACTERIUM INSIDE AND 2630 01:36:19,440 --> 01:36:20,120 ENDOSTUDIES OF MULTIPLE 2631 01:36:20,120 --> 01:36:20,800 ENDOCRINE THAT HAS 2632 01:36:20,800 --> 01:36:23,240 [INDISCERNIBLE] ON THE OUTER 2633 01:36:23,240 --> 01:36:25,760 MEMBRANE, THAT PERFORIN 2 IS 2634 01:36:25,760 --> 01:36:27,600 ABLE TO THEN RELOCATE AND 2635 01:36:27,600 --> 01:36:32,120 DEPOSIT ON THE BACTERIAL CELL 2636 01:36:32,120 --> 01:36:34,360 SURFACE AND LIES WITH BACTERIA. 2637 01:36:34,360 --> 01:36:37,440 BUT FOR US WE WERE NOT JUST 2638 01:36:37,440 --> 01:36:38,040 INTERESTED IN AN ENDOSTUDIES OF 2639 01:36:38,040 --> 01:36:39,240 MULTIPLE ENDOCRINE TEEP OF 2640 01:36:39,240 --> 01:36:40,040 EXPRESSION PATTERN BUT VERY 2641 01:36:40,040 --> 01:36:42,880 INTERESTED IN THE FACT THAT WE 2642 01:36:42,880 --> 01:36:45,480 HAD BEEN RECOGNIZE THAD PERFORIN 2643 01:36:45,480 --> 01:36:47,440 2 HAD TO BE ON THE PLASMA 2644 01:36:47,440 --> 01:36:47,680 MEMBRANE. 2645 01:36:47,680 --> 01:36:49,920 SO BACK WE WENT TO OUR OWN 2646 01:36:49,920 --> 01:36:51,880 TISSUE SAMPLES AND PARTICULARLY 2647 01:36:51,880 --> 01:36:53,080 THE NAISAL POP POLYPS AND YOU 2648 01:36:53,080 --> 01:36:56,000 CAN SEE HERE THE MICROSCOPY 2649 01:36:56,000 --> 01:36:57,280 APPROACH ALLOWED US TO CAPTURE 2650 01:36:57,280 --> 01:36:58,960 QUITE EXCITING 3 EXPRESSION OF 2651 01:36:58,960 --> 01:37:00,560 PERFORIN 2 WITH THE BUSY END 2652 01:37:00,560 --> 01:37:02,200 POINTING OUT INTO THE EXTRA 2653 01:37:02,200 --> 01:37:04,880 CELLULAR SPACE AND SEEMED TO BE 2654 01:37:04,880 --> 01:37:05,880 KIND OF EMBEDDED, I DON'T WANT 2655 01:37:05,880 --> 01:37:09,920 TO SAY IN THE MEMBRANE, MAYBE 2656 01:37:09,920 --> 01:37:11,880 SINCE GWEN IS IN THE AUDIENCE, I 2657 01:37:11,880 --> 01:37:13,440 WILL BE CAUTIOUS AS LI WANT TO 2658 01:37:13,440 --> 01:37:15,440 SIMPLY SAY THAT IT LOOKS LIKE 2659 01:37:15,440 --> 01:37:19,080 THE PERFORIN END OF THIS 2660 01:37:19,080 --> 01:37:21,200 MOLECULE IS POINTED OUTWARD AS 2661 01:37:21,200 --> 01:37:22,520 WE WOULD ENVISION IT TO WORK TO 2662 01:37:22,520 --> 01:37:24,000 DELIVER TO DLEA TO SOME OTHER 2663 01:37:24,000 --> 01:37:27,960 CELL TYPE AND THIS IS A C11 C 2664 01:37:27,960 --> 01:37:30,440 POSITIVE CELL IN A HUMAN NAISAL 2665 01:37:30,440 --> 01:37:30,680 POLYP. 2666 01:37:30,680 --> 01:37:32,880 SO THIS CERTAINLY AS A RELEVANCE 2667 01:37:32,880 --> 01:37:34,840 TO THE HUMAN UPPER WEAR A 2668 01:37:34,840 --> 01:37:36,600 EPITHELIUM AND THERE ARE--IT'S 2669 01:37:36,600 --> 01:37:38,280 THESE DCs THAT ARE FULL OF 2670 01:37:38,280 --> 01:37:39,480 PERFORIN 2, YOU CAN SEE HERE 2671 01:37:39,480 --> 01:37:41,880 THAT IT REALLY TAKES ON THIS 2672 01:37:41,880 --> 01:37:43,440 KIND OF CHANNEL LIKE 2673 01:37:43,440 --> 01:37:44,840 CONFIGURURATION IN CELLS AND 2674 01:37:44,840 --> 01:37:46,680 THEY'RE JUST CHOKED FULL OF IT, 2675 01:37:46,680 --> 01:37:48,320 BOTH IN ENDOSEEMS AS WELL AS 2676 01:37:48,320 --> 01:37:49,600 SOME PART OF THEIR LIFE CYCLE 2677 01:37:49,600 --> 01:37:53,640 MAKING IT TO THE CELL SURFACE. 2678 01:37:53,640 --> 01:37:54,600 >> ALL RIGHT, SO WHEN WE STARTED 2679 01:37:54,600 --> 01:38:00,120 TO LOOK AT THIS MORE INTENTLY, 2680 01:38:00,120 --> 01:38:02,720 WE SEE THAT PERFORIN 2 LOCALIZED 2681 01:38:02,720 --> 01:38:04,640 THIS INTERFACE AND WE LOCALIZE 2682 01:38:04,640 --> 01:38:07,240 THESE TOGETHER IT WAS IL33 2683 01:38:07,240 --> 01:38:09,280 DEPENDENT, IF THE DC'S LACK 33, 2684 01:38:09,280 --> 01:38:12,800 WE NO LONGER GOT THAT CO 2685 01:38:12,800 --> 01:38:14,440 LOCALIDESSATION AND THAT KIND 2686 01:38:14,440 --> 01:38:16,240 OF--YEAH, THAT POTERN AND MOST 2687 01:38:16,240 --> 01:38:17,880 IMPORTANTLY, WHEN WE USE A 2688 01:38:17,880 --> 01:38:20,120 COUPLE OF DIFFERENT APPROACHES 2689 01:38:20,120 --> 01:38:22,360 TO DELETE PERFORIN 2, HERE YOU 2690 01:38:22,360 --> 01:38:24,040 SEE THE MPEG 1, WE FOUND THAT 2691 01:38:24,040 --> 01:38:27,120 IL33 WAS NO LONGER ABLE TO MAKE 2692 01:38:27,120 --> 01:38:30,640 IT OUT INTO THE SUPERINATENT 2693 01:38:30,640 --> 01:38:32,160 WHERE WE LYSE THE CELL THERE WAS 2694 01:38:32,160 --> 01:38:34,360 NO DIFFERENCE IN CELLS FROM THE 2695 01:38:34,360 --> 01:38:34,720 DENDRITIC CELLS. 2696 01:38:34,720 --> 01:38:36,280 WE NOW KNOW THROUGH UNPUBLISHED 2697 01:38:36,280 --> 01:38:41,080 DATA THAT IT'S NOT JUST IL33, WE 2698 01:38:41,080 --> 01:38:43,880 KNOW THAT LACKING PERFORIN 2 2699 01:38:43,880 --> 01:38:46,120 IMPAIRS A VARIETY OF CYTOKINES, 2700 01:38:46,120 --> 01:38:48,560 WE THINK WE UNCOVERED SOMETHING 2701 01:38:48,560 --> 01:38:50,080 THAT'S IMPORTANT FOR CYTOKINE 2702 01:38:50,080 --> 01:38:51,200 DELIVERY FOR ANTIGEN CELLS AND 2703 01:38:51,200 --> 01:38:52,040 THAT'S WHAT OUR MIST IS ALL 2704 01:38:52,040 --> 01:38:55,240 ABOUT AND TO PUT THE NAIL ON THE 2705 01:38:55,240 --> 01:38:57,120 COFFIN, WE USE A COCULTURE 2706 01:38:57,120 --> 01:39:01,520 APPROACH WHERE WE CO CULT 2707 01:39:01,520 --> 01:39:02,960 CULTURE DENDRITIC CELLS AND 2708 01:39:02,960 --> 01:39:06,240 TREGS AND ASK IF WE BLOCK THE 2709 01:39:06,240 --> 01:39:08,480 PERFORIN TO DELIVER CYTOKINE 2710 01:39:08,480 --> 01:39:09,680 WOULD IT IMPAIR THE 2711 01:39:09,680 --> 01:39:10,960 DIFFERENTIATION OR EXPANSION OF 2712 01:39:10,960 --> 01:39:15,600 TREGS AND THE BOTTOM LINE IS, 2713 01:39:15,600 --> 01:39:18,800 CONTROL ANTIBODY HAS NO IMPACT 2714 01:39:18,800 --> 01:39:22,200 ON THE COMMITMENT OR 2715 01:39:22,200 --> 01:39:24,680 PROLIFERATIVE EXPANSION BY SFF 2716 01:39:24,680 --> 01:39:25,760 PHASE COMMITMENT OF T-REGS IF 2717 01:39:25,760 --> 01:39:27,760 YOU BLOCK THEM, THE CELLS COULD 2718 01:39:27,760 --> 01:39:29,200 COMMITMENT TO THE TREG BUT 2719 01:39:29,200 --> 01:39:32,480 THEY'RE NOT EXPANDING, RIGHT? 2720 01:39:32,480 --> 01:39:33,800 AND YOU CAN SEE HERE I SHOWED 2721 01:39:33,800 --> 01:39:35,320 YOU THE DAT HA THERE ARE MORE 2722 01:39:35,320 --> 01:39:37,560 SIGHTY KINES THAT ARE COMING 2723 01:39:37,560 --> 01:39:39,120 THROUGH, TO LIKELY THAN JUST 2724 01:39:39,120 --> 01:39:42,160 IL33 WHICH IS MOST LIKELY THE 2725 01:39:42,160 --> 01:39:43,360 EXPLANATION FOR WHY WE DIDN'T 2726 01:39:43,360 --> 01:39:45,280 GET AS MUCH SUPPRESSION OF THAT 2727 01:39:45,280 --> 01:39:47,240 PHENOMENAL IN THE IL33 KNOCK 2728 01:39:47,240 --> 01:39:47,680 OUT. 2729 01:39:47,680 --> 01:39:53,280 SO LET ME JUST WRAP THIS UP, I 2730 01:39:53,280 --> 01:39:54,960 THINK DENDRITIC CELLS AND IL33 2731 01:39:54,960 --> 01:39:58,840 AS WELL AS WE KNOW IT CAN MAKE A 2732 01:39:58,840 --> 01:40:02,360 LOT OF GCs MAKE A WHOLE HOST 2733 01:40:02,360 --> 01:40:03,480 OF CYTOKINES, PERFORIN 2 SEEMS 2734 01:40:03,480 --> 01:40:05,880 TO BE A CONDUIT AT LEAST THAT'S 2735 01:40:05,880 --> 01:40:07,320 WHAT WE'RE STUDYING RIGHT NOW AS 2736 01:40:07,320 --> 01:40:09,160 A POI TOGETHER SIS, WHETHER 2737 01:40:09,160 --> 01:40:11,520 THERE IT'S A CONDUIT FOR IL33 2738 01:40:11,520 --> 01:40:15,160 AND THIS MECHANISM CAN EFFECT 2739 01:40:15,160 --> 01:40:16,400 TREG ECPANGZ. 2740 01:40:16,400 --> 01:40:18,080 SO EPITHELIAL CELLS DIE AND THEY 2741 01:40:18,080 --> 01:40:21,040 THOUGHT TO EXPAND ILC2s FOR 2742 01:40:21,040 --> 01:40:23,880 ELABORATING INFLAMMATION AND 2743 01:40:23,880 --> 01:40:26,720 MUCOSAL SURFACES BUT OUR NEW 2744 01:40:26,720 --> 01:40:28,440 DATA SUGGESTS THAT THERE'S A 2745 01:40:28,440 --> 01:40:30,280 DIFFERENT CIRCUIT WHERE THEY CAN 2746 01:40:30,280 --> 01:40:32,840 FOLKALLY DELIVER 33 TO TREGS AT 2747 01:40:32,840 --> 01:40:35,280 MUCOSAL SURFACES THROUGH THE 2748 01:40:35,280 --> 01:40:36,880 POOR FORMING ACTIONS OF PERFORIN 2749 01:40:36,880 --> 01:40:43,720 2 AND SO WHAT THIS WOULD 2750 01:40:43,720 --> 01:40:45,880 INDICATE THEN IS THE IL33 HAS A 2751 01:40:45,880 --> 01:40:47,360 INFLAMMA ARE TOY ROLE THROUGH 2752 01:40:47,360 --> 01:40:49,960 THIS DEATH PATHWAY WHERE IT HAS 2753 01:40:49,960 --> 01:40:51,440 AN IMMUNOSUPPRESSIVE ROLE 2754 01:40:51,440 --> 01:40:53,600 THROUGH A DIFFERENT SOURCE AND 2755 01:40:53,600 --> 01:40:55,360 KIND OF INTERESTING THIS 2756 01:40:55,360 --> 01:40:56,960 DIFFERENCE, I WOULD ENVISION TO 2757 01:40:56,960 --> 01:40:59,200 BE HARMLESS FOR RATIONAL VACCINE 2758 01:40:59,200 --> 01:41:02,080 DESIGN, THE GOALS OF OUR GRANT 2759 01:41:02,080 --> 01:41:03,960 ARE WE WANT TO THICK THIS APART 2760 01:41:03,960 --> 01:41:07,920 AND PUT IT BACK TPGHT AGAIN TO 2761 01:41:07,920 --> 01:41:09,680 UNDERSTAND THE DIVERSITY OF 2762 01:41:09,680 --> 01:41:10,840 CYTOKINES RELEASED FOR IT AND 2763 01:41:10,840 --> 01:41:12,280 HOW THEY'RE TRAFFICKED TO THE 2764 01:41:12,280 --> 01:41:13,560 SURFACE AND WHAT CONTEXT VIRAL 2765 01:41:13,560 --> 01:41:17,160 INFECTION OR WORM INFECTION IS 2766 01:41:17,160 --> 01:41:17,720 PER FORIN 2 IMPORTANT. 2767 01:41:17,720 --> 01:41:19,880 I WOULD LIKE TO REALLY THANK THE 2768 01:41:19,880 --> 01:41:25,360 MEMBERS OF MY LAB RAARE TOY AND 2769 01:41:25,360 --> 01:41:28,000 I REALLY AND THE COLLABORATORS 2770 01:41:28,000 --> 01:41:30,680 AND THE CENTER, COHEN AND OTHERS 2771 01:41:30,680 --> 01:41:32,680 AND WITHOUT THE SUPPORT FROM 2772 01:41:32,680 --> 01:41:34,040 THERE, THIS WORK WOULD NOT BE 2773 01:41:34,040 --> 01:41:40,880 POSSIBLE, THANK YOU VERY MUCH. 2774 01:41:40,880 --> 01:41:45,600 >> THANK YOU DR. DEBROSKI. 2775 01:41:45,600 --> 01:41:46,160 WE'RE OVER ABOUT 3 MINUTE 2776 01:41:46,160 --> 01:41:47,320 SPECIALIZATION OF SPECIFIC 2777 01:41:47,320 --> 01:41:48,600 ENDOTHELIAL ANN IS IT OKAY IF WE 2778 01:41:48,600 --> 01:41:52,120 TACK A QUESTION. 2779 01:41:52,120 --> 01:41:57,120 >> YES, ABSOLUTELY. 2780 01:41:57,120 --> 01:41:57,560 >> THANK YOU. 2781 01:41:57,560 --> 01:41:58,760 >> ANYONE WITH A QUESTION CAN 2782 01:41:58,760 --> 01:42:00,280 JUST SPEAK UP OR IF YOU RAISE 2783 01:42:00,280 --> 01:42:07,720 YOUR HAND, I'LL CALL ON YOU. 2784 01:42:07,720 --> 01:42:11,160 WELL, I GUESS THAT WAS SUPER 2785 01:42:11,160 --> 01:42:12,640 CLEAR, THANK YOU DEBROSKI AND 2786 01:42:12,640 --> 01:42:14,400 THANK YOU EVERYONE FOR THESE 2787 01:42:14,400 --> 01:42:16,000 OUTSTANDING TALKS. 2788 01:42:16,000 --> 01:42:19,000 VERY MUCH APPRECIATED. 2789 01:42:19,000 --> 01:42:20,280 AND I THINK THEN WE WILL TURN IT 2790 01:42:20,280 --> 01:42:29,960 BACK TO DAN AND THE CONCEPT 2791 01:42:29,960 --> 01:42:30,360 CLEARANCES. 2792 01:42:30,360 --> 01:42:32,920 STHRKS YEAH, SO AS USUAL WE HAVE 2793 01:42:32,920 --> 01:42:38,360 SEVERAL CONCEPT CLEARANCES FOR 2794 01:42:38,360 --> 01:42:39,040 COUNCIL CONSIDERATION. 2795 01:42:39,040 --> 01:42:41,640 AND AND I THINK WHAT WE WILL DO 2796 01:42:41,640 --> 01:42:45,440 IS AS WE USUALLY DO GO THROUGH 2797 01:42:45,440 --> 01:42:53,480 THESE 1 BY 1 BUT IF YOU HAVE 2798 01:42:53,480 --> 01:42:54,960 QUESTIONS, COMMENTS, THAT RISE 2799 01:42:54,960 --> 01:43:01,840 TO A LEVEL THAT WARRANTS 2800 01:43:01,840 --> 01:43:04,040 INDIVIDUAL APPROVALS, WE CAN DO 2801 01:43:04,040 --> 01:43:04,520 THAT. 2802 01:43:04,520 --> 01:43:07,600 IF NOT, WE WILL ASK FOR AN 2803 01:43:07,600 --> 01:43:09,640 UNBLOCKED APPROVAL AT THE END OF 2804 01:43:09,640 --> 01:43:13,400 THE SESSION AND HOPEFULLY SAVE 2805 01:43:13,400 --> 01:43:14,960 TIME. 2806 01:43:14,960 --> 01:43:17,520 SO AS WE BEGIN, I THINK THERE'S 2807 01:43:17,520 --> 01:43:23,760 A SLIDE SET THAT SHOULD BE 2808 01:43:23,760 --> 01:43:24,280 PROJECTED NOW. 2809 01:43:24,280 --> 01:43:26,040 YVETTE DO YOU HAVE THAT OR DO 2810 01:43:26,040 --> 01:43:28,520 THE IT FOLKS HAVE IT. 2811 01:43:28,520 --> 01:43:30,520 >> THE IT. WILL PUT IT ON THERE, 2812 01:43:30,520 --> 01:43:31,480 THERE IT IS. 2813 01:43:31,480 --> 01:43:36,000 >> WE WILL HAVE, OKAY, THE USUAL 2814 01:43:36,000 --> 01:43:39,960 DISCUSSIONS OF CONCEPT 2815 01:43:39,960 --> 01:43:44,200 CLEARANCES FOR 3 GENERAL AREAS. 2816 01:43:44,200 --> 01:43:46,720 WE HAVE 2 CONCEPT CLEARANCES FOR 2817 01:43:46,720 --> 01:43:49,080 THE CONSORTIUM ON FOOD'LLERGY 2818 01:43:49,080 --> 01:43:49,360 RESEARCH. 2819 01:43:49,360 --> 01:43:51,080 ONE WILL BE FOR THE LEADERSHIP 2820 01:43:51,080 --> 01:43:56,000 CENTER AND 1 FOR THE CLINICAL 2821 01:43:56,000 --> 01:43:56,480 SITES. 2822 01:43:56,480 --> 01:43:59,560 WE HAVE RECOMPETITION OF THE 2823 01:43:59,560 --> 01:44:03,520 INSTITUTES ADJUVANT DISCOVERY 2824 01:44:03,520 --> 01:44:06,160 PROGRAM AND THEN 2 CONCEPTS IN 2825 01:44:06,160 --> 01:44:08,040 THE RADIATION COUNTERMEASURES 2826 01:44:08,040 --> 01:44:10,200 PROGRAM THAT OUR DIVISION IS 2827 01:44:10,200 --> 01:44:10,560 RESPONSIBLE FOR. 2828 01:44:10,560 --> 01:44:13,400 BEFORE WE GET TO THOSE, THOUGH, 2829 01:44:13,400 --> 01:44:20,880 I WANTED TO BRING TO YOUR 2830 01:44:20,880 --> 01:44:22,680 ATTENTION 3 INITIATIVES THAT 2831 01:44:22,680 --> 01:44:24,960 WERE DISCUSSED QUITE SOMETIME 2832 01:44:24,960 --> 01:44:27,640 AGO AT COUNSEL AS CONCEPT 2833 01:44:27,640 --> 01:44:29,120 CLEARANCES AND WE'RE BRINGING 2834 01:44:29,120 --> 01:44:31,520 THEM BACK NOW, NOT FOR 2835 01:44:31,520 --> 01:44:34,120 DISCUSSION, BUT JUST TO BE SURE, 2836 01:44:34,120 --> 01:44:38,720 PEOPLE FROM THE COMMUNITY ARE 2837 01:44:38,720 --> 01:44:41,680 AWARE, THESE SOLICITATIONS FOR 2838 01:44:41,680 --> 01:44:44,400 ALLERGY AND ASTHMA STAT CENTER 2839 01:44:44,400 --> 01:44:45,120 OR TRANSPLANTATION RESEARCH, 2840 01:44:45,120 --> 01:44:47,560 STAT CENTER FOR OUR CLINICAL 2841 01:44:47,560 --> 01:44:49,600 TRIAL NETWORKS AND CLINICAL DATA 2842 01:44:49,600 --> 01:44:53,560 AND SAFETY MANAGEMENT CENTER. 2843 01:44:53,560 --> 01:44:55,520 THESE WERE INITIALLY CONSIDERED 2844 01:44:55,520 --> 01:44:56,680 BY COUNCIL PROBABLY A COUPLE 2845 01:44:56,680 --> 01:45:01,880 YEARS AGO AND THEN SOLICITED AS 2846 01:45:01,880 --> 01:45:04,600 CONTRACT PROPOSALS AND THERE 2847 01:45:04,600 --> 01:45:07,160 WERE SOME IRREGULATEARS IN THE 2848 01:45:07,160 --> 01:45:10,160 PEER REVIEW STAGE THAT LED TO 2849 01:45:10,160 --> 01:45:14,440 PROTESTS AND AS A RESULT WE ARE 2850 01:45:14,440 --> 01:45:15,320 REISSUING THESE NOW. 2851 01:45:15,320 --> 01:45:18,360 AND ANYBODY INTERESTED CAN GO TO 2852 01:45:18,360 --> 01:45:21,000 THESE WEB LINKS AND SEE THE 2853 01:45:21,000 --> 01:45:21,960 APPLICATION REQUIREMENTS. 2854 01:45:21,960 --> 01:45:24,400 SO, I WON'T GO INTO THOSE IN ANY 2855 01:45:24,400 --> 01:45:24,800 MORE DETAIL NOW. 2856 01:45:24,800 --> 01:45:28,280 AND WE WILL GO ON TO THE NEXT 2857 01:45:28,280 --> 01:45:36,440 SLIDE, I GUESS WHICH IS PROBABLY 2858 01:45:36,440 --> 01:45:44,200 GANG DONG'S FIRST SLIDE ON THE 2859 01:45:44,200 --> 01:45:44,760 KOFAR INITIATIVE. 2860 01:45:44,760 --> 01:45:45,520 >> WHY DON'T YOU INTRODUCE 2861 01:45:45,520 --> 01:45:49,720 YOURSELF AND GO THROUGH THE 2862 01:45:49,720 --> 01:45:50,960 INITIATIVES AND SAME FOR EACH OF 2863 01:45:50,960 --> 01:45:55,600 OUR STAFF WHO FOLLOW YOU ON THE 2864 01:45:55,600 --> 01:45:59,400 ADJUVANT DISCOVERY AND RADIATION 2865 01:45:59,400 --> 01:46:00,440 DISCOVERY PROGRAMS MANAGEMENT. 2866 01:46:00,440 --> 01:46:04,880 >> YEAH, SOMEHOW I JUST SAW MY 2867 01:46:04,880 --> 01:46:06,600 PRESENTATION AND I CAN'T--I CAN 2868 01:46:06,600 --> 01:46:15,720 NO LONGER SEE THEM. 2869 01:46:15,720 --> 01:46:16,120 MY SCREEN-- 2870 01:46:16,120 --> 01:46:17,320 >> WE'RE NOT SEEING THEM EITHER. 2871 01:46:17,320 --> 01:46:21,360 >> CAN YOU SEE US RIGHT NOW? 2872 01:46:21,360 --> 01:46:26,760 >> NO, I WAS SEEING THEM WHEN 2873 01:46:26,760 --> 01:46:29,680 WE--I HAVE 1 MINITTOR, IS 2874 01:46:29,680 --> 01:46:31,000 THAT--YEAH, SO WITHIN THE ZOOM 2875 01:46:31,000 --> 01:46:33,680 WINDOW IF YOU SEE THE ZOOM 2876 01:46:33,680 --> 01:46:34,840 WINDOW YOUR COMMAND CONTROL 2877 01:46:34,840 --> 01:46:36,840 BUTTON IS AT THE BOTTOM OF THE 2878 01:46:36,840 --> 01:46:39,120 ZOOM WINDOW, YOU SHOULD SEE A 2879 01:46:39,120 --> 01:46:40,320 SHARE GREEN SCREEN BUTTON, DO 2880 01:46:40,320 --> 01:46:42,320 YOU SEE THAT, SO YOU WANT TO 2881 01:46:42,320 --> 01:46:43,480 SELECT THE GREEN SHARE SCREEN 2882 01:46:43,480 --> 01:46:46,560 BUTTON AND THEN SHARE THE 2883 01:46:46,560 --> 01:46:49,520 PRESENTATION THAT, YOU KNOW-- 2884 01:46:49,520 --> 01:46:56,720 >> I DON'T SEE MY OPEN SLIDE 2885 01:46:56,720 --> 01:46:58,560 SET, THE POWER POINT. 2886 01:46:58,560 --> 01:47:00,360 >> ANNETTE DO YOU HAVE A 2887 01:47:00,360 --> 01:47:01,080 CONSOLIDATED VERSION YOU CAN 2888 01:47:01,080 --> 01:47:01,320 SHARE. 2889 01:47:01,320 --> 01:47:03,440 >> I WAS GOING TO SUGGEST WE DO 2890 01:47:03,440 --> 01:47:05,800 SRO A BACK UP JUST IN CASE. 2891 01:47:05,800 --> 01:47:06,760 >> THAT'S WAWE WERE EXECKING SO 2892 01:47:06,760 --> 01:47:11,000 WHY DON'T YOU GO AHEAD AND 2893 01:47:11,000 --> 01:47:11,320 PROJECT THAT. 2894 01:47:11,320 --> 01:47:11,640 >> STAND BY. 2895 01:47:11,640 --> 01:47:12,720 >> GANG IF YOU COULD LET THEM 2896 01:47:12,720 --> 01:47:14,200 KNOW NEXT SLIDE, THEY WILL MOVE 2897 01:47:14,200 --> 01:47:16,080 THAT FOR YOU. 2898 01:47:16,080 --> 01:47:16,440 >> OH, OKAY. 2899 01:47:16,440 --> 01:47:20,280 YEAH, I WAS SURPRISED. 2900 01:47:20,280 --> 01:47:24,400 THAT'S WHY WE HAVE THE BACK UP. 2901 01:47:24,400 --> 01:47:29,040 >> OKAY, SO SHOULD I WAIT 2902 01:47:29,040 --> 01:47:29,600 UNTIL-- 2903 01:47:29,600 --> 01:47:30,480 >> PLEASE STAND BY. 2904 01:47:30,480 --> 01:47:30,840 PLEASE STAND BY. 2905 01:47:30,840 --> 01:47:34,480 , THEY WILL PUT IT UP FOR YOU. 2906 01:47:34,480 --> 01:47:35,120 >> BUT YOU CAN INTRODUCE 2907 01:47:35,120 --> 01:47:38,200 YOURSELF IN THE MEAN TIME GANG. 2908 01:47:38,200 --> 01:47:41,200 >> YEAH, HI, THIS IS GANG DONG 2909 01:47:41,200 --> 01:47:47,200 OFFICER FOR ASTHMA AIR WAY 2910 01:47:47,200 --> 01:47:48,320 BIOLOGY PROGRAM. 2911 01:47:48,320 --> 01:47:52,680 IF YOU NOTICED I AM LISTED TWICE 2912 01:47:52,680 --> 01:47:54,960 BUT ACTUALLY SINCE BOTH CONCEPT 2913 01:47:54,960 --> 01:47:56,040 CLEARANCE FOR THE SAME 2914 01:47:56,040 --> 01:47:57,560 CONSORTIUM SO I WILL PRESENT 2915 01:47:57,560 --> 01:48:01,360 THIS TOGETHER AS A SINGLE 2916 01:48:01,360 --> 01:48:02,160 CONCEPT CLEARANCE PRESENTATION 2917 01:48:02,160 --> 01:48:05,160 SO THE CONCEPT CLEARANCE 2918 01:48:05,160 --> 01:48:08,240 PRESENTING IS FOR THE RENEWAL 2919 01:48:08,240 --> 01:48:11,400 FOR CONSORTIUM FOR FOOD ALLERGY 2920 01:48:11,400 --> 01:48:13,280 RESEARCH, CO FAR. 2921 01:48:13,280 --> 01:48:14,880 NEXT SLIDE. 2922 01:48:14,880 --> 01:48:15,840 FOOD ALLERGY EFFECTS 2923 01:48:15,840 --> 01:48:17,600 APPROXIMATELY 8% OF CHILDREN AND 2924 01:48:17,600 --> 01:48:20,720 11% OF ADULTS IN THE U.S. 2925 01:48:20,720 --> 01:48:25,040 IT IS MOST FREQUENT CAUSE OF 2926 01:48:25,040 --> 01:48:28,560 EMERGENCY ROOM VISIT FOR 2927 01:48:28,560 --> 01:48:28,880 ANAPHYLAXIS. 2928 01:48:28,880 --> 01:48:31,920 THE SPECTRUM OF FULLY ENDORSE 2929 01:48:31,920 --> 01:48:34,400 THE IMMUNOLOGICAL DISEASES 2930 01:48:34,400 --> 01:48:38,880 CONTINUE TO EXPAND, AND ENCODE 2931 01:48:38,880 --> 01:48:41,560 ESO CENOPHILICI EOE AND FOOD 2932 01:48:41,560 --> 01:48:44,600 PROTEIN INDUCED ENTHUSIASMER O 2933 01:48:44,600 --> 01:48:48,920 COLITIS SYNDROME, FPIES 2934 01:48:48,920 --> 01:48:49,640 ALPHA-GAL SYNDROME, AGS. 2935 01:48:49,640 --> 01:48:51,400 THERE'S NO CURE FOR FOOD 2936 01:48:51,400 --> 01:48:55,600 ELSYNERGIES SO THEREFORE IN 2937 01:48:55,600 --> 01:48:57,680 2005, NIAID INITIATED CONSORTIUM 2938 01:48:57,680 --> 01:49:00,880 FOR FOOD ALLERGY RESEARCH, AIMED 2939 01:49:00,880 --> 01:49:02,640 TO CONDUCT CUTTING EDGE CLINICAL 2940 01:49:02,640 --> 01:49:05,720 TRIALS AND CLINICAL STUDIES TO 2941 01:49:05,720 --> 01:49:07,240 ADVANCE PREVENTION MANAGEMENT 2942 01:49:07,240 --> 01:49:09,040 STRATEGIES FOR FOOD ALLERGIES, 2943 01:49:09,040 --> 01:49:11,280 AND ALSO ENHANCE OUR KNOWLEDGE 2944 01:49:11,280 --> 01:49:15,400 ON THE ORIGE EPI-BLASTINS AND 2945 01:49:15,400 --> 01:49:17,280 THE PATHOPHYSIOLOGY OF IT 2946 01:49:17,280 --> 01:49:19,000 MEDIATED FOOD ALLERGY, NEXT 2947 01:49:19,000 --> 01:49:19,360 SLIDE, PLEASE. 2948 01:49:19,360 --> 01:49:24,120 >> AS I SAID BEFORE, CO FAR IS 2949 01:49:24,120 --> 01:49:26,040 ESTABLISHED IN 2005 AND RENEWAL 2950 01:49:26,040 --> 01:49:31,280 IN 2010, AND THE CURRENT CO FAR 2951 01:49:31,280 --> 01:49:33,440 IS RENEWED IN 2017, WE SUPPORTED 2952 01:49:33,440 --> 01:49:35,720 1 LEADERSHIP CENTER THAT 2953 01:49:35,720 --> 01:49:38,200 PROVIDED SCIENTIFIC LEADERSHIP 2954 01:49:38,200 --> 01:49:39,720 AND ADMINISTRATIVE STRUCTURE FOR 2955 01:49:39,720 --> 01:49:44,480 NETWORK WIDE TRIALS AND STUDIES 2956 01:49:44,480 --> 01:49:48,480 AND CO FAR ALSO SUPPORT 2957 01:49:48,480 --> 01:49:50,240 CURRENTLY SUPPORTING 7 CLINICAL 2958 01:49:50,240 --> 01:49:54,680 RESEARCH UNIT AS A SITE TO 2959 01:49:54,680 --> 01:49:55,880 IMPLEMENT NETWORK WIDE TRIALS 2960 01:49:55,880 --> 01:49:58,640 AND STUDIES. 2961 01:49:58,640 --> 01:50:00,960 NEXT SLIDE. 2962 01:50:00,960 --> 01:50:04,360 AND THEN LAST 17 YEARS CO FAR 2963 01:50:04,360 --> 01:50:08,680 HAS BEEN VERY SUCCESSFUL 2964 01:50:08,680 --> 01:50:11,120 COMPLETING MANY CLINICAL TRIALS, 2965 01:50:11,120 --> 01:50:15,000 NATURAL HISTORY STUDIES, AND 2966 01:50:15,000 --> 01:50:16,520 MECHANISTIC RESEARCH PROJECTS AS 2967 01:50:16,520 --> 01:50:18,760 IS LISTED, AS IS SHOWN IN THE 2968 01:50:18,760 --> 01:50:21,080 BAR AND CURRENT CO FAR, THERE 2969 01:50:21,080 --> 01:50:23,640 ARE 2 MAJOR STUDIES ONGOING, 1 2970 01:50:23,640 --> 01:50:25,600 IS CALLED OUTMATCH AND THE OTHER 2971 01:50:25,600 --> 01:50:26,680 IS SUN BEAM, WHICH WILL I 2972 01:50:26,680 --> 01:50:29,320 EXPLAIN IN THE NEXT COUPLE 2973 01:50:29,320 --> 01:50:29,840 SLIDES. 2974 01:50:29,840 --> 01:50:30,120 NEXT. 2975 01:50:30,120 --> 01:50:33,800 OUTMATCH IS A PHASE 3 CLINICAL 2976 01:50:33,800 --> 01:50:35,440 TRIAL ABOUT THE EFFICACY OF 2977 01:50:35,440 --> 01:50:39,760 ELOSE MAB WHICH IS THE 2978 01:50:39,760 --> 01:50:40,480 UN[INDISCERNIBLE] MONOCLONAL 2979 01:50:40,480 --> 01:50:42,200 ANTIBODY TO INCREASE THE AMOUNT 2980 01:50:42,200 --> 01:50:45,080 OF FOOD IT TAKES TO INDUCE THE 2981 01:50:45,080 --> 01:50:48,040 REACTION TO PEANUT AND OTHER 2982 01:50:48,040 --> 01:50:48,760 MAJOR FOOD ALLERGENS. 2983 01:50:48,760 --> 01:50:54,240 AND STUDY ALSO COMPARES 2984 01:50:54,240 --> 01:50:56,920 PROTECTION OF OMALIZUMAB 2985 01:50:56,920 --> 01:50:59,240 MONOTHERAPY TO FACILITATE THE 2986 01:50:59,240 --> 01:51:01,480 MULTIFOOD ORAL IMMUNOTHERAPY. 2987 01:51:01,480 --> 01:51:03,040 IF SUCCESSFUL, THIS STUDY MAY 2988 01:51:03,040 --> 01:51:05,200 LEAD TO FDA APPROVAL OF THE 2989 01:51:05,200 --> 01:51:07,440 FIRST BROAD SPECTRUM TREATMENT 2990 01:51:07,440 --> 01:51:10,840 FOR FOOD ELERGY. 2991 01:51:10,840 --> 01:51:16,520 NEXT SLIDE. 2992 01:51:16,520 --> 01:51:16,920 NEXT SLIDE. 2993 01:51:16,920 --> 01:51:20,680 SUN BEAM IS THE FIRST COHORT 2994 01:51:20,680 --> 01:51:23,480 STUDY STANDS FOR SISS BIOLOGY 2995 01:51:23,480 --> 01:51:25,960 AND STUDY INITIATE INDEED 2996 01:51:25,960 --> 01:51:29,840 MARCH 2021 CONDUCTED BY CO FAR 2997 01:51:29,840 --> 01:51:37,560 NETWORK AND WITH PARTIC PAIGDZ 2998 01:51:37,560 --> 01:51:38,840 BY DIVISIONS--PARTICIPATION 2999 01:51:38,840 --> 01:51:41,040 FUNDED BY ATOPIC DERMA TITIS 3000 01:51:41,040 --> 01:51:42,480 RESEARCH NETWORK AND IMMUNE 3001 01:51:42,480 --> 01:51:44,080 TOLERANCE NETWORK, THE 3002 01:51:44,080 --> 01:51:46,080 OBJECTIVES IS TO IDENTIFY RISK 3003 01:51:46,080 --> 01:51:47,080 FACTORS FOR DISEASE PRODICTION 3004 01:51:47,080 --> 01:51:49,880 AND EARLY STAGE MECHANISMS IN 3005 01:51:49,880 --> 01:51:52,400 THE DEVELOPMENT OF ATOPIC 3006 01:51:52,400 --> 01:51:54,360 DERMATITIS AND FOOD ALLERGY AND 3007 01:51:54,360 --> 01:51:58,640 THE STUDY UTILIZE TD 3008 01:51:58,640 --> 01:52:00,280 MULTI-OMICs APPROACH TO 3009 01:52:00,280 --> 01:52:01,840 IDENTIFY DETERMINANTS OF ATOPIC 3010 01:52:01,840 --> 01:52:04,000 DISEASE IN VERY YOUNG CHILDREN, 3011 01:52:04,000 --> 01:52:06,800 FOCUSING ON FOOD ALLERGY AND 3012 01:52:06,800 --> 01:52:13,240 ATOPIC DERMA TITIS. 3013 01:52:13,240 --> 01:52:14,440 NEXT SLIDE. 3014 01:52:14,440 --> 01:52:18,320 >> SO FOR RENEWAL, WE STILL 3015 01:52:18,320 --> 01:52:19,760 USE--WE PROPOSED COOPERATIVE 3016 01:52:19,760 --> 01:52:25,880 AGREEMENT FOR 7 YEARS OF WORK 3017 01:52:25,880 --> 01:52:28,160 AND WE--WE WILL SUPPORT A 3018 01:52:28,160 --> 01:52:30,600 LEADERSHIP CENTER THAT PROVIDES 3019 01:52:30,600 --> 01:52:32,680 SCIENTIFIC LEADERSHIP AND 3020 01:52:32,680 --> 01:52:33,600 ORGANIZATION THOUGH AND THE 3021 01:52:33,600 --> 01:52:36,760 STRUCTURE AND THE LEADERSHIP 3022 01:52:36,760 --> 01:52:38,200 CENTER WILL GUIDE THE NETWORK 3023 01:52:38,200 --> 01:52:41,200 FOR CLINICAL TRIALS AND STUDIES 3024 01:52:41,200 --> 01:52:43,240 WITH EMBEDDED MECHANISTIC 3025 01:52:43,240 --> 01:52:46,680 STUDIES, SO OBVIOUSLY THIS--THE 3026 01:52:46,680 --> 01:52:49,240 LEADERSHIP CENTER, WE INCLUDE 3027 01:52:49,240 --> 01:52:50,320 STRUCTURE, ADMINISTRATIVE CENTER 3028 01:52:50,320 --> 01:52:59,200 AND CLINICAL ROPERATIONS CENTER. 3029 01:52:59,200 --> 01:53:03,160 AND WE ALSO SUPPORT 10 CLINICAL 3030 01:53:03,160 --> 01:53:04,760 RESEARCH CENTERS AS THE CENTERS 3031 01:53:04,760 --> 01:53:08,520 WILL SERVE AS THE SITE FOR 3032 01:53:08,520 --> 01:53:09,440 IMPLEMENT NETWORK WIDE TRIALS 3033 01:53:09,440 --> 01:53:12,720 AND STUDIES IN ADDITION EACH 3034 01:53:12,720 --> 01:53:14,800 SIDE WILL CONDUCT 3035 01:53:14,800 --> 01:53:16,440 CENTER-SPECIFIC SMALL CLINICAL 3036 01:53:16,440 --> 01:53:18,880 RESEARCH PROJECTS AND TOGETHER 3037 01:53:18,880 --> 01:53:21,480 THEY CONTRIBUTE TO DEVELOPMENT 3038 01:53:21,480 --> 01:53:25,640 OF NEW NETWORK-WIDE PROTOCOLS, 3039 01:53:25,640 --> 01:53:27,200 WITH MECHANISTIC RESEARCH WITH 3040 01:53:27,200 --> 01:53:31,440 THE HOPE THAT THIS--THE STUDY, 3041 01:53:31,440 --> 01:53:33,080 THIS PROJECT, THIS PROPOSAL MAY 3042 01:53:33,080 --> 01:53:37,640 BECOME, MAY LEAD TO THE NETWORK 3043 01:53:37,640 --> 01:53:44,040 WIDE PROTOCOLS; NEXT SLIDE. 3044 01:53:44,040 --> 01:53:46,440 SO THE OBJECTIVE OF THE PROFAR 3045 01:53:46,440 --> 01:53:48,120 RENEWAL WILL BE EXPANDED TO 3046 01:53:48,120 --> 01:53:55,760 INCLUDE THE MORE DISEASES, I 3047 01:53:55,760 --> 01:53:58,760 DESCRIBED IN THE INTRODUCTION WE 3048 01:53:58,760 --> 01:54:05,040 ALSO THE--INCLUDE THE OBJECTIVE 3049 01:54:05,040 --> 01:54:07,120 WILL IMPROVE DIAGNOSTIC 3050 01:54:07,120 --> 01:54:09,760 PROCESSES TO POTENTIALLY REPLACE 3051 01:54:09,760 --> 01:54:15,880 R04 CHALLENGES AND ASSESS 3052 01:54:15,880 --> 01:54:17,760 INCIDENCE AND PREVALENCE OF FOOD 3053 01:54:17,760 --> 01:54:21,200 ALLERGY IN THE U.S. AND WE 3054 01:54:21,200 --> 01:54:25,040 EXPECT THE CO FAR WILL CONDUCT 3055 01:54:25,040 --> 01:54:28,080 RESEARCH TO ELUC DATE 3056 01:54:28,080 --> 01:54:30,400 INTERACTIONS BETWEEN 3057 01:54:30,400 --> 01:54:31,800 IMMUNOLOGICAL, ENVIRONMENTAL, 3058 01:54:31,800 --> 01:54:32,840 GENETIC, EPIGENETIC FACTORS 3059 01:54:32,840 --> 01:54:34,480 UNDERLYING DEVELOPMENT OF FOOD 3060 01:54:34,480 --> 01:54:37,360 ALLERGY, MOLL LECULAR MECHANISMS 3061 01:54:37,360 --> 01:54:39,200 ASSOCIATED WITH DEVELOPMENT AND 3062 01:54:39,200 --> 01:54:41,960 CLINICAL PRESENTATION OF FOOD 3063 01:54:41,960 --> 01:54:45,320 ALLERGY RESPONSE TO THERAPY, 3064 01:54:45,320 --> 01:54:47,920 SEVERITY OF ALLERGIC REACTIONS 3065 01:54:47,920 --> 01:54:56,840 AND ANAPHYLAXIS IN FOOD ALLERGY. 3066 01:54:56,840 --> 01:54:57,640 NEXT SLIDE. 3067 01:54:57,640 --> 01:55:01,240 AND IN ADDITION THE CO FAR 3068 01:55:01,240 --> 01:55:05,840 RENEWAL CO FAR WILL HAVE A 3069 01:55:05,840 --> 01:55:07,760 RESPONSIBILITY TO COMPLETE THE 3070 01:55:07,760 --> 01:55:09,120 OUTMATCH TRIAL AND ALSO 3071 01:55:09,120 --> 01:55:11,720 CONTINUATION OF SUN BEAM BIRTH 3072 01:55:11,720 --> 01:55:20,360 COHORT STUDIES. 3073 01:55:20,360 --> 01:55:21,080 NEXT SLIDE. 3074 01:55:21,080 --> 01:55:25,720 SO CO FAR NETWORK WILL RECEIVE 3075 01:55:25,720 --> 01:55:31,600 SUPPORT FROM DIVISION FUNDED 3076 01:55:31,600 --> 01:55:35,360 OTHER CENTERS THAT INCLUDE THE 3077 01:55:35,360 --> 01:55:37,120 STATISTICAL SUPPORT, DATA 3078 01:55:37,120 --> 01:55:39,520 MONITORING AND MANAGEMENT, 3079 01:55:39,520 --> 01:55:41,640 CLINICAL SITE MONITORING, 3080 01:55:41,640 --> 01:55:43,360 MEDICAL MONITORING, REGULATORY 3081 01:55:43,360 --> 01:55:44,680 SUPPORT AND DSMB WHICH ARE 3082 01:55:44,680 --> 01:55:51,920 PROVIDED BY THE DIVISION OF 3083 01:55:51,920 --> 01:55:53,640 DAIT, I THINK THIS IS MY LAST 3084 01:55:53,640 --> 01:55:55,600 SLIDE AND I WILL BE HAPPY TO 3085 01:55:55,600 --> 01:56:05,960 ANSWER ANY QUESTIONS. 3086 01:56:20,720 --> 01:56:21,120 >> LOOKS GREAT. 3087 01:56:21,120 --> 01:56:22,840 >> SO THIS IS A 7 YEAR PROJECT 3088 01:56:22,840 --> 01:56:25,240 AND YOU ANTICIPATED IT WOULD GET 3089 01:56:25,240 --> 01:56:25,560 STARTED WHEN? 3090 01:56:25,560 --> 01:56:27,360 I SAW THOSE TIMELINES BUT WHEN 3091 01:56:27,360 --> 01:56:32,600 WOULD IT ACTUALLY GET FIRED UP? 3092 01:56:32,600 --> 01:56:33,560 >> THIS IS FOR 2024. 3093 01:56:33,560 --> 01:56:36,440 SO WE ANTICIPATE THE PROJECT 3094 01:56:36,440 --> 01:56:40,760 WILL START MARCH 2024. 3095 01:56:40,760 --> 01:56:42,720 THAT'S WHERE THE CURRENT CO FAR 3096 01:56:42,720 --> 01:56:50,720 PROGRAM WILL END. 3097 01:56:50,720 --> 01:56:50,960 >> OKAY. 3098 01:56:50,960 --> 01:56:53,680 >> DAVID ARE YOU STILL ON? 3099 01:56:53,680 --> 01:57:00,960 I DON'T SEE YOU. 3100 01:57:00,960 --> 01:57:04,880 DAN AND I HAVE HAD SOME 3101 01:57:04,880 --> 01:57:06,200 CONVERSATIONS OVER PAST FEW 3102 01:57:06,200 --> 01:57:08,840 MONTHS ABOUT BRINGING SOME OF 3103 01:57:08,840 --> 01:57:11,040 THE ININIVATIONS IN MUCOSAL 3104 01:57:11,040 --> 01:57:15,320 IMMUNOLOGY INTO THE FOOD ALLERGY 3105 01:57:15,320 --> 01:57:18,840 PROGRAM. 3106 01:57:18,840 --> 01:57:20,240 AND I'M WONDERING IF ANY 3107 01:57:20,240 --> 01:57:24,000 THOUGHTS FROM COUNCIL MEMBERS OR 3108 01:57:24,000 --> 01:57:26,920 OTHERS ON HOW WE CAN ACCELERATE 3109 01:57:26,920 --> 01:57:30,360 THAT IN THE CO FAR NETWORK 3110 01:57:30,360 --> 01:57:32,360 EITHER THROUGH OPPORTUNITY FUND 3111 01:57:32,360 --> 01:57:40,640 PROJECTS OR OTHERS. 3112 01:57:40,640 --> 01:57:43,320 >> WOULD THAT BE, DAN, A 3113 01:57:43,320 --> 01:57:45,040 SEPARATE MECHANISM THEN TO 3114 01:57:45,040 --> 01:57:45,800 INTEGRATE MAYBE THE PROGRAMS 3115 01:57:45,800 --> 01:57:46,840 BECAUSE IT SEEMS NATURAL. 3116 01:57:46,840 --> 01:57:48,960 I MEAN EACH WOULD BENEFIT FROM 3117 01:57:48,960 --> 01:57:49,400 THE OTHER. 3118 01:57:49,400 --> 01:57:58,280 AND IT'S A GREAT IDEA. 3119 01:57:58,280 --> 01:58:00,520 >> YEAH, I MEAN, WE ARE LIMITED 3120 01:58:00,520 --> 01:58:03,600 AS I ALLUDED TO EARLIER WHAT WE 3121 01:58:03,600 --> 01:58:07,000 CAN DO IN HUMANS VERSUS MICE, SO 3122 01:58:07,000 --> 01:58:10,520 THERE'S SOME LIMITATIONS THERE, 3123 01:58:10,520 --> 01:58:12,800 BUT BUT IT REALLY IS IMPORTANT 3124 01:58:12,800 --> 01:58:15,760 TO KEEP THESE CLINICAL NETWORKS 3125 01:58:15,760 --> 01:58:17,840 GROUNDED ON KIND OF THE 3126 01:58:17,840 --> 01:58:21,320 FUNDAMENTAL IMMUNOLOGY AND 3127 01:58:21,320 --> 01:58:25,400 CUTTING EDGE RESEARCH THAT FLOWS 3128 01:58:25,400 --> 01:58:27,360 FROM THE MORE BASIC SCIENCE THAT 3129 01:58:27,360 --> 01:58:30,720 THE EN--STRATEGIESITUTE 3130 01:58:30,720 --> 01:58:30,960 SUPPORTS. 3131 01:58:30,960 --> 01:58:31,680 >> COULD YOU ENVISION, YOU KNOW 3132 01:58:31,680 --> 01:58:34,320 IF YOU DID WANT TO MAKE THOSE 3133 01:58:34,320 --> 01:58:35,760 CONNECTIONS, WOULD YOU ENVISION 3134 01:58:35,760 --> 01:58:42,160 OFFERING LIKEN SILLARY TO THE 3135 01:58:42,160 --> 01:58:43,600 TRIAL OPPORTUNITY AS WELL OR DO 3136 01:58:43,600 --> 01:58:45,520 YOU THINK THAT'S NOT POSSIBLE? 3137 01:58:45,520 --> 01:58:50,200 I MEAN, I COULD IMAGINE WHILE 3138 01:58:50,200 --> 01:58:51,600 STUDYING HUMANS IS CHALLENGING, 3139 01:58:51,600 --> 01:58:53,280 YOU KNOW HUMAN TISSUE IMAGING, 3140 01:58:53,280 --> 01:58:56,120 YOU KNOW OF THE OCCASIONS WHEN 3141 01:58:56,120 --> 01:58:57,440 BIOPSIES ARE AVAILABLE, IS NOT 3142 01:58:57,440 --> 01:58:58,880 IMPABL AND CAN BE VERY 3143 01:58:58,880 --> 01:59:00,400 INFORMATIVE AND THEN THERE'S A 3144 01:59:00,400 --> 01:59:01,720 NUMBER OF THINGS JUST WITH 3145 01:59:01,720 --> 01:59:03,280 RESPECT TO NUCLEOTIDES T-REGENT 3146 01:59:03,280 --> 01:59:05,600 ABSORPTION THAT 1 CAN DO WITH 3147 01:59:05,600 --> 01:59:06,880 FOR EXAMPLE, STABILIZE O TAUPE 3148 01:59:06,880 --> 01:59:08,920 TRACER TYPE STUDIES AND I THINK 3149 01:59:08,920 --> 01:59:10,920 THERE ARE REALLY, I DON'T KNOW 3150 01:59:10,920 --> 01:59:15,400 POTENTIALLY COULD BE VERY 3151 01:59:15,400 --> 01:59:15,720 INTERESTING. 3152 01:59:15,720 --> 01:59:19,000 BUT YEAH, IN SOME CASES THERE'S 3153 01:59:19,000 --> 01:59:19,760 THE ANCILLARY STUDIES THAT 3154 01:59:19,760 --> 01:59:20,800 ASSOCIATES WITH TRIALS AND 3155 01:59:20,800 --> 01:59:24,800 PEOPLE CAN APPLY TO THOSE, DO 3156 01:59:24,800 --> 01:59:27,040 YOU THINK THAT'S POSSIBLE? 3157 01:59:27,040 --> 01:59:30,280 >> YEAH, THAT IS A POSSIBILITY. 3158 01:59:30,280 --> 01:59:34,160 IT'S ALSO WE ALWAYS REGARDED IT 3159 01:59:34,160 --> 01:59:36,360 AS A STRENGTH IF LEADERSHIP 3160 01:59:36,360 --> 01:59:41,000 CENTERS FOR THESE PROGRAMS BRING 3161 01:59:41,000 --> 01:59:43,880 IN BASIC SCIENTISTS OR KIND OF 3162 01:59:43,880 --> 01:59:45,160 ADVISORY GROUPS TO HELP STEER 3163 01:59:45,160 --> 01:59:49,240 THE RESEARCH OVER AND YOU KNOW 3164 01:59:49,240 --> 01:59:51,440 AS JUST COMMENTED, THIS IS A 7 3165 01:59:51,440 --> 01:59:51,920 YEAR PROGRAM. 3166 01:59:51,920 --> 01:59:55,920 SO IT'S NOT SO EASY TO 3167 01:59:55,920 --> 01:59:57,160 ANTICIPATE SOME OF THE 3168 01:59:57,160 --> 02:00:02,160 OPPORTUNITIES TO THAT MIGHT COME 3169 02:00:02,160 --> 02:00:02,600 UP. 3170 02:00:02,600 --> 02:00:02,880 >> RIGHT. 3171 02:00:02,880 --> 02:00:04,480 I GUESS MY OTHER QUESTION MIGHT 3172 02:00:04,480 --> 02:00:08,560 BE, HOW LIKELY IS IT THAT THE 3173 02:00:08,560 --> 02:00:11,120 CURRENT CO FAR GROUPS ARE THE 3174 02:00:11,120 --> 02:00:12,440 MAIN COMPETITORS FOR THE 3175 02:00:12,440 --> 02:00:13,120 RENUCLEOTIDESSAL BECAUSE I DON'T 3176 02:00:13,120 --> 02:00:16,320 KNOW THAT THERE ARE SO MANY 3177 02:00:16,320 --> 02:00:21,200 GROUPS POISED TO ADDRESS THESE 3178 02:00:21,200 --> 02:00:21,640 QUESTIONS? 3179 02:00:21,640 --> 02:00:24,560 >> WELL, IT'S USUALLY THE CASE 3180 02:00:24,560 --> 02:00:27,720 THAT THE INCUMBENT REAPPLIES BUT 3181 02:00:27,720 --> 02:00:32,600 ON MANY OF THESE CLINICAL 3182 02:00:32,600 --> 02:00:34,280 CONSORTIA WE HAVE HAD TURNOVER 3183 02:00:34,280 --> 02:00:35,440 EITHER IN THE LEADERSHIP CENTERS 3184 02:00:35,440 --> 02:00:38,840 OR IN THE CLINICAL RESEARCH 3185 02:00:38,840 --> 02:00:41,360 SITES. 3186 02:00:41,360 --> 02:00:42,920 WE ALSO HAVE I THINK IT WAS 3187 02:00:42,920 --> 02:00:44,760 MENTIONED EARLIER THAT THERE'S A 3188 02:00:44,760 --> 02:00:49,960 CONGRESSIONAL INTEREST IN OUR 3189 02:00:49,960 --> 02:00:51,240 EXPANDING CO FAR CLINICAL SITES 3190 02:00:51,240 --> 02:00:52,440 BEYOND THE CURRENT NUMBER AND 3191 02:00:52,440 --> 02:00:59,240 THERE COULD BE OPPORTUNITIES 3192 02:00:59,240 --> 02:01:00,120 THERE AS WELL. 3193 02:01:00,120 --> 02:01:00,960 >> SO DAN, 1 THOUGHT THAT 3194 02:01:00,960 --> 02:01:04,000 CROSSED MY MIND IS WE USED TO 3195 02:01:04,000 --> 02:01:05,840 HAVE VIA NHLBI, THOSE CORE 3196 02:01:05,840 --> 02:01:08,240 GRANTS WHERE ACTUALLY THE BASIC 3197 02:01:08,240 --> 02:01:10,040 PROJECTS HAD TO BE BECAUSE OF A 3198 02:01:10,040 --> 02:01:11,480 REQUIREMENT TO BE SUPPORTED BY A 3199 02:01:11,480 --> 02:01:13,200 CLINICAL PROJECT AND THAT WOULD 3200 02:01:13,200 --> 02:01:14,680 KIND OF BE AN OVERARCHING THING 3201 02:01:14,680 --> 02:01:18,560 SO WOULD THAT BE A THOUGHT THAT 3202 02:01:18,560 --> 02:01:22,680 THE CO FAR PROJECTS HAVE? 3203 02:01:22,680 --> 02:01:24,160 LIKE INTEGRATED SOME MORE BASIC 3204 02:01:24,160 --> 02:01:28,600 PROJECT THAT COULD INVOLVE 3205 02:01:28,600 --> 02:01:31,800 IMAGING OF THAT GWEN POINTED OUT 3206 02:01:31,800 --> 02:01:33,600 BECAUSE IMAGING IS SO 3207 02:01:33,600 --> 02:01:34,840 [INDISCERNIBLE] WITH THE COMPLEX 3208 02:01:34,840 --> 02:01:36,280 IMAGING AND 1 CAN TOO WITH THE 3209 02:01:36,280 --> 02:01:38,040 SAMPLES SO WOULD THAT BE 3210 02:01:38,040 --> 02:01:40,440 SOMETHING FOR THE FUTURE TO 3211 02:01:40,440 --> 02:01:42,160 INCLUDE A BASIC WITH THE 3212 02:01:42,160 --> 02:01:46,520 CLINICAL, YOU KNOW? 3213 02:01:46,520 --> 02:01:47,720 >> I SEE, ALKIS JUST WENT OFF 3214 02:01:47,720 --> 02:01:50,280 MUTE, DID YOU WANT TO COMMENT ON 3215 02:01:50,280 --> 02:01:50,520 THAT. 3216 02:01:50,520 --> 02:01:53,240 >> YEAH, HI. 3217 02:01:53,240 --> 02:01:54,200 YEAH, THIS WOULD BE SOMETHING 3218 02:01:54,200 --> 02:01:56,320 VERY OF INTEREST TO US, NO 3219 02:01:56,320 --> 02:01:56,840 QUESTION ABOUT IT. 3220 02:01:56,840 --> 02:01:58,320 ONE OF OUR LIMITATIONS OF 3221 02:01:58,320 --> 02:02:00,840 COURSE, WE WOULD HAVE LOVED TO 3222 02:02:00,840 --> 02:02:02,240 BE ABLE TO HAVE ACCESS TO 3223 02:02:02,240 --> 02:02:05,720 TISSUE, BUT AS YOU ALL KNOW, 3224 02:02:05,720 --> 02:02:08,880 FOOD ALLERGY PRIMARILY AFFECTS 3225 02:02:08,880 --> 02:02:13,160 YOUNG CHILDREN AND IT BECOMES 3226 02:02:13,160 --> 02:02:15,280 QUITE DIFFICULT TO DO 3227 02:02:15,280 --> 02:02:16,280 EN'REENDOSCOPYS IN CHILDREN FOR 3228 02:02:16,280 --> 02:02:18,240 PURPOSES THAT HAVE TO DO WITH 3229 02:02:18,240 --> 02:02:18,480 RESEARCH. 3230 02:02:18,480 --> 02:02:19,480 THERE HAVE BEEN SOME ATTEMPTS IN 3231 02:02:19,480 --> 02:02:23,720 THE PAST FEW YEARS TO 3232 02:02:23,720 --> 02:02:26,000 INTRODUCEENDOSCOPY IN ADULTS OR 3233 02:02:26,000 --> 02:02:27,640 IN OLDER ADOLESCENTS WITH FOOD 3234 02:02:27,640 --> 02:02:29,720 ALLERGY AND THERE HAVE BEEN 3235 02:02:29,720 --> 02:02:30,560 QUITE INTERESTING FINDINGS 3236 02:02:30,560 --> 02:02:30,760 THERE. 3237 02:02:30,760 --> 02:02:33,080 SO, I THINK THAT THE FIELD IS 3238 02:02:33,080 --> 02:02:34,440 OPENING UP IN THIS DIRECTION. 3239 02:02:34,440 --> 02:02:36,480 IT'S JUST GOING TO TAKE A FEW 3240 02:02:36,480 --> 02:02:37,920 MORE YEARS, I THINK FOR 3241 02:02:37,920 --> 02:02:41,080 EVERYBODY TO FEEL COMFORTABLE 3242 02:02:41,080 --> 02:02:41,360 WITH THAT. 3243 02:02:41,360 --> 02:02:44,760 BUT OVER ALL THE IDEA BEHIND CO 3244 02:02:44,760 --> 02:02:47,080 FAR IS TO ALLOW FOR MECHANISTIC 3245 02:02:47,080 --> 02:02:49,640 STUDIES THAT WILL INTRODUCE NEW 3246 02:02:49,640 --> 02:02:52,080 CONCEPTS AND WE HOPE THAT WITH 3247 02:02:52,080 --> 02:02:53,360 THIS NEW STRUCTURE, WHICH MAKES 3248 02:02:53,360 --> 02:02:57,360 EACH 1 OF THE CLINICAL RESEARCH 3249 02:02:57,360 --> 02:03:00,880 SITES, DO ITS OWN SMALL PILOT 3250 02:03:00,880 --> 02:03:02,400 PROJECTS THAT SOME ADDITIONAL 3251 02:03:02,400 --> 02:03:03,960 IDEAS MECHANISTIC IDEAS WILL 3252 02:03:03,960 --> 02:03:08,320 COME OUT THAT WILL THEN BECOME A 3253 02:03:08,320 --> 02:03:09,960 SOURCE FOR APPLICATION TO LARGER 3254 02:03:09,960 --> 02:03:17,840 CLINICAL TRIALS AND STUDIES. 3255 02:03:17,840 --> 02:03:18,160 >> SORRY. 3256 02:03:18,160 --> 02:03:19,480 >> I WAS JUST GOING TO SAY SO 3257 02:03:19,480 --> 02:03:22,200 THOSE WHO ARE PART OF MIST IF 3258 02:03:22,200 --> 02:03:26,360 YOU HAVE IDEAS AND TO HAVE 3259 02:03:26,360 --> 02:03:28,000 POTENTIAL COLLABORATORS IN YOUR 3260 02:03:28,000 --> 02:03:28,800 OWN INSTITUTIONS OR ELSEWHERE 3261 02:03:28,800 --> 02:03:32,240 WHO WOULD BE APPLYING TO THIS 3262 02:03:32,240 --> 02:03:33,440 SORT OF STATION WHEN IT COMES 3263 02:03:33,440 --> 02:03:39,040 OUT THAT WOULD BE TERRIFIC. 3264 02:03:39,040 --> 02:03:40,920 >> GWEN-- 3265 02:03:40,920 --> 02:03:41,280 >> GO,A HEAD. 3266 02:03:41,280 --> 02:03:43,760 >> OH NO I WAS JUST GOING TO ASK 3267 02:03:43,760 --> 02:03:45,480 ALKIS, IN THE CONTEXT OF THE 3268 02:03:45,480 --> 02:03:46,800 DIAGNOSIS OF THESE DIFFERENT 3269 02:03:46,800 --> 02:03:50,240 LIKE FOOD PROTEIN INDUCED 3270 02:03:50,240 --> 02:03:51,880 ENTERIC COLITIS OR EOE, WHAT IS 3271 02:03:51,880 --> 02:03:55,200 THE BASIS OF THE DIAGNOSIS FOR 3272 02:03:55,200 --> 02:03:56,400 THESE DIFFERENT SUBFEATURES? 3273 02:03:56,400 --> 02:04:00,160 IS THERE AN OPPORTUNITY THERE TO 3274 02:04:00,160 --> 02:04:02,800 USE THE DIAGNOSTIC SETTING, YOU 3275 02:04:02,800 --> 02:04:09,560 KNOW TO ALSO ACQUIRE MATERIALS 3276 02:04:09,560 --> 02:04:10,000 MORE BASIC ANALYSIS. 3277 02:04:10,000 --> 02:04:14,840 >> VERY MUCH SO FOR EOE THE 3278 02:04:14,840 --> 02:04:16,920 DIAGNOSIS IS TRULY A PATHOLOGIC 3279 02:04:16,920 --> 02:04:18,920 DIAGNOSIS SO THEY DO UNDERGO EGD 3280 02:04:18,920 --> 02:04:21,480 ON A REGULAR BASIS, IN FACT, 3281 02:04:21,480 --> 02:04:21,840 THESE PATIENTS. 3282 02:04:21,840 --> 02:04:24,920 SO YES THAT COULD BE TISSUE 3283 02:04:24,920 --> 02:04:26,640 AVAILABILITY FROM THE ESOPHAGUS 3284 02:04:26,640 --> 02:04:29,480 IN THE STOMACH AND PROBABLY FROM 3285 02:04:29,480 --> 02:04:33,720 THE DUDE NEM AS WELL FROM THESE 3286 02:04:33,720 --> 02:04:34,160 PATIENTS. 3287 02:04:34,160 --> 02:04:35,520 FOR [INDISCERNIBLE] THESE ARE 3288 02:04:35,520 --> 02:04:38,520 INFANTS, RARELY DO THEY GET 3289 02:04:38,520 --> 02:04:39,680 SCOPED, DIAGNOSIS IS MOSTLY 3290 02:04:39,680 --> 02:04:42,120 CLINICAL BECAUSE THE CLINICAL 3291 02:04:42,120 --> 02:04:44,960 PRESENTATION IS QUITE DRAMATIC. 3292 02:04:44,960 --> 02:04:48,600 SO IT'S PRETTY MUCH EASY TO PUT 3293 02:04:48,600 --> 02:04:51,200 THAT DIAGNOSIS ON, THAT--BUT YOU 3294 02:04:51,200 --> 02:04:52,600 KNOW THIS IS--WE ARE FOR 3295 02:04:52,600 --> 02:04:53,920 [INDISCERNIBLE], WE ARE AT WHAT 3296 02:04:53,920 --> 02:04:56,560 I WOULD CALL EMBRYONIC STAGE OF 3297 02:04:56,560 --> 02:04:57,240 RESEARCH. 3298 02:04:57,240 --> 02:05:00,720 WE WANT TO REALLY DO SOMETHING 3299 02:05:00,720 --> 02:05:01,800 ABOUT THIS CONDITION, WHICH 3300 02:05:01,800 --> 02:05:12,240 SEEMS TO BE INCREASING IN 3301 02:05:14,320 --> 02:05:14,880 INCIDENCE THESE DAYS. 3302 02:05:14,880 --> 02:05:16,480 >> OKAY, WITH THAT IF THERE ARE 3303 02:05:16,480 --> 02:05:19,000 NO OTHER COMMENTS OR QUESTIONS 3304 02:05:19,000 --> 02:05:29,440 WE SHOULD MOVE ON TO THE 3305 02:05:45,360 --> 02:05:48,400 ADJUVANT DISCOVERY PROGRAM. 3306 02:05:48,400 --> 02:05:51,600 >> I AM WOLF GANG AND I AM WITH 3307 02:05:51,600 --> 02:05:53,680 THE BASIC IMMUNOLOGY BRANCH 3308 02:05:53,680 --> 02:05:55,120 WHERE THE VACCINE ADJUVANT 3309 02:05:55,120 --> 02:05:57,720 DISCOVERY PROGRAM RESIDES AND I 3310 02:05:57,720 --> 02:05:59,400 OVERSEE THE VACCINE ADJUVANT 3311 02:05:59,400 --> 02:06:01,280 DISCOVERY PROGRAM AND ITED I'M 3312 02:06:01,280 --> 02:06:02,600 PRESENTING CONCEPT OF RENEWAL OF 3313 02:06:02,600 --> 02:06:03,880 THIS PROGRAM FOR ANOTHER 5 3314 02:06:03,880 --> 02:06:04,240 YEARS. 3315 02:06:04,240 --> 02:06:07,000 SO THE DISCOVERY PROGRAM IS JUST 3316 02:06:07,000 --> 02:06:11,040 1 COMPONENT OF A MUCH LARGER 3317 02:06:11,040 --> 02:06:12,480 ADJUVANT PORTFOLIO THAT SUPPORTS 3318 02:06:12,480 --> 02:06:16,120 A WIDE VARIETY OF ASPECTS OF 3319 02:06:16,120 --> 02:06:17,040 RESEARCH STARTS WITH DISCOVERY 3320 02:06:17,040 --> 02:06:21,160 WHICH ESTABLISHES A PIPELINE OF 3321 02:06:21,160 --> 02:06:23,400 NEW IMMUNO STIMUTORS BUT ALSO 3322 02:06:23,400 --> 02:06:25,960 IMMUNE SUPPRESSORS THAT CAN BE 3323 02:06:25,960 --> 02:06:29,200 FURTHER DEVELOPED INTO SIM 3324 02:06:29,200 --> 02:06:33,080 LATTERY OR TOLL-LIKE 3325 02:06:33,080 --> 02:06:34,080 RECEPTORRERATTIC ADJUVANTS 3326 02:06:34,080 --> 02:06:34,400 RESPECTIVELY. 3327 02:06:34,400 --> 02:06:35,800 WITH EACH NEW ROUND THE FOCUS 3328 02:06:35,800 --> 02:06:37,880 HAS CHANGED AND THIS HAS CHANGED 3329 02:06:37,880 --> 02:06:39,640 AS INSIGHTS INTO THE INNATE 3330 02:06:39,640 --> 02:06:40,880 IMMUNE PATHWAYS AND RECEPTORS 3331 02:06:40,880 --> 02:06:42,960 HAVE EVOLVED AND IN THE CONTEXT 3332 02:06:42,960 --> 02:06:44,480 OF THE DISCOVERY PROGRAM, WE 3333 02:06:44,480 --> 02:06:48,360 ALSO SUPPORT THE EXPLORATION OF 3334 02:06:48,360 --> 02:06:50,920 ADJUVANT COMBINATIONS TO BROADEN 3335 02:06:50,920 --> 02:06:53,640 THE RESPONSE. 3336 02:06:53,640 --> 02:06:56,560 NOW THE NIDE ADJUVANT PROGRAM IS 3337 02:06:56,560 --> 02:06:57,560 NOT JUST A PROGRAM DEVELOPMENT 3338 02:06:57,560 --> 02:06:59,000 BUT WE HAVE A RESEARCH COMPONENT 3339 02:06:59,000 --> 02:07:06,000 AND WE SUPPORT STUDIES INTO THE 3340 02:07:06,000 --> 02:07:06,720 MECHANISM OF ADJUVANT PROGRAMS 3341 02:07:06,720 --> 02:07:13,720 AND THE DISCOVERY OF CORRELATES 3342 02:07:13,720 --> 02:07:16,160 OF ADJUVANTISSITY AND THE 3343 02:07:16,160 --> 02:07:18,960 INVITRO CORRELATES OF 3344 02:07:18,960 --> 02:07:19,720 ADJUVANTISSITY. 3345 02:07:19,720 --> 02:07:21,520 SO AT THE JANUARY MEETING OF THE 3346 02:07:21,520 --> 02:07:24,080 ADVISORY COUNCIL, YOU HAVE HEARD 3347 02:07:24,080 --> 02:07:25,880 ABOUT THE ADJUVANT DEVELOPMENT 3348 02:07:25,880 --> 02:07:27,240 PROGRAM WHICH REACHES THE VERY 3349 02:07:27,240 --> 02:07:31,480 WIDE AND VERY DEEP GAP BETWEEN 3350 02:07:31,480 --> 02:07:32,640 ADJUVANT DISCOVERY AND THE FIRST 3351 02:07:32,640 --> 02:07:35,040 TRIAL OF VACCINE THAT USES A 3352 02:07:35,040 --> 02:07:37,240 NOVEL ADJUVANT. 3353 02:07:37,240 --> 02:07:40,720 AND 1 FOCUS AREA WITHIN OUR 3354 02:07:40,720 --> 02:07:43,040 ADJUVANT DEVELOPMENT AREA IS 3355 02:07:43,040 --> 02:07:44,680 HEAD-TO-HEAD COMPARISONS OF 3356 02:07:44,680 --> 02:07:47,200 ADJUVANTS TO FACILITATE AND 3357 02:07:47,200 --> 02:07:50,120 ACCELERATE ADJUVANT SELECTION 3358 02:07:50,120 --> 02:07:54,520 FOR CLINICAL STUDIES. 3359 02:07:54,520 --> 02:07:58,680 AND FINALLY OUR ADJUVANT PROGRAM 3360 02:07:58,680 --> 02:08:04,360 ALLOWS US TO ADVANCE DEVELOPERS 3361 02:08:04,360 --> 02:08:08,760 AND WE EXCEEDED THE PROGRAM TO 3362 02:08:08,760 --> 02:08:10,440 ADVANCE NAID PRIORITIES AND WE 3363 02:08:10,440 --> 02:08:13,960 CONNECT WITH THE GOAL OF GETTING 3364 02:08:13,960 --> 02:08:15,560 NEW ADJUVANTS INTO THE CLINIC. 3365 02:08:15,560 --> 02:08:18,000 SO THIS NEXT SLIDE SUMMARIZES 3366 02:08:18,000 --> 02:08:21,880 THE VARIOUS PROGRAMS WITHIN OUR 3367 02:08:21,880 --> 02:08:23,200 ADJUVANT PORTFOLIO THAT WE USE 3368 02:08:23,200 --> 02:08:25,440 TO ACCOMPLISH THE GOALS I JUST 3369 02:08:25,440 --> 02:08:25,680 OUTLINES. 3370 02:08:25,680 --> 02:08:27,080 THE DISCOVERY PROGRAM IS THE 3371 02:08:27,080 --> 02:08:29,080 OLDEST 1 WITHIN THE PORTFOLIO, 3372 02:08:29,080 --> 02:08:31,040 IS IT STARTED IN 2003 AND THIS 3373 02:08:31,040 --> 02:08:34,200 IS THE PROGRAM I'M PRESENTING 3374 02:08:34,200 --> 02:08:35,760 FOR RENEWAL TODAY. 3375 02:08:35,760 --> 02:08:39,440 THIS PROGRAM IS COMPLEMENTED BY 3376 02:08:39,440 --> 02:08:40,320 AN ANNUAL SBIR SOLICITATION 3377 02:08:40,320 --> 02:08:42,160 THAT'S ON THE STREET RIGHT NOW, 3378 02:08:42,160 --> 02:08:46,520 AND THAT SUPPORTS THE DISCOVERY 3379 02:08:46,520 --> 02:08:49,120 OF NOVEL ADJUVANTS COMPANIES, 3380 02:08:49,120 --> 02:08:51,240 BASIC RESEARCH ON ADJUVANTS IS 3381 02:08:51,240 --> 02:08:54,080 SUPPORTED THROUGH THE MOLECULAR 3382 02:08:54,080 --> 02:08:58,280 MECHANISM OF COMBINATION 3383 02:08:58,280 --> 02:08:59,800 ADJUVANTS PROGRAM, AND SEEKS TO 3384 02:08:59,800 --> 02:09:02,560 GAIN INSIGHTS INTO THE HOW 3385 02:09:02,560 --> 02:09:05,600 ADJUVANTS WORK ON A MOLECULAR 3386 02:09:05,600 --> 02:09:14,760 LEVEL, THE ACC PROGRAM, TO 3387 02:09:14,760 --> 02:09:16,520 ESTABLISH THE PRINTS OF 3388 02:09:16,520 --> 02:09:21,200 ADJUSTICE ACCESS RANTS, NOW THE 3389 02:09:21,200 --> 02:09:22,680 DEVELOPMENT PROGRAM, NIAID 3390 02:09:22,680 --> 02:09:25,520 SUPPORTS PRECLINICAL STUDIES 3391 02:09:25,520 --> 02:09:27,640 THAT ARE NEEDED TO TO GET 3392 02:09:27,640 --> 02:09:30,960 VACCINES THAT ARE FORMULATED 3393 02:09:30,960 --> 02:09:33,040 WITH NOVEL ADJUVANTS TO THE 3394 02:09:33,040 --> 02:09:41,520 CLINIC OR CLOSER TO THE CLINIC. 3395 02:09:41,520 --> 02:09:43,040 THE AVAR-T PROGRAM WHICH JUST 3396 02:09:43,040 --> 02:09:47,240 STARTED LAST WEEK IS DESIGNED TO 3397 02:09:47,240 --> 02:09:48,800 IDENTIFY OPTIMAL ADJUVANTS FOR 3398 02:09:48,800 --> 02:09:49,960 VACCINES THROUGH SYSTEMATIC 3399 02:09:49,960 --> 02:09:53,400 COMPARISON AND PROFILING 3400 02:09:53,400 --> 02:09:53,680 STUDIES. 3401 02:09:53,680 --> 02:09:56,200 AND FINALLY I MENTIONED OUR GOAL 3402 02:09:56,200 --> 02:09:58,760 TO MAKE NOVEL ADJUVANTS MORE 3403 02:09:58,760 --> 02:09:59,720 ACCESSIBLE TO VACCINE 3404 02:09:59,720 --> 02:10:03,840 DEVELOPERS, THIS IS OUTLINED IN 3405 02:10:03,840 --> 02:10:05,600 THE NIDE STRATEGIC PLAN AND 3406 02:10:05,600 --> 02:10:06,640 RESEARCH AND 1 OF THE TOOLS WE 3407 02:10:06,640 --> 02:10:10,600 USE FOR THIS PURPLES IS THE 3408 02:10:10,600 --> 02:10:11,800 VACCINE ADJUVANT COMPENDIUM OR 3409 02:10:11,800 --> 02:10:14,560 VAC, THIS IS AN ONLINE 3410 02:10:14,560 --> 02:10:16,120 SEARCHABLE DATABASE WE LAUNCHED 3411 02:10:16,120 --> 02:10:18,560 LAST YEAR WHICH IS DESIGNED TO 3412 02:10:18,560 --> 02:10:21,320 CONNECT VACCINE AND ADJUVANT 3413 02:10:21,320 --> 02:10:21,680 DEVELOPERS. 3414 02:10:21,680 --> 02:10:23,880 NOW, TALKING SPECIFICALLY ABOUT 3415 02:10:23,880 --> 02:10:24,960 THE ADJUVANT DISCOVERY PROGRAM 3416 02:10:24,960 --> 02:10:27,360 CHA HAS BEEN ACCOMPLISHED SO 3417 02:10:27,360 --> 02:10:29,880 FAR, THE PROGRAM HAS SUPPORTED 3418 02:10:29,880 --> 02:10:33,880 THE SCREENING OF MORE THAN 3419 02:10:33,880 --> 02:10:35,640 3 MILLION COMPOUNDS INVITRO, BUT 3420 02:10:35,640 --> 02:10:39,680 OVER THE YEARS, WE'VE ALSO ADDED 3421 02:10:39,680 --> 02:10:44,840 INSILIC O EFFORT AND MORE THAN 3422 02:10:44,840 --> 02:10:50,440 10-24th COMPOUNDS HAVE BEEN 3423 02:10:50,440 --> 02:10:51,880 EVALUATED INSILICO, THE LEAD 3424 02:10:51,880 --> 02:10:54,480 COMPOUNDS THAT COME OUT OF THESE 3425 02:10:54,480 --> 02:10:55,680 SCREENS TRIGGER A WIDE VARIETY 3426 02:10:55,680 --> 02:10:59,040 OF PATHWAYS AND THE TLRs, 3427 02:10:59,040 --> 02:11:01,400 CLRs, AND SO ON AND SO ON, 3428 02:11:01,400 --> 02:11:03,960 FOLLOWING UP ON DR. HERBERT'S 3429 02:11:03,960 --> 02:11:04,800 PRESENTATION, I WANTED TO POINT 3430 02:11:04,800 --> 02:11:07,040 OUT THAT 1 OF OUR CURRENT 3431 02:11:07,040 --> 02:11:09,040 CONTRACTORS IS ALSO CONDUCTING A 3432 02:11:09,040 --> 02:11:11,160 SCREEN OF SMALL MOLECULES TO 3433 02:11:11,160 --> 02:11:14,520 IDENTIFY IL1 RECEPTOR AGONIST AS 3434 02:11:14,520 --> 02:11:16,080 NOVEL ADJUVANTS SO INSTEADY OF 3435 02:11:16,080 --> 02:11:17,920 USING THE WHOLE CYTOKINE THEY'RE 3436 02:11:17,920 --> 02:11:20,920 LOOKING FOR SMALL MOLECULE 3437 02:11:20,920 --> 02:11:21,160 INSTEADY. 3438 02:11:21,160 --> 02:11:23,480 EVEN THOUGH THIS IS AN EARLY 3439 02:11:23,480 --> 02:11:28,200 STAGE PROGRAM THAT IS MEANT TO 3440 02:11:28,200 --> 02:11:32,200 PRIME THE ADJUVANT PIPELINE, 3441 02:11:32,200 --> 02:11:34,280 LEAD CANDIDATES FROM ADJUVANT 3442 02:11:34,280 --> 02:11:36,320 CONTRACT HAS BEEN TESTED IN MORE 3443 02:11:36,320 --> 02:11:38,000 THAN 10 CLINICAL TRIALS SO FAR, 3444 02:11:38,000 --> 02:11:41,960 THESE TRIALS ARE SUPPORTED BY 3445 02:11:41,960 --> 02:11:43,600 NIAID PROGRAMS OR WITH OWDZ 3446 02:11:43,600 --> 02:11:43,880 FUNDING. 3447 02:11:43,880 --> 02:11:47,160 AND THEY'RE USE INDEED A WIDE 3448 02:11:47,160 --> 02:11:49,080 VARIETY OF VACCINES, FOR 3449 02:11:49,080 --> 02:11:50,560 INFLUENZA FOR ALLERGY, VACCINES 3450 02:11:50,560 --> 02:11:58,240 FOR SUBSTANCE ABUSE AND OTHERS. 3451 02:11:58,240 --> 02:12:00,000 A NUMBER OF ADJUVANTS FROM THE 3452 02:12:00,000 --> 02:12:01,440 PROGRAM HAVE BEEN AND ARE 3453 02:12:01,440 --> 02:12:03,720 CURRENTLY BEING USE INDEED 3454 02:12:03,720 --> 02:12:05,240 PRECLINICAL COVID VACCINE 3455 02:12:05,240 --> 02:12:08,400 STUDIES, 2 OF THEM HAVE MADE IT 3456 02:12:08,400 --> 02:12:12,400 INTO APPROVED VACCINES, 1 OF 3457 02:12:12,400 --> 02:12:16,080 THEM IS ALHYDROXY QUIM 2, A 3458 02:12:16,080 --> 02:12:18,960 TLR7/8 AGONIST USED IN COVAXIN, 3459 02:12:18,960 --> 02:12:22,880 SECOND 1 IS A NOVEL COMBINATION 3460 02:12:22,880 --> 02:12:26,880 ADJUVANT CONSISTING OF A 3461 02:12:26,880 --> 02:12:28,920 CARBOHYDRATE BASED STIMULATOR 3462 02:12:28,920 --> 02:12:30,240 AND A TLAGONIST THAT CAME OUT OF 3463 02:12:30,240 --> 02:12:39,920 1 OF THOSE SCREENS WHICH I AND 3464 02:12:39,920 --> 02:12:44,720 THIS COVAX 19 WHICH IS ON THE 3465 02:12:44,720 --> 02:12:47,760 MARKET UNDER THE NAME SPIKOGEN. 3466 02:12:47,760 --> 02:12:51,800 THE PROGRAM FEEDS INTO OTHER NIH 3467 02:12:51,800 --> 02:12:53,280 AND NIAID PROGRAMS, I MENTIONED 3468 02:12:53,280 --> 02:12:56,120 INFLUENZA WHO SUPPORT THE 3469 02:12:56,120 --> 02:12:59,320 INFLUENZA VACCINE PROGRAM 3470 02:12:59,320 --> 02:13:02,920 INCOLLABORATION WITH THE NIAID 3471 02:13:02,920 --> 02:13:05,800 WITH COLLEAGUES IN THE NIAID 3472 02:13:05,800 --> 02:13:07,560 DIVISION OF MICROBIOLOGY AND 3473 02:13:07,560 --> 02:13:08,360 INFECTIOUS DISEASES. 3474 02:13:08,360 --> 02:13:10,800 WE HAVE AN ONGOING OPIOID 3475 02:13:10,800 --> 02:13:14,880 VACCINE PROGRAM IN COLLABORATION 3476 02:13:14,880 --> 02:13:18,520 WITH THE NIH INSTITUTE FOR DRUG 3477 02:13:18,520 --> 02:13:19,600 ABUSE ANDAD JUSTICE ACCESS VANTS 3478 02:13:19,600 --> 02:13:22,840 ARE BEING PROVIDED TO THE NIAID 3479 02:13:22,840 --> 02:13:24,680 DIVISION OF AIDS FOR HIV 3480 02:13:24,680 --> 02:13:25,240 VACCINES. 3481 02:13:25,240 --> 02:13:29,000 NOW WHAT DOES THE OVERALL GOAL 3482 02:13:29,000 --> 02:13:30,960 OF THE PROGRAM, IT HASN'T 3483 02:13:30,960 --> 02:13:33,040 CHANGED, IT IS TO SUPPORT THE 3484 02:13:33,040 --> 02:13:37,560 DISCOVERY OF NOVEL IMMUNE 3485 02:13:37,560 --> 02:13:38,480 STIMLATTORY, IMMUNOMODULATORY OR 3486 02:13:38,480 --> 02:13:42,000 COAL O GENIC COMPOUNDS AND THEIR 3487 02:13:42,000 --> 02:13:45,080 PRECLINICAL EARLY STAGE 3488 02:13:45,080 --> 02:13:47,360 EVALUATION AS VACCINE ADJUVANTS 3489 02:13:47,360 --> 02:13:49,360 AND THEN THREEZ NOVEL LEAD 3490 02:13:49,360 --> 02:13:51,840 COMPOUNDS WOULD BE FED INTO 3491 02:13:51,840 --> 02:13:53,440 OTHER ADJUVANT PRESENTLYS 3492 02:13:53,440 --> 02:13:55,000 ESPECIALLY THE ADJUVANT 3493 02:13:55,000 --> 02:13:55,640 DEVELOPMENT PROGRAM. 3494 02:13:55,640 --> 02:13:57,240 WHAT IS OBVIOUSLY NOT SUPPORTED 3495 02:13:57,240 --> 02:13:58,800 BECAUSE THIS IS AN EARLY STAGE 3496 02:13:58,800 --> 02:14:00,360 PROGRAM IS CLINICAL TRIALS. 3497 02:14:00,360 --> 02:14:03,920 AND JUST TO SHOW YOU THE OVERALL 3498 02:14:03,920 --> 02:14:06,160 PROGRAM STRUCTURE, EACH PROJECT 3499 02:14:06,160 --> 02:14:09,000 STARTS WITH A HIGH THROUGH PUT 3500 02:14:09,000 --> 02:14:10,520 SCREENING, LIBRARIES, THE SCREEN 3501 02:14:10,520 --> 02:14:13,840 CAN BE CONDUCTED EITHER INVITRO 3502 02:14:13,840 --> 02:14:16,560 OR INSILIC O OR A COMBINATION OF 3503 02:14:16,560 --> 02:14:19,000 BOTH, LEAD COMPOWBDS UNDERGO 3504 02:14:19,000 --> 02:14:21,320 MECHANISM OF ACTION STUDIES AND 3505 02:14:21,320 --> 02:14:23,200 THEY ALSO UNDERGO OPTIMIZATION 3506 02:14:23,200 --> 02:14:25,040 STUDIES WHICH INTERNAL AUDIT 3507 02:14:25,040 --> 02:14:27,000 VOLVE STRUCTURE ACTIVITY 3508 02:14:27,000 --> 02:14:28,400 RELATIONSHIP OPTIMIZATION TO 3509 02:14:28,400 --> 02:14:32,080 OPTIMIZE THE ACTIVITY AND THEN 3510 02:14:32,080 --> 02:14:33,920 FINALLY THE COMPOUNDS ARE TESTED 3511 02:14:33,920 --> 02:14:37,760 AND THROW THE SELECTED TO IN 3512 02:14:37,760 --> 02:14:40,320 VIVO VACCINE HIM OWN O 3513 02:14:40,320 --> 02:14:43,960 GENERATEDISSITY AND EFFICACY 3514 02:14:43,960 --> 02:14:46,320 STUDIES. 3515 02:14:46,320 --> 02:14:48,800 FOR THIS PROGRAM WE'RE PROPOSING 3516 02:14:48,800 --> 02:14:51,560 WE WOULD LIKE TO USE THE 3517 02:14:51,560 --> 02:14:53,160 CONTRACT AND RENEW FOR ANOTHER 5 3518 02:14:53,160 --> 02:14:54,800 YEARS AND WE I WOULD BE HAPPY TO 3519 02:14:54,800 --> 02:15:05,120 TAKE ANY QUESTIONS. 3520 02:15:10,640 --> 02:15:12,560 >> SO I HAVE A QUESTION ABOUT 3521 02:15:12,560 --> 02:15:13,720 THE CURRENT PROGRAMS. 3522 02:15:13,720 --> 02:15:16,160 ARE THEY-OF DO THEY MAINLY 3523 02:15:16,160 --> 02:15:17,960 INVOLVE THE LAST STEP THAT YOU 3524 02:15:17,960 --> 02:15:24,400 SAID, IN VIVO TESTING, LARGELY 3525 02:15:24,400 --> 02:15:26,280 IN MOUSE MODELS OR AS WOULD BE 3526 02:15:26,280 --> 02:15:28,080 APPROPRIATE, I GUESS FOR THE 3527 02:15:28,080 --> 02:15:28,400 PROGRAM. 3528 02:15:28,400 --> 02:15:31,640 >> YEAH, I THINK I KNOW WHAT 3529 02:15:31,640 --> 02:15:32,400 YOUR CONCERN IS. 3530 02:15:32,400 --> 02:15:34,880 THE DIFFERENCE BETWEEN THE 3531 02:15:34,880 --> 02:15:38,800 DIFFERENT SPECIES AND IN 3532 02:15:38,800 --> 02:15:40,960 ORDER--YES, THE FINAL EVALUATION 3533 02:15:40,960 --> 02:15:42,960 IS FREQUENTLY DONE IN THE MOUSE 3534 02:15:42,960 --> 02:15:44,320 MODEL SIMPLY BECAUSE IT'S--WE 3535 02:15:44,320 --> 02:15:48,440 HAVE THE TOOLS, WE HAVE THE READ 3536 02:15:48,440 --> 02:15:53,080 OUTS, IN ORDER TO AVOID ANY KIND 3537 02:15:53,080 --> 02:15:57,280 OF IDENTIFICATION OF SPECIES 3538 02:15:57,280 --> 02:15:58,120 SPECIFIC ADJUVANTS, THE PROGRAM 3539 02:15:58,120 --> 02:15:58,960 STARTS WITH THE REQUIREMENT TO 3540 02:15:58,960 --> 02:16:04,440 DO THE SCREEN IN BOTH HUMAN 3541 02:16:04,440 --> 02:16:07,800 CELLS AND CELL TYPE FROM THE 3542 02:16:07,800 --> 02:16:09,760 SPECIES THAT THE ADJUVANT WILL 3543 02:16:09,760 --> 02:16:11,000 BE TESTED IN INVITRO. 3544 02:16:11,000 --> 02:16:14,160 AND THIS WAY WE'RE SCREENING OUT 3545 02:16:14,160 --> 02:16:15,800 OWL THE COMPOUNDS THAT ARE IN 3546 02:16:15,800 --> 02:16:21,840 THIS CASE, JUST MOUSE SPECIFIC. 3547 02:16:21,840 --> 02:16:23,040 >> IT BECOMES A CHALLENGE AND OF 3548 02:16:23,040 --> 02:16:24,360 COURSE WHEN WE'RE TALKING ABOUT 3549 02:16:24,360 --> 02:16:27,320 IMMUNE RESPONSE TO HAVE JUST 1 3550 02:16:27,320 --> 02:16:31,000 TYPE OF CELL, I MEAN THAT'S 3551 02:16:31,000 --> 02:16:33,760 WHERE I GUESS, ARE THEY PROGRAMS 3552 02:16:33,760 --> 02:16:35,600 THAT ARE INCLUDING ORGANOIDS OR 3553 02:16:35,600 --> 02:16:39,400 OTHER FORMS OF STRUCTURES TO 3554 02:16:39,400 --> 02:16:39,880 COMPLEMENT THE STUDIES. 3555 02:16:39,880 --> 02:16:44,040 >> I DO,A GREE WITH YOU. 3556 02:16:44,040 --> 02:16:46,880 THE CHALLENGE IS WITH ORGANOID 3557 02:16:46,880 --> 02:16:48,960 CULTURES YOU CANNOT DO HIGH 3558 02:16:48,960 --> 02:16:50,360 THROUGH PUT SCREENING SO DO YOU 3559 02:16:50,360 --> 02:16:51,760 NEED SOME KIND OF SYSTEM THAT 3560 02:16:51,760 --> 02:16:56,000 ALLOWS YOU TO GO THROUGH 10S OF 3561 02:16:56,000 --> 02:16:57,920 HUNDREDS OF THOUSANDS OF 3562 02:16:57,920 --> 02:16:58,480 COMPOUNDS. 3563 02:16:58,480 --> 02:17:01,360 I SHOULD HAVE A POINT OUT THAT 3564 02:17:01,360 --> 02:17:04,320 OVER THE YEARS, THE PROGRAM HAS 3565 02:17:04,320 --> 02:17:09,200 MOVED FROM THE USE FROM THE 3566 02:17:09,200 --> 02:17:11,320 RELIANCE ON REPORTER CELLS WHICH 3567 02:17:11,320 --> 02:17:15,040 ARE, YOU KNOW AS YOU POINTED OUT 3568 02:17:15,040 --> 02:17:15,560 SINGLE CELL TYPE. 3569 02:17:15,560 --> 02:17:19,880 THEY CAN BE RATHER ARTIFICIAL 3570 02:17:19,880 --> 02:17:26,000 TOWARDS PRIMARY CELLS, PBMCs, 3571 02:17:26,000 --> 02:17:27,040 AND HAS BEEN--SOME OF THE 3572 02:17:27,040 --> 02:17:29,080 FAILURES, SOME OF THE COMPOUNDS 3573 02:17:29,080 --> 02:17:33,840 THAT DID NOT TRANSLATE 3574 02:17:33,840 --> 02:17:35,800 TO--COMPOUNDS THAT HAVE ADJUVANT 3575 02:17:35,800 --> 02:17:38,800 ACTIVITY IN VIVO WERE DUE TO THE 3576 02:17:38,800 --> 02:17:43,200 USE OF REPORTER CELLS THAT 3577 02:17:43,200 --> 02:17:44,000 IDENTIFY FALSE-POSITIVES, THAT 3578 02:17:44,000 --> 02:17:46,600 IS BEING ADDRESSED THROUGH THE 3579 02:17:46,600 --> 02:17:48,640 USE OF PBMCs. 3580 02:17:48,640 --> 02:17:50,080 IN THE--IN THE PROGRAM I 3581 02:17:50,080 --> 02:17:52,560 MENTIONED BEFORE, THE 3582 02:17:52,560 --> 02:17:53,880 ACC PROGRAM, THE ADJUSTICE 3583 02:17:53,880 --> 02:17:56,520 ACCESS HAVEN'T CHARACTERIZATION 3584 02:17:56,520 --> 02:17:58,120 PROGRAM, THAT PROGRAM DOES 3585 02:17:58,120 --> 02:18:02,240 INVOLVE THE USE OF ORGANOID 3586 02:18:02,240 --> 02:18:03,960 CULTURES TO CHARACTERIZING 3587 02:18:03,960 --> 02:18:06,400 RESPONSES INDUCED BY DIFFERENT 3588 02:18:06,400 --> 02:18:07,800 ADJUVANTS BUT IT'S MEANT TO BE A 3589 02:18:07,800 --> 02:18:11,280 VERY LOW THROUGH PUT APPROACH. 3590 02:18:11,280 --> 02:18:21,560 >> THANK YOU. 3591 02:18:22,200 --> 02:18:22,640 THANK YOU. 3592 02:18:22,640 --> 02:18:23,960 >> OKAY BEING IF THERE ARE NO 3593 02:18:23,960 --> 02:18:27,080 OTHER COMMENTS OR QUESTIONS WE 3594 02:18:27,080 --> 02:18:29,120 SHOULD MOVE ON. 3595 02:18:29,120 --> 02:18:31,240 LANYN YOU HAVE 2 INITIATIVES TO 3596 02:18:31,240 --> 02:18:33,160 DISCUSS. 3597 02:18:33,160 --> 02:18:41,960 >> YES, I DO AND LET ME SHARE MY 3598 02:18:41,960 --> 02:18:42,200 SCREEN. 3599 02:18:42,200 --> 02:18:44,440 NCAN YOU SEE THE RIGHT SCREEN. 3600 02:18:44,440 --> 02:18:45,240 >> YES, IT'S CORRECT. 3601 02:18:45,240 --> 02:18:46,600 THANK YOU. 3602 02:18:46,600 --> 02:18:51,440 >> SO TODAY, MY NAME IS 3603 02:18:51,440 --> 02:18:52,680 LANYN TALIAFERRO, AND I AM A 3604 02:18:52,680 --> 02:18:55,320 PROGRAM WOF WITH THE DAITs, 3605 02:18:55,320 --> 02:18:58,280 AND I WILL TALK ABOUT 2 STUDIES 3606 02:18:58,280 --> 02:18:59,160 FOR APPROVAL. 3607 02:18:59,160 --> 02:19:01,040 THE FIRST AND ENTITLED 3608 02:19:01,040 --> 02:19:02,280 DEVELOPMENT OF RADIATION 3609 02:19:02,280 --> 02:19:06,200 NUCLEOTIDES CLER MEDICAL 3610 02:19:06,200 --> 02:19:06,920 COUNTERMEASURES AND BIODOSIMETRY 3611 02:19:06,920 --> 02:19:09,760 DEVICES AND THIS IS MAKING USE 3612 02:19:09,760 --> 02:19:12,480 OF OUR AGENCY ANNOUNCEMENT BROAD 3613 02:19:12,480 --> 02:19:13,200 CONTRACT VEHICLE. 3614 02:19:13,200 --> 02:19:19,360 SO TO GIVE YOU A BIT OF 3615 02:19:19,360 --> 02:19:20,480 BACKGROUND, THE INITIATIVE WAS 3616 02:19:20,480 --> 02:19:22,160 DEVELOPED AND IT WAS FOR TRIAGE 3617 02:19:22,160 --> 02:19:27,120 AND TREATMENTS IN THE EVENT OF A 3618 02:19:27,120 --> 02:19:29,320 RADIATION PUBLIC EMERGENCY FOR 3619 02:19:29,320 --> 02:19:30,240 RADIATION. 3620 02:19:30,240 --> 02:19:32,880 NIAID WAS ASKED ABOUT THESE 3621 02:19:32,880 --> 02:19:35,440 PLANS AND ESTABLISHED CRMCP AND 3622 02:19:35,440 --> 02:19:37,360 OUR PRIORITIES INCLUDE TWEPPING 3623 02:19:37,360 --> 02:19:39,840 COUNTERMEASURES FOR AXIEWT AND 3624 02:19:39,840 --> 02:19:42,040 RADIATION INJURIES AND ALSO 3625 02:19:42,040 --> 02:19:43,680 DEVELOPMENT OF INCORPORATED 3626 02:19:43,680 --> 02:19:46,440 AGENTS AND FINALLY, DEVELOPING 3627 02:19:46,440 --> 02:19:47,720 TRIAGE TOOLS TO INSURE WE CAN 3628 02:19:47,720 --> 02:19:53,000 SORT A LARGE POPULATION OF 3629 02:19:53,000 --> 02:20:01,520 PEOPLE FROM THE [INDISCERNIBLE]. 3630 02:20:01,520 --> 02:20:03,640 SO THE RNCP EXPANDS BASIC 3631 02:20:03,640 --> 02:20:05,000 DEVELOPMENT TO RESEARCH AND I 3632 02:20:05,000 --> 02:20:07,080 WILL TELL YOU ABOUT WHAT WE DO 3633 02:20:07,080 --> 02:20:08,480 AND HOW WOE DO IT. 3634 02:20:08,480 --> 02:20:11,520 UNDER THE BASIC RESEARCH PREMISE 3635 02:20:11,520 --> 02:20:14,760 WE HAVE SOME NECKIMISMS OF 3636 02:20:14,760 --> 02:20:16,000 ACTION STUDIES, WE HAVE STUDIES 3637 02:20:16,000 --> 02:20:17,400 THAT ALSO FOCUS ON THE TARGETS, 3638 02:20:17,400 --> 02:20:19,520 THAT WE CAN USE TO MITIGATE SOME 3639 02:20:19,520 --> 02:20:21,720 OF THE RADIATION INJURIES, ALSO 3640 02:20:21,720 --> 02:20:24,840 INVITRO IN SMALL ANIMAL ANIMAL 3641 02:20:24,840 --> 02:20:26,160 EFFICACY IS ARE DONE. 3642 02:20:26,160 --> 02:20:27,200 UNDER THE PRECLINICAL 3643 02:20:27,200 --> 02:20:28,040 DEVELOPMENT THAT HELPS PUSH 3644 02:20:28,040 --> 02:20:31,920 THINGS ALONG THE PIPELINE, WE 3645 02:20:31,920 --> 02:20:33,560 HAVE LEAD OPTIMIZATION WHERE WE 3646 02:20:33,560 --> 02:20:38,560 ARE FIGURING OUT DOSING AND 3647 02:20:38,560 --> 02:20:40,160 ADMINISTRATION OF LEADING AND WE 3648 02:20:40,160 --> 02:20:43,080 ALSO USE LARGE ANIMAL EFFICACY 3649 02:20:43,080 --> 02:20:44,840 MODELS, USING CANINES AND PIG 3650 02:20:44,840 --> 02:20:45,920 MODELS, THESE STUDIES ARE DONE 3651 02:20:45,920 --> 02:20:49,920 UNDER THIS AREA, WE CAN ALSO 3652 02:20:49,920 --> 02:20:54,120 FORMULATE DRUGS AND FORMULATION 3653 02:20:54,120 --> 02:20:59,880 FOR OUR VRCOs AND 3654 02:20:59,880 --> 02:21:02,120 PK/PD STUDIES AND TOX. 3655 02:21:02,120 --> 02:21:05,840 WE HAVE MOVED INTO SOMEWHAT OF A 3656 02:21:05,840 --> 02:21:08,800 PHASE 1, PHASE 3 CLINICAL TRIAL, 3657 02:21:08,800 --> 02:21:10,680 WE'RE STILL KIND OF IN INFANCY 3658 02:21:10,680 --> 02:21:12,240 THERE BUT HOPING THAT WILL BE 3659 02:21:12,240 --> 02:21:13,560 MORE FREQUENT AND EVENTUALLY, 3660 02:21:13,560 --> 02:21:15,880 YOU KNOW WE HELP WITH THE 3661 02:21:15,880 --> 02:21:17,160 LICENSURE AND PROCUREMENT OF 3662 02:21:17,160 --> 02:21:17,520 THESE DRUGS. 3663 02:21:17,520 --> 02:21:19,920 ON SO HOW DO WE DO THIS? 3664 02:21:19,920 --> 02:21:20,720 UNDER THE BASIC RESEARCH 3665 02:21:20,720 --> 02:21:21,240 COMOPPOSITE BEHAVIORIAL 3666 02:21:21,240 --> 02:21:21,920 PHENOTYPE AND THEN THE UMBRELLA 3667 02:21:21,920 --> 02:21:23,360 WE HAVE GRANTS AND COOPERATIVE 3668 02:21:23,360 --> 02:21:25,080 AGREEMENTS AS WELL AS 3669 02:21:25,080 --> 02:21:26,240 INTERAGENCY GREAPTS THAT HELP US 3670 02:21:26,240 --> 02:21:28,000 MOVE THAT PATH ALONG AND IN 3671 02:21:28,000 --> 02:21:30,520 PARTICULAR, THIS PATH HERE, THAT 3672 02:21:30,520 --> 02:21:32,160 KIND OF VALID BETWEEN THE BASIC 3673 02:21:32,160 --> 02:21:35,160 AND ADVANCE DEVELOPMENT IS 3674 02:21:35,160 --> 02:21:36,880 REALLY SPEARHEADED BOO I THE 3675 02:21:36,880 --> 02:21:37,600 BROAD AGENCY ANNOUNCEMENT 3676 02:21:37,600 --> 02:21:38,560 CONTRACT IS WHAT WE'RE SHOWING 3677 02:21:38,560 --> 02:21:43,440 HERE AND THIS IS A FOA WE ISSUE 3678 02:21:43,440 --> 02:21:45,320 ONCE EVERY 2 OR 3 YEARS AND 3679 02:21:45,320 --> 02:21:48,480 THEY'RE AWARDS AND OFFERS ARE 3680 02:21:48,480 --> 02:21:49,600 EXPECTED TO [INDISCERNIBLE] 3681 02:21:49,600 --> 02:21:51,480 WORK, SINCE THERE IS REALLY A 3682 02:21:51,480 --> 02:21:52,280 BROAD AGENCY ANNOUNCEMENT TO 3683 02:21:52,280 --> 02:21:55,120 KIND OF CAPTURE A LOT OF THE NEW 3684 02:21:55,120 --> 02:21:56,480 MEDICAL COUNTERMEASURES THAT MAY 3685 02:21:56,480 --> 02:21:58,880 BE COMING DOWN THE PIPELINE OR 3686 02:21:58,880 --> 02:22:01,440 MAYBE EVEN SOME OF THE 3687 02:22:01,440 --> 02:22:02,360 BIOINDUSTRY TOOLS. 3688 02:22:02,360 --> 02:22:03,640 SO THE CORE THAT'S IN CHARGE 3689 02:22:03,640 --> 02:22:05,560 WILL WORK WITH THE CONTRACTOR AT 3690 02:22:05,560 --> 02:22:06,840 HAND TO DEVELOP THIS CRITICAL 3691 02:22:06,840 --> 02:22:08,120 PATH TO LICENSURE TO MAKE SURE 3692 02:22:08,120 --> 02:22:10,680 WE CAN PUSH IT DOWN THE ADVANCED 3693 02:22:10,680 --> 02:22:11,200 DEVELOPMENT PIPELINE. 3694 02:22:11,200 --> 02:22:17,000 AND WHEN THAT HAPPENS WE WORK 3695 02:22:17,000 --> 02:22:20,320 WITH A PRODUCT DEVELOPMENT IQ 3696 02:22:20,320 --> 02:22:22,280 CONTRACT OR WITH BARTA AS WELL 3697 02:22:22,280 --> 02:22:27,000 AS FDA TO HELP PUSH THAT ALONG. 3698 02:22:27,000 --> 02:22:28,320 SO GIVEN THIS MOVEMENT OR 3699 02:22:28,320 --> 02:22:31,600 PIPELINE, WE HAVE TO HAVE 3700 02:22:31,600 --> 02:22:34,920 SUCCESS AND HAVE PRODUCTS 3701 02:22:34,920 --> 02:22:37,160 APPROVED FOR THE SPACE, 4 OF 3702 02:22:37,160 --> 02:22:39,560 THOSE PRODUCTS HAVE BEEN 3703 02:22:39,560 --> 02:22:41,280 APPROVED UNDER THE U.S. FDA 3704 02:22:41,280 --> 02:22:42,960 ANIMAL RULE AND 3 OF THEM HAVE 3705 02:22:42,960 --> 02:22:45,800 BEEN FUNDED UNDER OUR UMBRELLA 3706 02:22:45,800 --> 02:22:48,240 SO IN 2017, [INDISCERNIBLE] WAS 3707 02:22:48,240 --> 02:22:50,240 FUNDED BY NAID AND WE PUSHED IT 3708 02:22:50,240 --> 02:22:51,280 THROUGH LICENSURE AND BARTA WAS 3709 02:22:51,280 --> 02:22:55,120 ABLE TO ACQUIRE IT AT THE END. 3710 02:22:55,120 --> 02:22:57,520 IN 2018, LUKINE WAS ACQUIRED 3711 02:22:57,520 --> 02:23:00,680 BY--SORRY WAS PUSHED DOWN THE 3712 02:23:00,680 --> 02:23:04,000 PIPELINE BY BARTA, AND IT HAS 3713 02:23:04,000 --> 02:23:05,840 BEEN ACQUIRED SINCE THEN. 3714 02:23:05,840 --> 02:23:08,040 BOTH OF THESE STIMULATE BONE 3715 02:23:08,040 --> 02:23:10,280 MARROW TO INCREASE NUTRIFILLS SO 3716 02:23:10,280 --> 02:23:12,440 IT CAPTURES THAT PART OF THE 3717 02:23:12,440 --> 02:23:13,000 [INDISCERNIBLE] ERA HOWEVER 3718 02:23:13,000 --> 02:23:14,400 THERE WAS NOT ANOTHER COMPONENT 3719 02:23:14,400 --> 02:23:17,560 THAT WAS NOT TAKEN CARE OF AND 3720 02:23:17,560 --> 02:23:21,240 THAT ALLEVIATED BY THE PUSH WITH 3721 02:23:21,240 --> 02:23:22,920 ANTI[INDISCERNIBLE] THE PRODUCT 3722 02:23:22,920 --> 02:23:24,520 DEVELOPMENT PIPELINE. 3723 02:23:24,520 --> 02:23:27,880 AND THIS WAS REALLY NIAID'S PUSH 3724 02:23:27,880 --> 02:23:29,560 AND BARTA PARTNERED UP UP WITH 3725 02:23:29,560 --> 02:23:32,440 US AT THE END TO HELP US PUSH IT 3726 02:23:32,440 --> 02:23:35,920 ALONG TO THE LICENSURE. 3727 02:23:35,920 --> 02:23:37,040 AND THIS DRUG INCREASES 3728 02:23:37,040 --> 02:23:41,240 PARTICIPATE IN A TRIALLETS 3729 02:23:41,240 --> 02:23:41,760 STIMULATING CARIO SIGHTS. 3730 02:23:41,760 --> 02:23:43,440 SO ULTIMATELY WE HAVE HAD 4 3731 02:23:43,440 --> 02:23:49,000 SUCCESSFUL DRUGS COME DOWN THE 3732 02:23:49,000 --> 02:23:51,280 PIPELINES FOR [INDISCERNIBLE], 3733 02:23:51,280 --> 02:23:52,600 HOWEVER, RADIATION HAS MANY 3734 02:23:52,600 --> 02:23:53,880 RADIATION ORGAN INJURIES WE HAVE 3735 02:23:53,880 --> 02:23:55,440 TO WORRY ABOUT, GI, LUNG AND 3736 02:23:55,440 --> 02:23:57,840 SKIN BEING THE TOP 3 THAT WE'RE 3737 02:23:57,840 --> 02:24:01,200 FOCUSING ON NEXT. 3738 02:24:01,200 --> 02:24:03,920 SO A LITTLE BIT ABOUT THE 3739 02:24:03,920 --> 02:24:04,760 [INDISCERNIBLE] AND HOW IT 3740 02:24:04,760 --> 02:24:08,720 HELPED US ALONG THE WAY, SINCE 3741 02:24:08,720 --> 02:24:10,280 FISCAL YEAR 2010 BONDS WERE PART 3742 02:24:10,280 --> 02:24:12,280 OF OUR PROGRAM TO GET THINGS 3743 02:24:12,280 --> 02:24:14,160 MOVING ALONG AND TO THE ADVANCE 3744 02:24:14,160 --> 02:24:16,320 DEVELOPMENT REALM AND YOU CAN 3745 02:24:16,320 --> 02:24:18,720 SEE WE HAD 9 FACILITATIONS SO 3746 02:24:18,720 --> 02:24:20,400 FAR, WHERE 24 CONTRACT VS BEEN 3747 02:24:20,400 --> 02:24:22,760 AWARDED AND THESE SPAN A VARIETY 3748 02:24:22,760 --> 02:24:24,880 OF RADIATION INDUCED DISEASES, 3749 02:24:24,880 --> 02:24:26,480 BEGINNING FROM GHAST ROW 3750 02:24:26,480 --> 02:24:35,280 INTESTINAL INJURIES TO LUNG, TO 3751 02:24:35,280 --> 02:24:36,840 BIODISSYMMETRY AND CUTEAINIOUS 3752 02:24:36,840 --> 02:24:37,240 RADIATION INJURY. 3753 02:24:37,240 --> 02:24:38,560 THE ACHIEVEMENTS ARE PRETTY 3754 02:24:38,560 --> 02:24:38,760 GOOD. 3755 02:24:38,760 --> 02:24:41,920 WE'VE HAD 3 FDA INVESTIGATIONAL 3756 02:24:41,920 --> 02:24:44,160 NEW DRUGS UNDER THESE CONTRACTS, 3757 02:24:44,160 --> 02:24:45,080 SO, YOU COMPANIES THAT HAVE 3758 02:24:45,080 --> 02:24:46,240 BYE-BYE WORKING WITH US HAVE 3759 02:24:46,240 --> 02:24:47,960 BEEN ABLE TO OBLIGATIONS STAIN 3760 02:24:47,960 --> 02:24:50,840 THOSE, WE'VE HAD 12 FDA PRIOR 3761 02:24:50,840 --> 02:24:52,600 IND MEETING THIS FAR AND 3762 02:24:52,600 --> 02:24:54,240 DEFINITELY PUSHING THE UMBRELLA 3763 02:24:54,240 --> 02:24:56,000 AND PUSHING THAT AGENDA TO GET 3764 02:24:56,000 --> 02:24:58,240 THEM TO FDA AND GET THESE 3765 02:24:58,240 --> 02:24:59,080 PRODUCTS TRANSITIONED AND LOOK 3766 02:24:59,080 --> 02:25:00,720 THOSE LINES WE'VE ALSO HAD 3767 02:25:00,720 --> 02:25:04,640 PRODUCTS TRANSITION TO BARREDDA. 3768 02:25:04,640 --> 02:25:05,400 --BARDA. 3769 02:25:05,400 --> 02:25:09,680 THE FISCAL YEAR 23, AWARDS ARE 3770 02:25:09,680 --> 02:25:10,880 CURRENTLY UNDER, I GUESS 3771 02:25:10,880 --> 02:25:11,560 NEGOTIATIONS, SO THERE'S NOT 3772 02:25:11,560 --> 02:25:14,920 MUCH WE CAN SAY ABOUT THOSE BUT 3773 02:25:14,920 --> 02:25:20,120 THEY ARE BEING NEGOTIATED AS WE 3774 02:25:20,120 --> 02:25:20,600 SPEAK. 3775 02:25:20,600 --> 02:25:21,760 PROPOSED BOND INITIATIVE, WE 3776 02:25:21,760 --> 02:25:23,440 WANT TO BECAUSE IT PROET MODEL 3777 02:25:23,440 --> 02:25:24,600 CITIZENS ACCELERATION OF 3778 02:25:24,600 --> 02:25:28,920 PRECLINICAL AND MCMs AND 3779 02:25:28,920 --> 02:25:30,440 BIODOS IMPEDIMENTSETRY ASSAY 3780 02:25:30,440 --> 02:25:31,080 DEVELOPMENT FOR RADIATION 3781 02:25:31,080 --> 02:25:32,320 INJURY, WE WANT TO HAVE A 3782 02:25:32,320 --> 02:25:34,720 MECHANISM THAT WILL TAKE THESE 3783 02:25:34,720 --> 02:25:36,240 YOU KNOW MEDICAL COUNTER 3784 02:25:36,240 --> 02:25:37,160 MEASURES AND BIOCHEMISTRY 3785 02:25:37,160 --> 02:25:40,080 DEVICES ALL THE WAY THROUGH THE 3786 02:25:40,080 --> 02:25:41,120 ADVANCE DEVELOPMENT AND THIS 3787 02:25:41,120 --> 02:25:43,080 REALLY KIND OF SPANS THAT IN 3788 02:25:43,080 --> 02:25:43,440 BETWEEN. 3789 02:25:43,440 --> 02:25:46,600 SO WE HOPE TO SUPPORT SOME LARGE 3790 02:25:46,600 --> 02:25:47,520 ANIMAL EFFICACY STUDIES, AND 3791 02:25:47,520 --> 02:25:51,200 ALSO SUPPORT ANY IND AND IUO 3792 02:25:51,200 --> 02:25:54,120 ENABLING STUDIES FOR ANY FDA 3793 02:25:54,120 --> 02:25:55,720 LICENSURE APPROVAL OF THESE 3794 02:25:55,720 --> 02:25:56,360 DEVICES. 3795 02:25:56,360 --> 02:26:00,600 WE EXPECT ABOUT 8-10 PROPOSALS, 3796 02:26:00,600 --> 02:26:02,080 FOR THIS PARTICULAR BOND AND WE 3797 02:26:02,080 --> 02:26:05,640 HOPE TO AWARD 2-3 YEAR AWARDS 3798 02:26:05,640 --> 02:26:15,880 FOR THIS BOND. 3799 02:26:18,800 --> 02:26:19,400 ANY QUESTIONS? 3800 02:26:19,400 --> 02:26:20,280 IF THERE ARE NONE I WILL 3801 02:26:20,280 --> 02:26:24,640 CONTINUE ON TO THE NEXT 3802 02:26:24,640 --> 02:26:24,960 INITIATIVE. 3803 02:26:24,960 --> 02:26:29,600 >> JUST REAL QUICK ONCE YOU GET 3804 02:26:29,600 --> 02:26:36,600 THESE PRODUCTS FOR THESE AND ARE 3805 02:26:36,600 --> 02:26:38,080 THOSE--THE NEXT STEP ANTICIPATED 3806 02:26:38,080 --> 02:26:48,600 TO WHERE, PRODUCTION OF THOSE 3807 02:26:55,960 --> 02:26:56,840 DEVICES OR--HOSPITALS AND 3808 02:26:56,840 --> 02:26:58,480 DOCTORS ALL AROUND THE WORLD, SO 3809 02:26:58,480 --> 02:27:03,360 IN THAT CASE, WE HAVE WHAT THEY 3810 02:27:03,360 --> 02:27:04,040 CALL [INDISCERNIBLE] INVENTOR 3811 02:27:04,040 --> 02:27:06,600 EXPE THAT HAS BEEN ACQUIRED BY 3812 02:27:06,600 --> 02:27:08,200 THE BARDA, THEY ARE THE 1S THAT 3813 02:27:08,200 --> 02:27:10,840 DEAL WITH THAT SIDE OF THE HOUSE 3814 02:27:10,840 --> 02:27:12,240 AND WE'RE JUST REQUIRING THEM. 3815 02:27:12,240 --> 02:27:13,440 AS FAR AS SOME OF THE NEWER 3816 02:27:13,440 --> 02:27:15,040 DRUGS THAT MAY NOT BE OUT THERE, 3817 02:27:15,040 --> 02:27:16,920 THEN THAT'S A LITTLE BIT MORE 3818 02:27:16,920 --> 02:27:20,440 DIFFICULT, BUT WE'RE--WE'RE 3819 02:27:20,440 --> 02:27:21,240 HOPING TO [INDISCERNIBLE] FACT 3820 02:27:21,240 --> 02:27:23,920 CALL THEM IN SOME WAY SHAPE OR 3821 02:27:23,920 --> 02:27:24,920 FORM AND BARDA USUALLY WORKS 3822 02:27:24,920 --> 02:27:27,880 WITH THE COMPANIES TO TRY TO AT 3823 02:27:27,880 --> 02:27:30,360 LEAST PUSH FORWARD A PRIMARY 3824 02:27:30,360 --> 02:27:31,080 IMPLICATIONS WHERE THEY SUPPORT 3825 02:27:31,080 --> 02:27:33,600 THE USE OF THESE DRUGS NOT JUST 3826 02:27:33,600 --> 02:27:35,120 WITHIN THE RADIATION SPACE THAT 3827 02:27:35,120 --> 02:27:38,520 WAS IN THE CLINICAL. 3828 02:27:38,520 --> 02:27:41,640 >> RIGHT. 3829 02:27:41,640 --> 02:27:44,480 >> THANK YOU. 3830 02:27:44,480 --> 02:27:47,560 >> OF COURSE THE BIODOSEMITRY 3831 02:27:47,560 --> 02:27:49,520 TOOLS ARE MORE SPECIFIC TO THE 3832 02:27:49,520 --> 02:27:51,680 OUR AREA BUT SOME OF OF THE 3833 02:27:51,680 --> 02:27:52,760 PEOPLE DEVELOPING THE TOOL 3834 02:27:52,760 --> 02:27:55,520 TRYING NOT TO DEVELOPMENT JUST 3835 02:27:55,520 --> 02:27:56,480 FOR OUR INDICATION BUT THINGS 3836 02:27:56,480 --> 02:27:58,200 THEY CAN USE FOR CLINICAL 3837 02:27:58,200 --> 02:28:03,400 INDICATION AS WELL. 3838 02:28:03,400 --> 02:28:10,840 ANY OTHER QUESTIONS? 3839 02:28:10,840 --> 02:28:11,880 OKAY, WELL MOVING ON TO THE NEXT 3840 02:28:11,880 --> 02:28:16,840 1 THAT WE'RE HOPING TO GET 3841 02:28:16,840 --> 02:28:17,240 APPROVED. 3842 02:28:17,240 --> 02:28:19,280 OUR NEXT INITIATIVE IS ENTITLED 3843 02:28:19,280 --> 02:28:22,480 SEX DIFFERENCES IN RADIATION IN 3844 02:28:22,480 --> 02:28:24,160 NUCLEAR RESEARCH MODELS WHICH 3845 02:28:24,160 --> 02:28:26,520 LOOKS AT UNDERLYING PATHWAYS, 3846 02:28:26,520 --> 02:28:29,080 BIOMARKERS OF INJURY AND MEDICAL 3847 02:28:29,080 --> 02:28:29,880 COUNTERMEASURES RESPONSES THAT 3848 02:28:29,880 --> 02:28:34,440 ARE AFFECTED BY DIFFERENCES IN 3849 02:28:34,440 --> 02:28:35,000 SEX. 3850 02:28:35,000 --> 02:28:36,160 SO WHY DOES THIS MATTER? 3851 02:28:36,160 --> 02:28:37,240 WELL WE KNOW THAT SEX AND AGE 3852 02:28:37,240 --> 02:28:38,760 CAN AFFAIRS TEAM LEADERRER 3853 02:28:38,760 --> 02:28:40,360 RESPONSES TO RADIATION DRUG AND 3854 02:28:40,360 --> 02:28:42,800 EFFICACY AND IN GENERAL 8-10 3855 02:28:42,800 --> 02:28:44,440 PRESCRIPTION DRUGS WERE DRAWN TO 3856 02:28:44,440 --> 02:28:46,080 THE MARKET FOR DANGEROUS SIDE 3857 02:28:46,080 --> 02:28:47,040 EFFECTS IN WOMEN COMPARED TO MEN 3858 02:28:47,040 --> 02:28:50,760 AND THIS WAS IN A 3859 02:28:50,760 --> 02:28:52,400 [INDISCERNIBLE] AUDIT BACK IN 3860 02:28:52,400 --> 02:28:52,960 97. 3861 02:28:52,960 --> 02:28:54,880 THERE'S A HIGHER INCIDENCE OF 3862 02:28:54,880 --> 02:28:58,240 ADVERSE EVENTS IN WOMEN THAT 3863 02:28:58,240 --> 02:29:00,080 INCLUDES ISSUES SUCH AS HIGHER 3864 02:29:00,080 --> 02:29:01,480 BLOOD CONCENTRATIONS OF DRUGS, 3865 02:29:01,480 --> 02:29:04,320 LONGER TIME FOR CIRCULATION, ON 3866 02:29:04,320 --> 02:29:06,280 THE HISTORICALLY EXCLUSION OF 3867 02:29:06,280 --> 02:29:07,800 FEMALE ANIMALS IN PRECLINICAL 3868 02:29:07,800 --> 02:29:09,240 ANIMAL MODELS, LED TO SOME OF 3869 02:29:09,240 --> 02:29:11,560 THESE PROBLEMS AND WE CONTINUED 3870 02:29:11,560 --> 02:29:15,280 TO SEE SOME OF THOSE 3871 02:29:15,280 --> 02:29:15,760 RAMIFICATIONS. 3872 02:29:15,760 --> 02:29:17,800 SO WHY DO WE NEED THIS 3873 02:29:17,800 --> 02:29:18,240 INITIATIVE. 3874 02:29:18,240 --> 02:29:20,120 WELL, IN OUR CASE RADIATION 3875 02:29:20,120 --> 02:29:21,400 INDUCED SEX DRVESS HAPPEN BUT 3876 02:29:21,400 --> 02:29:24,040 WE'RE NOT SURE WHY, AND WE'RE 3877 02:29:24,040 --> 02:29:27,840 TRYING TO FIGURE OUT WHY THIS IS 3878 02:29:27,840 --> 02:29:28,800 HAPPENING AND UNFORTUNATELY 3879 02:29:28,800 --> 02:29:30,400 HISTORICALLY A LOT OF THE WORK 3880 02:29:30,400 --> 02:29:31,920 HAS BEEN DONE AND HAS BEEN DONE 3881 02:29:31,920 --> 02:29:36,800 IN MALES SO WE'RE JUST BEGINNING 3882 02:29:36,800 --> 02:29:39,680 TO REALLY PUSH THE GETTING MORE 3883 02:29:39,680 --> 02:29:40,480 FEMALES--MORE FEMALE ANIMALS 3884 02:29:40,480 --> 02:29:42,240 INTO THE SPACE AND 3885 02:29:42,240 --> 02:29:44,080 UNFORTUNATELY, THERE'S JUST NOT 3886 02:29:44,080 --> 02:29:46,360 ENOUGH NUMBERS FOR US TO REALLY 3887 02:29:46,360 --> 02:29:47,800 SAY, YOU KNOW THESE TRENDS 3888 02:29:47,800 --> 02:29:49,640 REALLY HAVE A STATISTICAL 3889 02:29:49,640 --> 02:29:50,840 SIGNIFICANCE SO WE'RE TRYING TO 3890 02:29:50,840 --> 02:29:55,600 REALLY HELP PUSH THAT NOTE 3891 02:29:55,600 --> 02:29:55,800 ALONG. 3892 02:29:55,800 --> 02:29:58,800 UNTIL RECENTLY WE ONLY HAD A 3893 02:29:58,800 --> 02:30:02,920 VERY SMALL NUMBER OF FEMALE 3894 02:30:02,920 --> 02:30:03,640 NONHUMAN PRIMATES IS AVAILABLE 3895 02:30:03,640 --> 02:30:04,960 WHICH IS A VARIETY OF REASONS 3896 02:30:04,960 --> 02:30:08,400 WHY THAT HAPPENS NOT ONLY WAS IT 3897 02:30:08,400 --> 02:30:09,840 A MALE DOMAIN NATIVE AMERICANS 3898 02:30:09,840 --> 02:30:10,240 NATIVE AMERICANS 3899 02:30:10,240 --> 02:30:12,320 IN THE NORTHERNED RESEARCH 3900 02:30:12,320 --> 02:30:14,040 COMPONENT BUT ALSO SOME OF THESE 3901 02:30:14,040 --> 02:30:15,320 THINGS ARE LIKE THAT BECAUSE OF 3902 02:30:15,320 --> 02:30:18,800 BREEDING THAT SORT OF THINGS, SO 3903 02:30:18,800 --> 02:30:22,240 CHALLENGES IN THE EFFECTS OF 3904 02:30:22,240 --> 02:30:23,640 NONHUMAN PRIMATES, SO WE NEED TO 3905 02:30:23,640 --> 02:30:25,200 MAKE USE OF THESE ANIMAL MODELS 3906 02:30:25,200 --> 02:30:26,480 AND IF WE DON'T HAVE THEM AND 3907 02:30:26,480 --> 02:30:29,920 THE DON'T HAVE THE RIGHT, YOU 3908 02:30:29,920 --> 02:30:31,880 KNOW CORRELATION BETWEEN MALES 3909 02:30:31,880 --> 02:30:33,200 AND FEMALES THEN WE CAN'T USE 3910 02:30:33,200 --> 02:30:34,680 THEM FOR WHAT WE WANT AND/OR 3911 02:30:34,680 --> 02:30:37,240 WHAT WE NEED. 3912 02:30:37,240 --> 02:30:38,960 AND YOU KNOW WE'VE BEEN LOOKING 3913 02:30:38,960 --> 02:30:40,600 AT THESE SEX DIFFERENCES, THERE 3914 02:30:40,600 --> 02:30:43,720 HAS BEEN A LOT OF RESEARCH DONE 3915 02:30:43,720 --> 02:30:45,120 AND LOTS OF NEW FINDINGS THAT 3916 02:30:45,120 --> 02:30:46,880 HAVE COME TO BEAR. 3917 02:30:46,880 --> 02:30:48,800 IN 2021, THE RADIATION RESEARCH 3918 02:30:48,800 --> 02:30:51,080 SOCIETY MEETING WHICH IS A VERY 3919 02:30:51,080 --> 02:30:53,520 IMPORTANT MEETING FOR OUR SPACE 3920 02:30:53,520 --> 02:30:57,000 HAD A SYMPOSIUM JUST ABOUT THE 3921 02:30:57,000 --> 02:30:58,080 EFFECT ABOUT RADIATION AND 3922 02:30:58,080 --> 02:30:59,240 BIOLOGY AND MEDICINE CAN THERE 3923 02:30:59,240 --> 02:31:01,440 WERE OVER 27 THAT WERE PRESENTED 3924 02:31:01,440 --> 02:31:03,200 AT THIS MEETING. 3925 02:31:03,200 --> 02:31:05,720 FOLLOWING THAT WE DECIDED TO DO 3926 02:31:05,720 --> 02:31:08,920 AND HOST A TRANS-AGENCY WORKSHOP 3927 02:31:08,920 --> 02:31:11,280 WHERE NIAID LED THE WORKSHOP 3928 02:31:11,280 --> 02:31:15,440 WITH PARTNERS IN THE U.S. GENE. 3929 02:31:15,440 --> 02:31:16,720 WE ALSO PUT OUT REQUEST FOR 3930 02:31:16,720 --> 02:31:18,960 RESEARCH AND WE'VE HAD MULTIPLE 3931 02:31:18,960 --> 02:31:21,120 RESPONSES TO THIS AREA. 3932 02:31:21,120 --> 02:31:26,160 SO WHAT IS THE GOAL OF THIS 3933 02:31:26,160 --> 02:31:27,080 INITIATIVE? 3934 02:31:27,080 --> 02:31:28,800 WE WANT TO EXPLORE THE SEX 3935 02:31:28,800 --> 02:31:30,240 RELATED DIFFERENCES IN RADIATION 3936 02:31:30,240 --> 02:31:31,400 RESPONSES BUT WHY? 3937 02:31:31,400 --> 02:31:33,600 WE WANT TO IMPROVE THOSE ACROSS 3938 02:31:33,600 --> 02:31:35,000 THE STUDY PORTFOLIO, WE WANT TO 3939 02:31:35,000 --> 02:31:36,480 MAKE SURE WE HAVE MEDICAL 3940 02:31:36,480 --> 02:31:37,680 MEASURE DEVELOPMENT. 3941 02:31:37,680 --> 02:31:39,840 WE HAVE PRECLINICAL AN MODELS 3942 02:31:39,840 --> 02:31:41,440 AND THEY MAKE SENSE TO HELP US 3943 02:31:41,440 --> 02:31:44,280 UNDERSTAND WHAT THOSE LITTLE 3944 02:31:44,280 --> 02:31:47,640 DETAILS THAT WE'VE BEEN MISSING 3945 02:31:47,640 --> 02:31:47,880 SHOW. 3946 02:31:47,880 --> 02:31:48,920 WE UNDERSTAND--WANT TO 3947 02:31:48,920 --> 02:31:50,360 UNDERSTAND THESE UNDERLYING 3948 02:31:50,360 --> 02:31:51,320 CAUSES AND ULTIMATELY INCREASE 3949 02:31:51,320 --> 02:31:52,720 SAFETY AND EFFICACY OF OUR 3950 02:31:52,720 --> 02:31:53,880 MEDICAL COUNTERMEASURES THAT MAY 3951 02:31:53,880 --> 02:31:55,120 BE GOIVEN PEOPLE WHO DOT 3952 02:31:55,120 --> 02:31:56,120 NONAPOPTOTIC HAVE ANY DAMAGE IN 3953 02:31:56,120 --> 02:31:58,960 A CASE OF A MASS CASUALTY EVENT. 3954 02:31:58,960 --> 02:32:01,560 WE WANT TO IDENTIFY WHAT THESE 3955 02:32:01,560 --> 02:32:03,440 SEX DIFFERENCES ARE, EMERGING 3956 02:32:03,440 --> 02:32:04,920 DECKNOLOGYS AND WORKING ON THE 3957 02:32:04,920 --> 02:32:07,920 CHIP, SO, THESE ARE ALL THE KIND 3958 02:32:07,920 --> 02:32:10,880 OF IDEAS THAT WE HAVEON BOARD 3959 02:32:10,880 --> 02:32:13,280 WITH THESE SEX DIFFERENCES AND 3960 02:32:13,280 --> 02:32:13,920 THE SEX DIFFERENCE INITIATIVE 3961 02:32:13,920 --> 02:32:15,680 AND WE WANT TO ADVANCE 3962 02:32:15,680 --> 02:32:17,520 BIOMARKERS THAT ARE ROBUST AND 3963 02:32:17,520 --> 02:32:18,760 SEX DEPENDENT SO WE CAN DETECT 3964 02:32:18,760 --> 02:32:20,960 WHETHER OR NOT SOMEBODY HAS BEEN 3965 02:32:20,960 --> 02:32:22,480 EXPOSED TO RADIATION REGARDLESS 3966 02:32:22,480 --> 02:32:23,400 WHO THEY ARE. 3967 02:32:23,400 --> 02:32:25,520 AND ULTIMATELY THE FDA ANIMAL 3968 02:32:25,520 --> 02:32:27,280 RULE LICENSURE XEBTS ADEQUATE 3969 02:32:27,280 --> 02:32:28,880 REPRESENTATION FROM BOTH SEXES 3970 02:32:28,880 --> 02:32:32,160 SO THEREFORE WE HAVE A NEED FOR 3971 02:32:32,160 --> 02:32:37,320 THIS DEMAND OF HAVING BOTH 3972 02:32:37,320 --> 02:32:37,800 SEXES. 3973 02:32:37,800 --> 02:32:39,080 SEX RELATED RADIATION ASSOCIATED 3974 02:32:39,080 --> 02:32:41,520 EEIVETS HAVE BEEN DOCUMENTED FOR 3975 02:32:41,520 --> 02:32:42,480 DECADES, YET MUCH REMAINS TO BE 3976 02:32:42,480 --> 02:32:43,920 LEARN BODY THE BASIS FOR THESE 3977 02:32:43,920 --> 02:32:47,160 EFFECTS AND IN FACT IN 2006, WE 3978 02:32:47,160 --> 02:32:48,800 HAD THE NATIONAL ACADEMIES 3979 02:32:48,800 --> 02:32:52,240 PREPORT ON OCCUPATIONAL AND 3980 02:32:52,240 --> 02:32:54,200 ACCIDENTAL RADIATION EXPOSURES, 3981 02:32:54,200 --> 02:32:56,280 THE SURVIVORS OF CHIRN OBSESSIVE 3982 02:32:56,280 --> 02:32:57,760 ILLEGALS AND OCCUPATIONAL 3983 02:32:57,760 --> 02:32:59,520 EXPOSURES AND AS YOU CAN SEE 3984 02:32:59,520 --> 02:33:00,880 THERE'S PLENTY OF DISEASE STATES 3985 02:33:00,880 --> 02:33:03,520 THAT WERE FOUND BETWEEN MALES 3986 02:33:03,520 --> 02:33:04,600 AND FEMALES, HOWEVER, WHEN 3987 02:33:04,600 --> 02:33:05,760 YOU'RE LOOKING AT THE 3988 02:33:05,760 --> 02:33:07,960 DIFFERENCES, THERE ARE MANY 3989 02:33:07,960 --> 02:33:10,400 DIFFERENCES HERE, PROMINENCE OF 3990 02:33:10,400 --> 02:33:11,920 DISEASES THAT ARE BASED ON SEX, 3991 02:33:11,920 --> 02:33:14,880 NOT NECESSARILY THE FACT THAT 3992 02:33:14,880 --> 02:33:15,600 THEY'RE HUMAN, THERE'S CANCER 3993 02:33:15,600 --> 02:33:18,760 RATES THAT ARE INCREASED BUT NO 3994 02:33:18,760 --> 02:33:20,760 CANCER IS--1 THAT IS PREDOMINANT 3995 02:33:20,760 --> 02:33:24,840 THAN THE OTHER, THERE'S VERY 3996 02:33:24,840 --> 02:33:25,600 DIFFERENCE ACUTE DIFFERENCES 3997 02:33:25,600 --> 02:33:30,720 BETWEEN THE 2 SEXES. 3998 02:33:30,720 --> 02:33:31,480 FURGT MORE WE'VE SEEN 3999 02:33:31,480 --> 02:33:32,680 DIFFERENCES IN OUR STUDIES WHERE 4000 02:33:32,680 --> 02:33:34,960 WE HAD THE RESPONSES FOR 4001 02:33:34,960 --> 02:33:36,160 READYIATION DONE ON NONHUMAN 4002 02:33:36,160 --> 02:33:37,920 PRIMATES SPECIAL AND WE SEE THAT 4003 02:33:37,920 --> 02:33:40,000 THE FEMALE MONKEYS ARE MORE 4004 02:33:40,000 --> 02:33:40,680 SENSITIVE TO RADIATION, AS YOU 4005 02:33:40,680 --> 02:33:43,560 CAN SEE ON THE LEFT HERE WE HAVE 4006 02:33:43,560 --> 02:33:45,400 2 FEMALE DOSE RESPONSE CURVES TO 4007 02:33:45,400 --> 02:33:47,920 HAVE BEEN DONE IN DIFFERENT 4008 02:33:47,920 --> 02:33:49,560 PLACES AND FEMALE DOSE RESPONSE 4009 02:33:49,560 --> 02:33:51,000 CURVE DONE IN DIFFERENT 4010 02:33:51,000 --> 02:33:53,600 LOCATIONS AND AS YOU CAN SEE 4011 02:33:53,600 --> 02:33:54,880 THEY REPEAT THEMSELVES PRETTY 4012 02:33:54,880 --> 02:33:56,040 EQUALLY AND IN DIFFERENT PLACES, 4013 02:33:56,040 --> 02:33:58,520 HOUR, WHEN YOU ARE LOOKING AT 4014 02:33:58,520 --> 02:33:59,680 THEM SEPARATELY, YOU CAN SEE 4015 02:33:59,680 --> 02:34:00,280 THOSE DIFFERENCES BETWEEN THE 4016 02:34:00,280 --> 02:34:01,880 MAIL AND THE FEMALE WHERE THE 4017 02:34:01,880 --> 02:34:05,040 FELL MALE IS MUCH MORE--FEMALE 4018 02:34:05,040 --> 02:34:07,040 IS MUCH MORE SENSITIVE THAN THE 4019 02:34:07,040 --> 02:34:07,440 MALE. 4020 02:34:07,440 --> 02:34:10,960 WE ALSO LOOKEDDA THE OTHER 4021 02:34:10,960 --> 02:34:12,280 MEDICAL COUNTERMEASURES THAT ARE 4022 02:34:12,280 --> 02:34:13,760 COMING TO OUR PORTFOLIO WHERE WE 4023 02:34:13,760 --> 02:34:15,520 SEE PRETTY GOOD EFFICACY, 4024 02:34:15,520 --> 02:34:18,040 PROFILES IN THE MALES AND THEN, 4025 02:34:18,040 --> 02:34:19,880 THE FEMALE IN THIS CASE, SHOWS 4026 02:34:19,880 --> 02:34:21,320 NO PROMISE. 4027 02:34:21,320 --> 02:34:24,320 AND SO, AGAIN, IT COULD BE A 4028 02:34:24,320 --> 02:34:25,040 MATTER OF DOSING--DOSE 4029 02:34:25,040 --> 02:34:26,840 OPTIMIZATION, IT COULD BE A 4030 02:34:26,840 --> 02:34:29,000 MATTER OF DETERMINING WHY THAT 4031 02:34:29,000 --> 02:34:31,480 IS, BUT WE--WE ARE AT THIS POINT 4032 02:34:31,480 --> 02:34:32,840 WE CAN'T REALLY DETERMINE WHAT 4033 02:34:32,840 --> 02:34:38,440 THOSE DIFFERENCES WILL BE. 4034 02:34:38,440 --> 02:34:41,800 SO BECAUSE OF ALL THESE FINDINGS 4035 02:34:41,800 --> 02:34:42,760 AND THESE DIFFERENT I GUESS 4036 02:34:42,760 --> 02:34:43,800 PROBLEMS THAT WE HAVE BEEN 4037 02:34:43,800 --> 02:34:45,040 SEEING, IS WE WANTED TO 4038 02:34:45,040 --> 02:34:46,160 UNDERSTAND THE STATE OF THE 4039 02:34:46,160 --> 02:34:48,320 SCIENCE IN OUR RADIATION SPACE 4040 02:34:48,320 --> 02:34:51,280 AND SO WE HOSTED THE NIAID 4041 02:34:51,280 --> 02:34:54,360 WORKSHOP IN 2022 AND THIS WAS 4042 02:34:54,360 --> 02:34:56,200 PARTNERED WITH THE NIH OFFICE OF 4043 02:34:56,200 --> 02:34:57,520 RESEARCH OF WOMEN'S HEALTH, IF, 4044 02:34:57,520 --> 02:35:00,000 DA OFFICE OF WOMEN'S HEALTH AND 4045 02:35:00,000 --> 02:35:01,560 BIOMEDICAL ADVANCE RESEARCH 4046 02:35:01,560 --> 02:35:02,880 AUTHORITY OR BARDA. 4047 02:35:02,880 --> 02:35:05,240 WE HAD OVER 24 PRESENTERS AND 4048 02:35:05,240 --> 02:35:07,440 OUR MEETDING GOALS WERE TO 4049 02:35:07,440 --> 02:35:09,120 EXAMINE SEX DIFFERENCES IN 4050 02:35:09,120 --> 02:35:10,440 PRECLIENAL PRODLES AND IDENTIFY 4051 02:35:10,440 --> 02:35:12,520 SEX DIFFERENCES AND BIOMARKERS 4052 02:35:12,520 --> 02:35:14,920 FOR AND TO ASSESS RADIATION 4053 02:35:14,920 --> 02:35:16,040 INJURIES AND EXPLORE CHALLENGES 4054 02:35:16,040 --> 02:35:17,520 IN MEDICAL RESEARCH LACKING 4055 02:35:17,520 --> 02:35:19,960 REPRESENTATION FROM BOTH SEXES 4056 02:35:19,960 --> 02:35:22,600 AND TO DISCUSS REGULATORY 4057 02:35:22,600 --> 02:35:24,360 POLICIES THAT INCLUDE WOMEN IN 4058 02:35:24,360 --> 02:35:24,720 RESEARCH. 4059 02:35:24,720 --> 02:35:27,800 AND FOINALLY TO EXPLORE THE REAL 4060 02:35:27,800 --> 02:35:29,760 WORLD SCENARIOS OF RADIATION AND 4061 02:35:29,760 --> 02:35:31,880 HOW THESE CAN IMPACT THE REAL 4062 02:35:31,880 --> 02:35:32,560 LIFE SCENARIO. 4063 02:35:32,560 --> 02:35:33,280 THERE ARE MANY. 4064 02:35:33,280 --> 02:35:34,560 WE SHOWED MANY GAPS IN THE 4065 02:35:34,560 --> 02:35:35,240 UNDERSTANDING OF THESE 4066 02:35:35,240 --> 02:35:37,880 DIFFERENCES AND WE THINK WE NEED 4067 02:35:37,880 --> 02:35:38,280 TO EXPLORE MORE AND HEPATITIS E 4068 02:35:38,280 --> 02:35:39,800 TO CAPTURE MORE OF THAT WITH THE 4069 02:35:39,800 --> 02:35:40,320 THIS INITIATIVE. 4070 02:35:40,320 --> 02:35:45,400 SO WE HOPE TO USE THE YEAR 1 4071 02:35:45,400 --> 02:35:47,640 COPRAATIVE AGREEMENTS SO THAT WE 4072 02:35:47,640 --> 02:35:49,080 CAN DO MORE WITH THE BASIC 4073 02:35:49,080 --> 02:35:51,040 RESEARCH THAT'S NECESSARY IN THE 4074 02:35:51,040 --> 02:35:51,240 SPACE. 4075 02:35:51,240 --> 02:35:53,800 BUT WE ALSO WANT TO HAVE THAT 4076 02:35:53,800 --> 02:35:55,760 PROGRAM ATDIC INPUT SO THAT IT'S 4077 02:35:55,760 --> 02:35:58,480 NOT JUST AN RO-1 THAT'S NOT 4078 02:35:58,480 --> 02:36:03,040 BEING, YOU KNOW I GUESS GUIDED 4079 02:36:03,040 --> 02:36:03,360 BY PROGRAM. 4080 02:36:03,360 --> 02:36:05,400 SO WE WANT TO DISCUSS MAYBE 4081 02:36:05,400 --> 02:36:06,960 POTENTIALLY CO FUNDING SOMETHING 4082 02:36:06,960 --> 02:36:08,280 WITH THE NIH OFFICE OF RESEARCH 4083 02:36:08,280 --> 02:36:10,200 ON WOMEN'S HEALTH AND THAT'S 4084 02:36:10,200 --> 02:36:12,280 STILL UP IN THE AIR BUT WE ARE 4085 02:36:12,280 --> 02:36:13,160 INTERESTED IN IT. 4086 02:36:13,160 --> 02:36:14,080 WE HAD A GOOD OPPORTUNITY TO 4087 02:36:14,080 --> 02:36:16,640 WORK WITH THEM AND THEY WERE 4088 02:36:16,640 --> 02:36:18,040 GREAT PARTNERS, AND WE HOPE THAT 4089 02:36:18,040 --> 02:36:20,600 THESE WILL BE 3 YEAR AWARDS. 4090 02:36:20,600 --> 02:36:23,840 AND WE EXPECT ABOUT 30 4091 02:36:23,840 --> 02:36:24,880 APPLICATIONS, AND 17 AWARDS 4092 02:36:24,880 --> 02:36:35,320 ANTICIPATED AND THAT'S IT. 4093 02:36:36,560 --> 02:36:38,320 ANY QUESTIONS? 4094 02:36:38,320 --> 02:36:39,040 >> GREAT PRESENTATIONS, IT'S 4095 02:36:39,040 --> 02:36:42,120 PRETTY OBVIOUS, THE NEED. 4096 02:36:42,120 --> 02:36:45,680 >> JUST 1 THING I'M WONDERING, 4097 02:36:45,680 --> 02:36:48,600 YOU SHOWED OR MENTIONED 4098 02:36:48,600 --> 02:36:53,600 DIFFERENCES IN HUMANS LIKE AFTER 4099 02:36:53,600 --> 02:36:55,480 CHERNYOBOL, AND THEN NONHUMAN 4100 02:36:55,480 --> 02:36:56,520 PRIMATE STUDIES, ALLUDED TO AS 4101 02:36:56,520 --> 02:36:58,600 WELL AS MOUSE, HOW IN THE MOUSE 4102 02:36:58,600 --> 02:37:00,360 STUDIES WHICH, YOU KNOW ARE 4103 02:37:00,360 --> 02:37:02,720 REALLY UNIVERSAL AND BASIC 4104 02:37:02,720 --> 02:37:03,880 RESEARCH LABORATORIES, HOW MUCH 4105 02:37:03,880 --> 02:37:06,040 OF A CORRELATE DO YOU THINK 4106 02:37:06,040 --> 02:37:09,680 THERE IS FOR, YOU KNOW FEMALE 4107 02:37:09,680 --> 02:37:10,880 MICE BEING AFFECTED AND THAT 4108 02:37:10,880 --> 02:37:13,240 ALSO BEING TRUE IN SAY HUMAN? 4109 02:37:13,240 --> 02:37:17,000 I MEAN THERE ARE GOOD EXAMPLES 4110 02:37:17,000 --> 02:37:18,760 OF SCENARIOS WHERE YOU KNOW 4111 02:37:18,760 --> 02:37:21,080 FEMALE AND 1 SPECIES IS SOMEHOW 4112 02:37:21,080 --> 02:37:23,840 ANALOGOUS TO YOU KNOW FEMALE 4113 02:37:23,840 --> 02:37:24,120 HUMAN? 4114 02:37:24,120 --> 02:37:26,600 >> SO WHAT WE FIND IS THAT IT 4115 02:37:26,600 --> 02:37:30,160 CAN BE VERY DEPENDENT ON WHAT 4116 02:37:30,160 --> 02:37:34,280 MODEL IT IS, SO, FOR INSTANCE, 4117 02:37:34,280 --> 02:37:35,920 WE HAVE TOTAL BODY RADIATION 4118 02:37:35,920 --> 02:37:37,720 MODELS, WE HAVE THE RADIATION 4119 02:37:37,720 --> 02:37:39,120 MODELS AND IN SOME CASES WE HAVE 4120 02:37:39,120 --> 02:37:41,440 PEOPLE THAT SHOW THE FEMALES ARE 4121 02:37:41,440 --> 02:37:44,560 MORE SENSITIVE AND IT LOOKS LIKE 4122 02:37:44,560 --> 02:37:45,880 THE NONHUMAN PRIMATE SCENARIO, 4123 02:37:45,880 --> 02:37:47,520 BUT IN SOME CASES IT'S OPPOSITE 4124 02:37:47,520 --> 02:37:49,600 SO WE'RE TRYING TO FIGURE THAT 4125 02:37:49,600 --> 02:37:50,400 OUT BECAUSE THERE'S NO 4126 02:37:50,400 --> 02:37:52,480 DIFFERENCES AND IT COULD BE ALSO 4127 02:37:52,480 --> 02:37:55,560 DUE TO THE SOURCE OF RADIATION 4128 02:37:55,560 --> 02:37:56,880 THAT THEY'RE USING IN SOME CASES 4129 02:37:56,880 --> 02:37:58,840 SO THERE'S A LOT OF QUESTIONS 4130 02:37:58,840 --> 02:38:01,000 THERE, BUT CERTAINLY WE SEE 4131 02:38:01,000 --> 02:38:02,200 DIFFERENCES IN SEXES. 4132 02:38:02,200 --> 02:38:03,360 WHY THOSE DIFFERENCES ARE 4133 02:38:03,360 --> 02:38:04,280 OCCURRING, WE'RE STILL FIGURING 4134 02:38:04,280 --> 02:38:14,560 THAT OUT AS WE GO. 4135 02:38:19,320 --> 02:38:19,560 NOTHING ELSE? 4136 02:38:19,560 --> 02:38:21,400 THANK YOU SO MUCH, I APPRECIATE 4137 02:38:21,400 --> 02:38:26,440 YOUR TIME AND HOPE THAT WAS 4138 02:38:26,440 --> 02:38:27,440 PRETTY CLEAR. 4139 02:38:27,440 --> 02:38:30,280 >> THANK YOU. 4140 02:38:30,280 --> 02:38:31,240 OKAY, THANK YOU. 4141 02:38:31,240 --> 02:38:36,440 LET'S THEN ASK FOR A APPROVAL, 4142 02:38:36,440 --> 02:38:39,800 RECOMMENDATION TO PROCEED WITH 4143 02:38:39,800 --> 02:38:40,440 THESE AND A SECOND. 4144 02:38:40,440 --> 02:38:44,600 AND WE WILL DO THAT ON BLOCK. 4145 02:38:44,600 --> 02:38:49,640 >> JUST REAL QUICK, SO DOCTOR 4146 02:38:49,640 --> 02:38:52,440 ARE YOU OKAY WITH THE ADJUVANT 4147 02:38:52,440 --> 02:38:54,560 PROGRAM, THE REQUESTY ABOUT-- 4148 02:38:54,560 --> 02:38:57,400 >> YEAH, YEAH, WE RECOGNIZE IT 4149 02:38:57,400 --> 02:38:58,400 WAS MORE A QUESTION. 4150 02:38:58,400 --> 02:38:59,440 IT'S THE SAME QUESTION FOR THE 4151 02:38:59,440 --> 02:39:02,280 NEXT 1 AS WELL. 4152 02:39:02,280 --> 02:39:05,240 THE RADIATION SO WE ARE A LITTLE 4153 02:39:05,240 --> 02:39:07,000 HAND STRONG WITH THE WEAR WE 4154 02:39:07,000 --> 02:39:11,960 COMPARE HUMANS AND MICE, YES, 4155 02:39:11,960 --> 02:39:12,440 ABSOLUTELY. 4156 02:39:12,440 --> 02:39:14,080 >> YEAH, THANK YOU FOR BRINGING 4157 02:39:14,080 --> 02:39:16,280 THAT UP, IF ANYBODY HAS CONCERNS 4158 02:39:16,280 --> 02:39:17,320 WE SHOULD DISCUSS THESE 4159 02:39:17,320 --> 02:39:20,280 INDIVIDUALLY BUT I DIDN'T TAKE 4160 02:39:20,280 --> 02:39:21,200 THAT FROM THE DISCUSSION AFTER 4161 02:39:21,200 --> 02:39:23,240 EACH OF THEM THAT THERE WERE 4162 02:39:23,240 --> 02:39:24,320 CONCERNS THAT ROSE TO THAT 4163 02:39:24,320 --> 02:39:31,400 LEVEL, BUT IF HAVE YOU CONCERNS, 4164 02:39:31,400 --> 02:39:33,560 LET US KNOW, IF NOT WE SHOULD 4165 02:39:33,560 --> 02:39:34,040 MOVE AHEAD. 4166 02:39:34,040 --> 02:39:35,680 >> MOVE TO ADOPT THEM ALL. 4167 02:39:35,680 --> 02:39:36,040 >> SECOND,. 4168 02:39:36,040 --> 02:39:36,360 >> SECOND? 4169 02:39:36,360 --> 02:39:37,200 I HAVE A QUESTION ABOUT THE 4170 02:39:37,200 --> 02:39:40,440 VOTING SHOULD WE ALSO VOTEOT 4171 02:39:40,440 --> 02:39:42,280 ELECTRONIC COUNCIL BOOK? 4172 02:39:42,280 --> 02:39:42,520 >> YES. 4173 02:39:42,520 --> 02:39:42,880 >> PLEASE DO. 4174 02:39:42,880 --> 02:39:45,440 >> I THINK THE ANSWER IS YES 4175 02:39:45,440 --> 02:39:51,440 BUT-- 4176 02:39:51,440 --> 02:39:58,160 >> YES, ABSOLUTELY, PLEASE VOTE. 4177 02:39:58,160 --> 02:39:58,560 >> GOOD. 4178 02:39:58,560 --> 02:40:01,160 >> WELL, THAT WRAPS US UP THEN 4179 02:40:01,160 --> 02:40:03,040 FOR THE DAY AND I JUST WANT TO 4180 02:40:03,040 --> 02:40:05,200 THANK YOU ALL FOR STICKING WITH 4181 02:40:05,200 --> 02:40:09,240 US AN EXTRA 10 OR 11 MINUTES AND 4182 02:40:09,240 --> 02:40:12,480 ALSO FOR YOUR ACTIVE 4183 02:40:12,480 --> 02:40:18,480 PARTICIPATION THROUGHOUT THE DAY 4184 02:40:18,480 --> 02:40:23,440 AND GWEN AND ANURADHA, AND 4185 02:40:23,440 --> 02:40:24,920 ELLING AND THANK YOU TO YOUR 4186 02:40:24,920 --> 02:40:27,160 SERVICE TO THE INSTITUTE AS 4187 02:40:27,160 --> 02:40:28,240 COUNCIL MEMBERS I REALLY REGRET 4188 02:40:28,240 --> 02:40:31,760 THAT MOST OF THAT TIME HAS BEEN 4189 02:40:31,760 --> 02:40:33,960 BY ZOOM AND THAT'S CHALLENGING 4190 02:40:33,960 --> 02:40:37,000 BUT HOPEFULLY, WE WILL HAVE THE 4191 02:40:37,000 --> 02:40:40,960 OPPORTUNITY TO SEE YOU IN PERSON 4192 02:40:40,960 --> 02:40:41,680 AT UPCOMING MEETINGS. 4193 02:40:41,680 --> 02:40:42,040 >> THANK YOU. 4194 02:40:42,040 --> 02:40:44,000 >> THANK YOU TO THE ENTIRE TEAM 4195 02:40:44,000 --> 02:40:45,240 THERE, I MEAN I KNOW THERE'S A 4196 02:40:45,240 --> 02:40:48,560 LOT OF PEOPLE IN THE BACKGROUND, 4197 02:40:48,560 --> 02:40:50,400 PRESENTATIONS ARE EVERY MEETING 4198 02:40:50,400 --> 02:40:52,400 ARE JUST FANTASTIC. 4199 02:40:52,400 --> 02:40:52,800 >> YES. 4200 02:40:52,800 --> 02:40:53,880 >> THERE'S ALWAYS ANTICIPATION, 4201 02:40:53,880 --> 02:40:55,080 SEEMS LIKE ANTICIPATE QUESTIONS 4202 02:40:55,080 --> 02:40:56,960 WE MIGHT HAVE AND BRING THEM UP 4203 02:40:56,960 --> 02:40:58,440 ON THE PRESENTATION, JUST, I 4204 02:40:58,440 --> 02:40:59,680 HAVE TO SAY IT'S BEEN MORE THAN 4205 02:40:59,680 --> 02:41:01,320 A PRIVILEGE TO BE ON THIS 4206 02:41:01,320 --> 02:41:03,360 COUNCIL AND I REALLY APPRECIATE 4207 02:41:03,360 --> 02:41:04,760 THE HARD WORK THAT EVERYBODY AND 4208 02:41:04,760 --> 02:41:06,840 THE TEAM THERE DOES TO MAKE IT 4209 02:41:06,840 --> 02:41:08,240 ALL HAPPEN. 4210 02:41:08,240 --> 02:41:11,320 THANK YOU. 4211 02:41:11,320 --> 02:41:12,040 SNSHES TOTALLY. 4212 02:41:12,040 --> 02:41:14,000 >> WELL, WE APPRECIATE THE HARD 4213 02:41:14,000 --> 02:41:14,640 WORK YOU DO. 4214 02:41:14,640 --> 02:41:16,080 THERE'S ALSO A LOAT BEHIND THE 4215 02:41:16,080 --> 02:41:19,920 SCENES THAT YOU ALL DO WITH THE 4216 02:41:19,920 --> 02:41:27,200 GRANTS THAT DON'T EVEN GET 4217 02:41:27,200 --> 02:41:28,520 DISCUSSED HERE BUT REQUIRE SOME 4218 02:41:28,520 --> 02:41:29,600 LEVEL OF REVIEW ON YOUR PART. 4219 02:41:29,600 --> 02:41:31,400 OKAY, WITH THAT I THINK THAT 4220 02:41:31,400 --> 02:41:32,800 WRAPS IT UP. 4221 02:41:32,800 --> 02:41:33,000 GWEN-- 4222 02:41:33,000 --> 02:41:34,920 >> NO, NO I WAS SAYING THANKS IS 4223 02:41:34,920 --> 02:41:36,320 ALL. 4224 02:41:36,320 --> 02:41:36,680 ADDING IT ON. 4225 02:41:36,680 --> 02:41:40,760 WHAT A TIME TO BE ON COUNSEL 4226 02:41:40,760 --> 02:41:41,120 THOUGH RIGHT? 4227 02:41:41,120 --> 02:41:43,160 AND THEN WE GOT TO SEE COVID AND 4228 02:41:43,160 --> 02:41:43,600 EVERYTHING. 4229 02:41:43,600 --> 02:41:48,400 >> I KNOW, I KNOW. 4230 02:41:48,400 --> 02:41:50,080 >> ALTHOUGH MOST OF THE TIME WE 4231 02:41:50,080 --> 02:41:52,920 DID SEE THE TRANSITION, IT'S 4232 02:41:52,920 --> 02:41:56,680 QUITE MEMORABLE. 4233 02:41:56,680 --> 02:41:59,800 >> YEAH AND YOU WITNESSED TONY'S 4234 02:41:59,800 --> 02:42:00,600 LAST COUNCIL. 4235 02:42:00,600 --> 02:42:00,880 >> YEAH. 4236 02:42:00,880 --> 02:42:02,800 AT LEAST AS THE HEAD OF THE 4237 02:42:02,800 --> 02:42:04,480 INSTITUTE, I HOPE, YOU KNOW, I'M 4238 02:42:04,480 --> 02:42:07,760 SURE SOMEBODY WILL INVITE HIM 4239 02:42:07,760 --> 02:42:15,400 BACK TO GIVE TALKS ON THIS OR 4240 02:42:15,400 --> 02:42:18,240 THAT AT SOME POINT, AND IT'S 4241 02:42:18,240 --> 02:42:18,520 HISTORIC. 4242 02:42:18,520 --> 02:42:19,400 ALL RIGHT, WELL THANK YOU AND 4243 02:42:19,400 --> 02:42:21,160 ENJOY THE REST OF THE DAY AND 4244 02:42:21,160 --> 00:00:00,000 HOPE TO SEE YOU ALL SOON.