1 00:00:42,212 --> 00:00:12,758 SO WELCOME, I AM VICKI AND IT'S 2 00:00:12,758 --> 00:00:14,426 A PLEASURE TO HAVE YOU WITH US 3 00:00:14,426 --> 00:00:14,660 TODAY. 4 00:00:14,660 --> 00:00:18,097 WE ARE EXCITED TO HAVA A 5 00:00:18,097 --> 00:00:20,099 WONDIRBFUL SET OF SPEAKERS 6 00:00:20,099 --> 00:00:22,801 TALKING ABOUT XIST AND THE 7 00:00:22,801 --> 00:00:24,770 XISTING DATA ON WHY AUTOIMMUNE 8 00:00:24,770 --> 00:00:26,505 DISEASES MAY BE MORE COMMON IN 9 00:00:26,505 --> 00:00:26,872 WOMEN. 10 00:00:26,872 --> 00:00:27,806 COUPLE OF HOUSEKEEPING THINGS 11 00:00:27,806 --> 00:00:30,242 JUST TO GET US STARTED, THIS 12 00:00:30,242 --> 00:00:32,778 EVENT IS BEING RECORDED AND WILL 13 00:00:32,778 --> 00:00:34,847 BE VIDEOCAST, IT WILL BE 14 00:00:34,847 --> 00:00:36,682 AVAILABLE IN THE VIDEOCAST 15 00:00:36,682 --> 00:00:39,218 ARCHIVE, IF YOU HAVE TECHNICAL 16 00:00:39,218 --> 00:00:41,153 CHALLENGES, PLEASE USE THE CHAT 17 00:00:41,153 --> 00:00:48,627 FUNCTION TO CHAT WITH I.T. 18 00:00:48,627 --> 00:00:49,028 SUPPORT. 19 00:00:49,028 --> 00:00:51,664 IF YOU HAVE ANY TECHNICAL 20 00:00:51,664 --> 00:00:53,832 DIFFICULTYYS, AND THEN ALSO BE 21 00:00:53,832 --> 00:00:54,567 THOUGHTFUL AND CONSIDERATE IN 22 00:00:54,567 --> 00:00:56,869 YOUR CHAT IF YOU ARE TALKING TO 23 00:00:56,869 --> 00:00:57,836 FELLOW PARTICIPANTS. 24 00:00:57,836 --> 00:00:59,505 A COUPLE HOUSEKEEPING ISSUES 25 00:00:59,505 --> 00:01:01,173 REGARDING Q&A, WE ARE GOING TO 26 00:01:01,173 --> 00:01:02,708 HAVE QUESTIONS FOR THE PANELISTS 27 00:01:02,708 --> 00:01:05,177 AT THE END OF ALL 3 TALKS, IF 28 00:01:05,177 --> 00:01:06,345 YOU CAN SUBMIT KEQUESTIONS 29 00:01:06,345 --> 00:01:07,880 THROUGH THE Q&A FUNCTION, WHICH 30 00:01:07,880 --> 00:01:09,582 IS RIGHT NEXT TO THE CHAT 31 00:01:09,582 --> 00:01:11,684 FUNCTION ON YOUR ZOOM, IF YOU 32 00:01:11,684 --> 00:01:12,985 THERE ARE QUESTIONS YOU WOULD 33 00:01:12,985 --> 00:01:16,121 REALLY LIKE TO HAVE ASK ASKED, 34 00:01:16,121 --> 00:01:17,389 WE WILL MODERATE THOSE THROUGH 35 00:01:17,389 --> 00:01:19,425 THE Q&A FUNCTION. 36 00:01:19,425 --> 00:01:22,228 SO I WANTED TO GET STARTED, JUST 37 00:01:22,228 --> 00:01:24,263 QUICKLY INTRODUCING OUR 2 38 00:01:24,263 --> 00:01:25,731 MODERATORS FOR TODAY, DR. STACEY 39 00:01:25,731 --> 00:01:29,168 FERGUSON IS THE CHIEF OF THE 40 00:01:29,168 --> 00:01:29,768 AUTOIMMUNE AND PRIMARY IMMUNO 41 00:01:29,768 --> 00:01:31,036 DEFICIENCY SECTION AT THE 42 00:01:31,036 --> 00:01:32,438 NATIONAL INSTITUTE OF ALLERGY 43 00:01:32,438 --> 00:01:35,474 AND INFECIOUS DISEASES AND 44 00:01:35,474 --> 00:01:36,742 DR. MARIE MANCINI IS PROGRAM 45 00:01:36,742 --> 00:01:38,711 DIRECTOR OF THE SYSTEMIC 46 00:01:38,711 --> 00:01:39,311 AUTOIMMUNE DISEASE BIOLOGY 47 00:01:39,311 --> 00:01:42,214 PROGRAM AT THE NATIONAL 48 00:01:42,214 --> 00:01:49,021 INSTITUTE OF ARTHRITIS AND MUSK 49 00:01:49,021 --> 00:01:50,489 LO SKELETAL AND SKIN CONDITIONS. 50 00:01:50,489 --> 00:01:51,724 IT'S A PLEASURE TO HAVE THEM 51 00:01:51,724 --> 00:01:52,224 WITH US TODAY. 52 00:01:52,224 --> 00:01:56,762 I WANT TO INTRODUCE OUR 3 53 00:01:56,762 --> 00:01:57,496 SPEAKERS, DR. [INDISCERNIBLE] IS 54 00:01:57,496 --> 00:01:59,565 IN THE DEPARTMENT OF BIOMEDICAL 55 00:01:59,565 --> 00:02:02,034 SCIENCES AT THE UNIVERSITY OF 56 00:02:02,034 --> 00:02:02,868 SCHOOL OF VETERINARY SCHOOL 57 00:02:02,868 --> 00:02:05,237 MEDICINE, SHE IS A MEMBER OF THE 58 00:02:05,237 --> 00:02:06,305 EPIGENETICS INSTITUTE, INSTITUTE 59 00:02:06,305 --> 00:02:08,707 FOR IMMUNOLOGY AND THE INSTITUTE 60 00:02:08,707 --> 00:02:10,976 FOR REGENERATIVE MEDICINE AT 61 00:02:10,976 --> 00:02:11,310 PENN. 62 00:02:11,310 --> 00:02:14,146 Y RECEIVED HER MASTER IN 63 00:02:14,146 --> 00:02:16,215 [INDISCERNIBLE] AND HER Ph.D. 64 00:02:16,215 --> 00:02:18,350 FROM CORNELL, SHE WAS DID HER 65 00:02:18,350 --> 00:02:20,786 POST GRAD AT HARVARD WHERE SHE 66 00:02:20,786 --> 00:02:24,657 DID INACTIVATION OF THE 67 00:02:24,657 --> 00:02:25,124 X-CHROMOSOME. 68 00:02:25,124 --> 00:02:27,226 DR. ANG UERA HAS STUDIED IMMUNE 69 00:02:27,226 --> 00:02:28,260 RESPONSES IN RESPONSE TO 70 00:02:28,260 --> 00:02:29,795 INFECTION AND MORE RECENTLY IN 71 00:02:29,795 --> 00:02:31,096 AUTOIMMUNITY AND IT'S A GREAT 72 00:02:31,096 --> 00:02:34,266 PLEASURE TO HAVE HER GIVE THE 73 00:02:34,266 --> 00:02:37,136 OPENING LECTURE OF THIS 74 00:02:37,136 --> 00:02:39,104 SYMPOSIUM TODAY EMPLOY OUR 75 00:02:39,104 --> 00:02:40,973 SPECCED SPEAKER WILL BE 76 00:02:40,973 --> 00:02:48,080 DR. DIANEA DOU, SHE IS A N IAMS 77 00:02:48,080 --> 00:02:50,616 FELLOW, SHE AND HER B. S. DEGREE 78 00:02:50,616 --> 00:02:53,218 WITH HONORS FROM CALTECH AND 79 00:02:53,218 --> 00:02:55,621 DOUBLE MAJORED IN BOTH BIOLOGY 80 00:02:55,621 --> 00:02:56,755 IN BIOLOGY AND BUSINESS 81 00:02:56,755 --> 00:02:57,056 MANAGEMENT. 82 00:02:57,056 --> 00:02:59,224 SHE THEN WAS INTRODUCED TO RNA 83 00:02:59,224 --> 00:03:01,627 BIOLOGY AS BOTH AN UNDERGRADUATE 84 00:03:01,627 --> 00:03:05,564 RESEARCH AND SUBSEQUENT LOW IN 85 00:03:05,564 --> 00:03:08,767 THE INTRAMURAL AND RESEARCH 86 00:03:08,767 --> 00:03:09,835 TRAINING BACCALAUREATE TRAINING 87 00:03:09,835 --> 00:03:13,539 AT NIH IN DR. FAUCI'S LAB, 88 00:03:13,539 --> 00:03:17,209 DR. DOU WENT ON TO COMPLETE A 89 00:03:17,209 --> 00:03:19,545 Ph.D. IN MOLECULAR BIOLOGY 90 00:03:19,545 --> 00:03:20,679 INVESTIGATING HEMATOPOIETIC STEM 91 00:03:20,679 --> 00:03:22,548 CELLS AND CURRENTLY STUDYING THE 92 00:03:22,548 --> 00:03:25,851 STEM CELLS OF NONLONG CODING 93 00:03:25,851 --> 00:03:28,020 RNAs AND ACCESSIBILITY IN 94 00:03:28,020 --> 00:03:30,222 AUTOIMMUNE DISEASE, RECENTLY SHE 95 00:03:30,222 --> 00:03:33,625 DISCOVERED A NOVEL ROLE EXISTS 96 00:03:33,625 --> 00:03:36,795 IN THE RIBONUCLEAR PROTEIN AT 97 00:03:36,795 --> 00:03:38,464 THE DRIVER PROTEIN USHED LYING 98 00:03:38,464 --> 00:03:39,832 THE DOMINANCE OF AUTOIMMUNE 99 00:03:39,832 --> 00:03:41,100 DISEASE, AND THEN OUR THIRD 100 00:03:41,100 --> 00:03:46,905 SPEAKER TODAY WOULD BE 101 00:03:46,905 --> 00:03:48,273 DR. BRENDAN ANTIOCHO, HE IS A 102 00:03:48,273 --> 00:03:51,009 PHYSICIAN SCIENTIST AT JOHNS 103 00:03:51,009 --> 00:03:53,112 HOPKINS SCHOOL OF MEDICINE. 104 00:03:53,112 --> 00:03:54,380 HE HAS PRIMARY RESEARCH INTEREST 105 00:03:54,380 --> 00:03:56,248 IN THE INNATE IMMUNE SYSTEM IN 106 00:03:56,248 --> 00:03:57,916 THE PATHOGENESIS OF RHEUMATIC 107 00:03:57,916 --> 00:04:00,085 DISEASE, HE RECEIVED HIS 108 00:04:00,085 --> 00:04:01,787 BACHELOR'S DEGREE FROM DARTMOUTH 109 00:04:01,787 --> 00:04:03,389 UNIVERSITY AND HIS MEDICAL 110 00:04:03,389 --> 00:04:05,224 SCHOOL FROM DARTMOUTH MEDICAL 111 00:04:05,224 --> 00:04:05,924 SCHOOL. 112 00:04:05,924 --> 00:04:08,026 HE THEN COMPLETED RESIDENCY IN 113 00:04:08,026 --> 00:04:09,261 INTERNAL MEDICINE AT OREGON 114 00:04:09,261 --> 00:04:10,396 HEALTH SCIENCE UNIVERSITY 115 00:04:10,396 --> 00:04:11,363 FOLLOWED BY RHEUMATOLOGY 116 00:04:11,363 --> 00:04:12,531 FELLOWSHIP AT JOHNS HOPKINS 117 00:04:12,531 --> 00:04:14,533 SCHOOL OF MEDICINE WHERE HE IS 118 00:04:14,533 --> 00:04:16,502 NOW AN ASSISTANT PROFESSOR OF 119 00:04:16,502 --> 00:04:17,202 RHEUMATOLOGY. 120 00:04:17,202 --> 00:04:18,771 HE STUDIES THE IDENTITY OF 121 00:04:18,771 --> 00:04:20,639 SPECIFIC INDOAJ NOWS NUCLEIC 122 00:04:20,639 --> 00:04:22,941 ACIDS AND SINCE THE LIGAND 123 00:04:22,941 --> 00:04:25,244 INTERACTIONS RESPONSIBLE FOR 124 00:04:25,244 --> 00:04:29,782 INTERFORON RESPONSES IN LUPUS 125 00:04:29,782 --> 00:04:30,282 AND SHOGREN'S SYNDROME. 126 00:04:30,282 --> 00:04:31,383 IT IS A GREAT PLEASURE TO HAVE 127 00:04:31,383 --> 00:04:32,818 ALL 3 OF OUR SPEAKERS WITH US 128 00:04:32,818 --> 00:04:36,388 TODAY AND WITH THAT I WILL HAND 129 00:04:36,388 --> 00:04:39,024 THE MICROPHONE TO DR. ANG UERA, 130 00:04:39,024 --> 00:04:43,729 TO OPEN US UP WITH HER TALK ON 131 00:04:43,729 --> 00:04:45,063 X-CHROMESOME ACTIVATION AND 132 00:04:45,063 --> 00:04:46,965 IMMUNE SYSTEMS. 133 00:04:46,965 --> 00:04:49,601 DOCTOR ANG UERA IN CAN YOU HEAR 134 00:04:49,601 --> 00:04:50,068 ME? 135 00:04:50,068 --> 00:04:52,271 CAN YOU HEAR ME NOW IN. 136 00:04:52,271 --> 00:04:54,406 >> YES NTHANK YOU SO MUCH VICKI 137 00:04:54,406 --> 00:04:56,141 AND THANKS TO EVERYONE FOR THIS 138 00:04:56,141 --> 00:04:57,309 OPPORTUNITY EVERYONE AT THE 139 00:04:57,309 --> 00:04:58,777 OFFICE FOR RESEARCH ON WOMEN'S 140 00:04:58,777 --> 00:05:01,680 HEALTH FOR THIS CHANCE TO SHARE 141 00:05:01,680 --> 00:05:02,748 SOME EXCITING PUBLISHED AND 142 00:05:02,748 --> 00:05:03,615 UNPUB LIBRARY FOUNDATIONED DATA 143 00:05:03,615 --> 00:05:04,316 WITH YOU TODAY. 144 00:05:04,316 --> 00:05:08,921 SO IN MY LAB AT PEIN, N, WE'RE 145 00:05:08,921 --> 00:05:11,523 VERY INTERESTED IN X-CHROMOSOME 146 00:05:11,523 --> 00:05:12,925 ACTIVATION AND SEX DIFFERENCES 147 00:05:12,925 --> 00:05:16,795 AND HOW THE GENETICS AND THE 148 00:05:16,795 --> 00:05:18,363 EPIGENETICS CONTRIBUTE TO FEMALE 149 00:05:18,363 --> 00:05:20,799 BIAS WITH IMMUNE RESPONSES AND 150 00:05:20,799 --> 00:05:22,167 ALSO AUTOIMMUNE DECS, SO JUST A 151 00:05:22,167 --> 00:05:25,370 LITTLE BIT OF BACKGROUND ABOUT 152 00:05:25,370 --> 00:05:29,241 LUPUS OR SYSTEMIC LUPUS 153 00:05:29,241 --> 00:05:32,778 ERYTHEMAITOSEIS, THIS A SYSTEMIC 154 00:05:32,778 --> 00:05:34,279 RHEUMATIC AUTOIMMUNE DEC THAT 155 00:05:34,279 --> 00:05:36,682 AFFECTS A VARIETY OF ORGANS ANDS 156 00:05:36,682 --> 00:05:38,851 ISS, LUPUS IS CHARACTERIZED BY A 157 00:05:38,851 --> 00:05:40,552 VARIETY OF PHENOTYPES WHICH I 158 00:05:40,552 --> 00:05:41,320 WILL HIGHLIGHT-- 159 00:05:41,320 --> 00:05:43,255 >> CAN I JUST YUSM IN-- 160 00:05:43,255 --> 00:05:45,357 >> WE'RE NOT SEEING YOUR SLIDES, 161 00:05:45,357 --> 00:05:48,627 CAN YOU SHARE? 162 00:05:48,627 --> 00:05:59,071 >> UH, OH, OKAY, SORRY! 163 00:06:03,208 --> 00:06:10,816 OKAY. 164 00:06:10,816 --> 00:06:11,283 OKAY. 165 00:06:11,283 --> 00:06:21,827 FOR SOME REASON, I CAN'T SEE ... 166 00:07:14,746 --> 00:07:17,215 YOU CAN SEE YOUR SLIDES NOW, SO 167 00:07:17,215 --> 00:07:18,483 SHARE SCREEN BUT SHARE THE 1 168 00:07:18,483 --> 00:07:21,753 WITH JUST ALL YOUR SLIDES. 169 00:07:21,753 --> 00:07:29,895 NWITH THE PRESENTER? 170 00:07:29,895 --> 00:07:30,462 >> WITHOUT PRESENTER. 171 00:07:30,462 --> 00:07:32,297 >> NOW YOU CAN SEE THE 172 00:07:32,297 --> 00:07:36,802 PRESENTER, SO SELECT PRESENTER. 173 00:07:36,802 --> 00:07:38,770 >> DO YOU SEE MY SLIDES NOW. 174 00:07:38,770 --> 00:07:39,571 >> PERFECT. 175 00:07:39,571 --> 00:07:41,406 >> YES, WE DO NPERFECT. 176 00:07:41,406 --> 00:07:41,873 PERFECT. 177 00:07:41,873 --> 00:07:42,074 GREAT. 178 00:07:42,074 --> 00:07:46,011 THANK YOU SO MUCH, THANK YOU. 179 00:07:46,011 --> 00:07:47,980 OKAY, SO LUPUS, SO LUPUS DISEASE 180 00:07:47,980 --> 00:07:49,881 IS CHARACTERIZED BY A VARIETY OF 181 00:07:49,881 --> 00:07:51,917 DIFFERENT PHENOTYPES, SO LOOKING 182 00:07:51,917 --> 00:07:55,454 IN LUPUS PATIENTS AT THE SERUM, 183 00:07:55,454 --> 00:07:59,124 SLE PATIENTS HAVE ELEVATED 184 00:07:59,124 --> 00:08:03,261 LEVELS OF AUTOANTIBODIES 185 00:08:03,261 --> 00:08:04,630 SPECIFICALLY, ANTIDOUBLE 186 00:08:04,630 --> 00:08:07,399 STRANDED DNA, OR DSDNA, 187 00:08:07,399 --> 00:08:10,002 AUTOASPECT BODIES AND ALSO 188 00:08:10,002 --> 00:08:11,403 ANTISMITH, RMP COMPLEX 189 00:08:11,403 --> 00:08:14,373 ANTIBODIES, LUPUS DISEASE IS 190 00:08:14,373 --> 00:08:16,408 ALSO KNOWN TO AFFAIRS TEAM 191 00:08:16,408 --> 00:08:18,810 LEADERRER THE B-CELL COMPOSITION 192 00:08:18,810 --> 00:08:19,678 WHERE SLE PATIENTS HAVE 193 00:08:19,678 --> 00:08:22,447 INCREASED NUMBERS OF ACTIVATED 194 00:08:22,447 --> 00:08:24,182 B-CELLS AND THERE'S ALSO 195 00:08:24,182 --> 00:08:26,051 INCREASED NUMBERS OF AGE 196 00:08:26,051 --> 00:08:26,852 ASSOCIATED B-CELLS, LUPUS 197 00:08:26,852 --> 00:08:31,423 PATIENTS ALSO HAVE HIGH NUMBERS 198 00:08:31,423 --> 00:08:34,559 OF PLASMA CELLS. 199 00:08:34,559 --> 00:08:38,096 SLE PATIENTS ARE ALSO SOMETIMES 200 00:08:38,096 --> 00:08:42,167 DEVELOP KIDNEY PATHOLOGY, SO 201 00:08:42,167 --> 00:08:44,336 DPLU MARRIAL NEPHRITIS, WHERE IT 202 00:08:44,336 --> 00:08:47,205 WILL INFILTRATE INTO THE KIDNEYS 203 00:08:47,205 --> 00:08:48,273 RESULTING IN TISSUE BREAK DOWN, 204 00:08:48,273 --> 00:08:52,310 SO WE KNOW THAT B-CELLS ARE 205 00:08:52,310 --> 00:08:53,412 IMPORTANT OFFICIATORS AND 206 00:08:53,412 --> 00:08:54,579 EFFECTORS OF NORMAL IMMUNE 207 00:08:54,579 --> 00:09:01,486 RESPONSE, AND ALSO KNOWN TO BE 208 00:09:01,486 --> 00:09:02,654 IMPORTANT PLAYERS, SO AUTOBODY 209 00:09:02,654 --> 00:09:04,289 PRODUCTION AND DETECTION IS KEY 210 00:09:04,289 --> 00:09:06,358 TO MAKING A DIAGNOSIS OF LUPUS 211 00:09:06,358 --> 00:09:08,326 DISEED AND OFTEN TIMES, 212 00:09:08,326 --> 00:09:09,761 AUTOANTIBODIES CAN BECOME 213 00:09:09,761 --> 00:09:12,097 ELEVATED IN THE PATIENT EVEN 214 00:09:12,097 --> 00:09:15,734 BEFORE THERE'S EVIDENCE OF 215 00:09:15,734 --> 00:09:17,436 CLINICAL DISEASE. 216 00:09:17,436 --> 00:09:19,771 NOW B-CELLS ALSO SURVEYS CRETE 217 00:09:19,771 --> 00:09:21,540 AUTOANTIBODIES BUT THEY PLAY 218 00:09:21,540 --> 00:09:22,941 IMPORTANT ROLES IN ANTIGEN 219 00:09:22,941 --> 00:09:24,643 PRESENTATION AND ALSO IN 220 00:09:24,643 --> 00:09:26,645 CYTOKINE PRESENTATION. 221 00:09:26,645 --> 00:09:27,879 SO RHEUMATOLOGISTS HAVE BEEN 222 00:09:27,879 --> 00:09:28,780 MAKING THE OBSERVATION FOR 223 00:09:28,780 --> 00:09:31,149 DECADES THAT IF YOU LOOK AT 224 00:09:31,149 --> 00:09:32,451 AUTOIMMUNE DISEASES, THE 225 00:09:32,451 --> 00:09:34,753 MAIORITY OF PATIENTS ARE 226 00:09:34,753 --> 00:09:38,190 BIOLOGICALLY FEMALE AND IN THIS 227 00:09:38,190 --> 00:09:40,292 GRAF, IT SHOWS 25 AUTOIMMUNE 228 00:09:40,292 --> 00:09:41,660 DISORDERS, WHERE GREATER THAN 229 00:09:41,660 --> 00:09:44,229 50% OF THE PATIENTS ARE FEMALE 230 00:09:44,229 --> 00:09:45,697 AND THESE 25 DIFFERENT 231 00:09:45,697 --> 00:09:47,132 AUTOIMMUNE DISEASES ARE SHOWN 232 00:09:47,132 --> 00:09:48,200 ALONG THE X-AXIS HERE AND THE 233 00:09:48,200 --> 00:09:51,503 PERCENTAGE OF PATIENTS THAT ARE 234 00:09:51,503 --> 00:09:53,705 EITHER MALES OR FEMALES IS SHOWN 235 00:09:53,705 --> 00:09:56,241 IN THE XAXIS AND IT WAS THOUGHT 236 00:09:56,241 --> 00:09:57,409 THAT SEX HORMONES ALONE WERE 237 00:09:57,409 --> 00:10:00,011 RESPONSIBLE FOR THE SEX BIAS, 238 00:10:00,011 --> 00:10:01,847 BUT NOW, WE KNOW THAT THE SEX 239 00:10:01,847 --> 00:10:03,448 SCROAM STUDIES OF MULTIPLE 240 00:10:03,448 --> 00:10:05,650 ENDOCRINE, IN PARTICULAR THE 241 00:10:05,650 --> 00:10:06,918 GENETICS AND EPIGENETICS ALSO 242 00:10:06,918 --> 00:10:08,286 PLAY AN IMPORTANT ROLE. 243 00:10:08,286 --> 00:10:10,555 AND SO WHAT A STRIKING 244 00:10:10,555 --> 00:10:11,556 OBSERVATION THAT REALLY CAUGHT 245 00:10:11,556 --> 00:10:13,692 OUR ATTENTION IS THAT THERE'S AN 246 00:10:13,692 --> 00:10:15,193 INCREASED RISK FOR DEVELOPING 247 00:10:15,193 --> 00:10:17,262 SOME OF THESE SEX BIAS 248 00:10:17,262 --> 00:10:18,897 AUTOIMMUNE DECS, THAT CORRELATES 249 00:10:18,897 --> 00:10:21,199 WITH THE NUMBER OF X-CHROMOSOMES 250 00:10:21,199 --> 00:10:23,034 THAT AN INDIVIDUAL HAS, SO 251 00:10:23,034 --> 00:10:24,936 INDIVIDUALS WITH WOOR MORE 252 00:10:24,936 --> 00:10:26,538 X-CHROMOSOMES, ARE AT INCREASED 253 00:10:26,538 --> 00:10:29,107 RISK TO DEVELOP LUPUS, IN 254 00:10:29,107 --> 00:10:32,978 ADDITION TO 4 OTHER AUTOIMMUNE 255 00:10:32,978 --> 00:10:34,846 DISEASES THAT ARE PREDOMINANTLY 256 00:10:34,846 --> 00:10:36,481 FEMALE BIASED EMPLOY SO 1 COULD 257 00:10:36,481 --> 00:10:38,917 ASK, WHAT'S SO SPECIAL ABOUT THE 258 00:10:38,917 --> 00:10:39,284 X-CHROMOSOME. 259 00:10:39,284 --> 00:10:40,685 WELL, ON THE X-CHROMOSOME IN 260 00:10:40,685 --> 00:10:43,955 HUMAN ANDS IN MICE, THERE'S A 261 00:10:43,955 --> 00:10:45,390 IMPORTANT DENSITY OF IMMUNE 262 00:10:45,390 --> 00:10:46,391 RELATED YEENS THAT ARE 263 00:10:46,391 --> 00:10:47,459 PRESCRIBINGENT ON THIS 264 00:10:47,459 --> 00:10:49,094 CHROMOSOME, AND SO, TODAY I JUST 265 00:10:49,094 --> 00:10:50,862 BRIEFLY WANT TO TELL YOU ABOUT 1 266 00:10:50,862 --> 00:10:53,031 OF THESE EXCELLENT YEENS CALLED 267 00:10:53,031 --> 00:10:54,566 TLR 7, WE WILL HEAR MORE ABOUT 268 00:10:54,566 --> 00:10:57,702 THIS FROM BRENDA IN THE LAST 269 00:10:57,702 --> 00:11:00,238 PRESENTATION, AND SO, TOLL-LIKE 270 00:11:00,238 --> 00:11:02,240 RECEPTOR 7 OR TLR-7, THE DOSAGE 271 00:11:02,240 --> 00:11:05,443 OF THIS YEEN, OR THE EXPRESSION 272 00:11:05,443 --> 00:11:06,378 LEVEL IS CRITICAL BECAUSE IF 273 00:11:06,378 --> 00:11:07,813 THERE'S TOO MUCH OF IT CAN 274 00:11:07,813 --> 00:11:09,314 RESULT IN THE DEVELOPMENT OF 275 00:11:09,314 --> 00:11:10,515 LUPUS LIKE DISEASE IN A MOUSE 276 00:11:10,515 --> 00:11:13,385 MODEL AND SO THE EXAMPLE OF THIS 277 00:11:13,385 --> 00:11:14,920 MOUSE MODEL THAT I WANT TO SHARE 278 00:11:14,920 --> 00:11:18,423 WITH YOU IS THIS BXSB MICE WHERE 279 00:11:18,423 --> 00:11:21,059 A HUNDRED% OF THE MALE ANIMALS 280 00:11:21,059 --> 00:11:23,428 DEVELOP LUPUS LIKE DISEASE AND 281 00:11:23,428 --> 00:11:27,766 THESE ANIMALS HAVE ELEVATED 282 00:11:27,766 --> 00:11:29,167 PRODUCTION OF AUTOANTIBODIES, 283 00:11:29,167 --> 00:11:30,302 GLUE MARRIAL PATHOLOGY SIMILAR 284 00:11:30,302 --> 00:11:31,803 TO LUPUS PATIENTS AND ALSO VERY 285 00:11:31,803 --> 00:11:33,805 HIGH NUMBERS OF ACTIVATED 286 00:11:33,805 --> 00:11:34,039 B-CELLS. 287 00:11:34,039 --> 00:11:35,941 AND SO IT TURNS OUT THAT IN THIS 288 00:11:35,941 --> 00:11:38,577 MOUSE STRAIN, THERE WAS A 289 00:11:38,577 --> 00:11:39,644 TRANSLOCATION EVENT WHERE A 290 00:11:39,644 --> 00:11:42,414 REGION OF THE X-CHROMOSOME 291 00:11:42,414 --> 00:11:44,482 CONTAINING TLR 7 WAS 292 00:11:44,482 --> 00:11:45,851 TRANSLOCATED ON TO THE Y. 293 00:11:45,851 --> 00:11:47,719 SO IN THESE MALE MICE THEY HAVE 294 00:11:47,719 --> 00:11:51,156 DOUBLE THE EXPRESSION OF TLR 7 295 00:11:51,156 --> 00:11:53,859 THAT RESULTS IN THESE 296 00:11:53,859 --> 00:11:54,993 PATHOLOGIES. 297 00:11:54,993 --> 00:11:59,898 AND SO THEN 1 COULD ASK HOW IS 298 00:11:59,898 --> 00:12:00,799 THE X-CHROMOSOME REGULATED? 299 00:12:00,799 --> 00:12:02,667 SO IN THEORY IN MAMMALS HAVE 300 00:12:02,667 --> 00:12:04,636 THIS REALLY SPECIAL AND EXCITING 301 00:12:04,636 --> 00:12:07,105 WAY TO REGULATE EXPRESSION FROM 302 00:12:07,105 --> 00:12:08,306 THE X-CHROMOSOME CALLED 303 00:12:08,306 --> 00:12:08,940 X-CHROMOSOME AND ACTIVATION, SO 304 00:12:08,940 --> 00:12:11,243 IF YOU LOOK AT THE NUMBERS OF 305 00:12:11,243 --> 00:12:13,211 SEX CHROMOSOMES, BETWEEN THE 306 00:12:13,211 --> 00:12:16,047 SEXES THEY'RE DEFINITE SO 307 00:12:16,047 --> 00:12:17,883 FEMALES HAVE 2 Xs AND WOULD 308 00:12:17,883 --> 00:12:20,518 EXPRESS TWICE AS MANY COMPARED 309 00:12:20,518 --> 00:12:22,120 TO MALES SO WHAT THE MAMMALS 310 00:12:22,120 --> 00:12:25,056 HAVE DONE IS DEVELOP THIS 311 00:12:25,056 --> 00:12:27,025 MECHANISM WHERE 1 X CHOSEN AT 312 00:12:27,025 --> 00:12:28,026 RANDOM FOR TRANSCRIPTIONAL 313 00:12:28,026 --> 00:12:30,729 SILENCING AND THIS PROCESS 314 00:12:30,729 --> 00:12:31,796 HAPPENS EARLY DURING EMBRYONIC 315 00:12:31,796 --> 00:12:36,468 DEVELOP AM WHERE THE FUTURE 316 00:12:36,468 --> 00:12:37,869 INACTIVE X-CHROMOSOME REGULATES 317 00:12:37,869 --> 00:12:41,406 THIS NONCODING RNA CALLED XIST, 318 00:12:41,406 --> 00:12:42,707 AND XIST WILL REMAIN TETHERED 319 00:12:42,707 --> 00:12:45,210 FROM THE CHROMOSOME WHERE IT'S 320 00:12:45,210 --> 00:12:47,112 EXPRESSED AND RESULT IN 321 00:12:47,112 --> 00:12:49,047 TRANSCRIPTIONAL SILENCING, THIS 322 00:12:49,047 --> 00:12:50,782 INACTIVE X-CHROMOSOME ACQUIRES A 323 00:12:50,782 --> 00:12:53,418 NUMBER OF REPRESSIVE EPIGENETIC 324 00:12:53,418 --> 00:12:54,286 MODIFICATIONS THAT AID IN THE 325 00:12:54,286 --> 00:12:55,453 SILENCING AND SOME OF THESE 326 00:12:55,453 --> 00:12:58,890 MARKS CAN BE VISUALIZED AT THE 327 00:12:58,890 --> 00:13:01,826 SIGNIFY TO LOGICAL LEVEL, SO 328 00:13:01,826 --> 00:13:05,964 THIS IS XIST R NA INSITU 329 00:13:05,964 --> 00:13:08,133 HYBRIDIZATION IN FISH, AND THIS 330 00:13:08,133 --> 00:13:09,901 IS XIST CHROMOSOME WITH THE RNA 331 00:13:09,901 --> 00:13:11,336 ENCODING IT AND THIS IS THE SAME 332 00:13:11,336 --> 00:13:12,304 NUCLEUS GOING FROM LEFT TO RIGHT 333 00:13:12,304 --> 00:13:16,608 AND YOU CAN SEE THERE A H3 334 00:13:16,608 --> 00:13:21,546 KTRI-METHYLATION AND ALSO H2A 335 00:13:21,546 --> 00:13:22,714 UCIBOL WIDE JUMPSIN VENTILATION, 336 00:13:22,714 --> 00:13:24,282 SO ALL THESE WORK TO SILENCE THE 337 00:13:24,282 --> 00:13:27,052 X, HOWEVER, THERE ARE SOME GENES 338 00:13:27,052 --> 00:13:31,189 THAT ESCAPE SILENCING FROM THE 339 00:13:31,189 --> 00:13:33,124 INACTIVE X-CHROMOSOME INCLUDING 340 00:13:33,124 --> 00:13:34,192 RNA XIST ITSELF, AND THESE ARE 341 00:13:34,192 --> 00:13:35,260 ALL IMPORTANT TO WORK TOGETHER 342 00:13:35,260 --> 00:13:37,228 IN ORDER TO MAINTAIN DOSAGE 343 00:13:37,228 --> 00:13:38,496 COMPENSATION, SO IT WAS 344 00:13:38,496 --> 00:13:39,564 TRADITIONALLY THOUGHT THAT ONCE 345 00:13:39,564 --> 00:13:42,867 YOU FORM AN INACTIVE 346 00:13:42,867 --> 00:13:45,270 X-CHROMOSOME DURING DEVELOPMENT, 347 00:13:45,270 --> 00:13:45,904 IT'S MAINTAINED 348 00:13:45,904 --> 00:13:46,871 TRANSCRIPTIONALLY SILENT IN THE 349 00:13:46,871 --> 00:13:48,273 SAME WAY, NO MATTER WHAT TYPE OF 350 00:13:48,273 --> 00:13:49,341 CELL YOU'RE LOOKING AT WHETHER 351 00:13:49,341 --> 00:13:50,976 IT'S A MUSCLE CELL OR NEURON, 352 00:13:50,976 --> 00:13:54,479 HOWEVER, WORK FROM OUR LAB HAS 353 00:13:54,479 --> 00:13:58,116 FOUND THAT THE IMMUNE CELLS DO 354 00:13:58,116 --> 00:13:59,517 ACTIVATION VERY DIFFERENTLY AND 355 00:13:59,517 --> 00:14:01,486 SO IN B-CELLS RESTING NAIVE 356 00:14:01,486 --> 00:14:05,590 B-CELLS FROM BOTH THE MOUSE AND 357 00:14:05,590 --> 00:14:07,826 THE HUMAN LACK SIGNIFY TO 358 00:14:07,826 --> 00:14:10,195 LOGICAL MODIFICATION FROM THESE 359 00:14:10,195 --> 00:14:11,329 MODIFICATIONS ENCLOUDING XIST 360 00:14:11,329 --> 00:14:13,832 RNA, APPROXIMATE WHEN YOU 361 00:14:13,832 --> 00:14:14,666 STIMULATE THESE INVITRO, AND 362 00:14:14,666 --> 00:14:16,868 THESE COME BACK TO THE 363 00:14:16,868 --> 00:14:18,603 X-CHROMESOME AND WE ALSO FOUND 364 00:14:18,603 --> 00:14:20,338 THIS PROCESS IS INDEPENDENT OF 365 00:14:20,338 --> 00:14:21,973 TRANSCRIPTION OF THE XIST GENE, 366 00:14:21,973 --> 00:14:26,378 SO THE LOCALIZATION OF XIST, 367 00:14:26,378 --> 00:14:27,746 HAPPENS JUST GENETICALLY 368 00:14:27,746 --> 00:14:29,014 DISTINCTION FROM ITS 369 00:14:29,014 --> 00:14:30,749 TRANSCRIPTION EMPLOY AND O IN 370 00:14:30,749 --> 00:14:32,484 OUR LAB, WE'VE BEEN 371 00:14:32,484 --> 00:14:34,919 INVESTIGATING THE EPIGENETIC 372 00:14:34,919 --> 00:14:36,755 MECHANISMS OF X-INACTIVATION IN 373 00:14:36,755 --> 00:14:38,056 TYPES DIFFERENT TYPES OF IMMUNE 374 00:14:38,056 --> 00:14:39,858 CELLS IN THE HEALTHY STATE BUT 375 00:14:39,858 --> 00:14:41,059 WE'VE ALSO BEEN INVESTIGATING 376 00:14:41,059 --> 00:14:42,794 HOW THESE MECHANISMS ARE 377 00:14:42,794 --> 00:14:44,095 PERTURBED IN AUTOIMMUNE DISEASE 378 00:14:44,095 --> 00:14:46,331 SUCH AS LUPUS, SO WE'VE BEEN 379 00:14:46,331 --> 00:14:47,165 EXAMINING THE EPIGENETIC 380 00:14:47,165 --> 00:14:49,367 FEATURES OF THE INACTIVE 381 00:14:49,367 --> 00:14:51,770 X-CHROMOSOME IN BOTH ADULT AND 382 00:14:51,770 --> 00:14:52,937 PEDEIATE RICK LUPUS PATIENT 383 00:14:52,937 --> 00:14:55,473 LYMPHOCYTES AND WE MADE THE 384 00:14:55,473 --> 00:14:58,109 OBSERVATION THAT IN B-CELLS 385 00:14:58,109 --> 00:15:01,713 EXIST RNA, IS MISLOCALLIZED IN 386 00:15:01,713 --> 00:15:03,148 ACTIVATED B-CELLS IN LUPUS 387 00:15:03,148 --> 00:15:04,549 PATIENTS COMPARED TO ADULT, 388 00:15:04,549 --> 00:15:05,583 HEALTHY INDIVIDUALS AND THIS IS 389 00:15:05,583 --> 00:15:07,552 TRUE BOTH FOR ARK DULT PATIENTS 390 00:15:07,552 --> 00:15:10,555 AND ALSO FOR PEDIATRIC PATIENTS. 391 00:15:10,555 --> 00:15:12,824 AND WE'VE ALSO MADE THE 392 00:15:12,824 --> 00:15:14,993 OBSERVATION THAT CIRCULATING 393 00:15:14,993 --> 00:15:17,328 NAIVE B-CELLS AND ALSO IN VIVO 394 00:15:17,328 --> 00:15:20,165 ACTIVATED B-CELLS FROM LUPUS 395 00:15:20,165 --> 00:15:22,133 PATIENTS HAVE A BARREN 396 00:15:22,133 --> 00:15:23,601 EXPRESSION OF GENES SUGGESTING 397 00:15:23,601 --> 00:15:25,136 THAT THE MISLOCALLIZATION OF 398 00:15:25,136 --> 00:15:27,105 XIST RNA MIGHT BE AFFECTING GENE 399 00:15:27,105 --> 00:15:27,839 SILENCING AND ALSO GENE 400 00:15:27,839 --> 00:15:30,809 EXPRESSION FROM THE INACTIVE 401 00:15:30,809 --> 00:15:31,142 X-CHROMOSOME. 402 00:15:31,142 --> 00:15:33,711 AND SO WORK WITH MOUSE MODELS OF 403 00:15:33,711 --> 00:15:37,015 SPONTANEOUS LUPUS LIKE DISEASE, 404 00:15:37,015 --> 00:15:39,884 THE NTBW F1, WE'VE SEEN THESE 405 00:15:39,884 --> 00:15:41,953 FEMALE ANIMALS WITH LATE STAGES 406 00:15:41,953 --> 00:15:44,155 OF DISEASE ALSO EXHIBIT 407 00:15:44,155 --> 00:15:45,557 MISLOCALLIZATION OF XIST RNA 408 00:15:45,557 --> 00:15:47,659 FROM THE INACTIVE X-CHROMOSOME, 409 00:15:47,659 --> 00:15:50,095 AND SO TAKEN TOGETHER, WE'VE 410 00:15:50,095 --> 00:15:54,499 PROPOSED THIS HYPOTHESIS THAT 411 00:15:54,499 --> 00:15:56,367 PERHAPS IMPAIRED DYNAMIC 412 00:15:56,367 --> 00:15:58,770 X-INACTIVATION MAINTENANCE IN 413 00:15:58,770 --> 00:16:00,939 B-CELLS MIGHT CONTRIBUTE TO THE 414 00:16:00,939 --> 00:16:02,540 SUSCEPTIBILITY FOR INDIVIDUALS 415 00:16:02,540 --> 00:16:07,545 WITH 2 X-CHROMOSOMES TO DEVELOP 416 00:16:07,545 --> 00:16:15,220 AUTOIMMUNE IMMUNE DISEASES. 417 00:16:15,220 --> 00:16:16,721 SO WHEN THEY RETURN TO THE 418 00:16:16,721 --> 00:16:20,125 ACTIVE X TO MAINTAIN 419 00:16:20,125 --> 00:16:21,192 TRANSCRIPTIONAL SILENCING FOR 420 00:16:21,192 --> 00:16:22,460 THESE IMPORTANT IMMUNE 421 00:16:22,460 --> 00:16:25,163 REGULATORY GENES ON THE INACTIVE 422 00:16:25,163 --> 00:16:28,099 X-CHROMESOME, HOWEVER, IN THE 423 00:16:28,099 --> 00:16:31,136 CONTEXT OF LUPUS LIKE DISEASE 424 00:16:31,136 --> 00:16:32,470 AND FEMALE IMMUNITY DISEASES, 425 00:16:32,470 --> 00:16:35,140 THE TETHERS OF THE X-CHROMESOME 426 00:16:35,140 --> 00:16:37,675 IS COMPROMISED AND THERE'S ALSO 427 00:16:37,675 --> 00:16:39,144 ENRICHEDMENT OF THE 428 00:16:39,144 --> 00:16:40,145 MODIFICATIONS ALONG THE 429 00:16:40,145 --> 00:16:42,413 CHROMESOME, SO THE CHROMATIN OF 430 00:16:42,413 --> 00:16:45,750 THE INACTIVE X-CHANGES AND 431 00:16:45,750 --> 00:16:46,918 BECOMES PERMISSIVE FOR CERTAIN 432 00:16:46,918 --> 00:16:48,987 GENES TO BECOME REACTIVATED FROM 433 00:16:48,987 --> 00:16:50,255 THIS CHROMESOME RESULT NOTHING 434 00:16:50,255 --> 00:16:56,594 THE OBSERVATION THAT THERE'S 435 00:16:56,594 --> 00:16:59,063 INCREASED EXPRESSION OF SOME 436 00:16:59,063 --> 00:17:00,331 IMMUNE ACTIVATED GENES. 437 00:17:00,331 --> 00:17:02,133 SO ALL THESE OBSERVATIONS TODAY 438 00:17:02,133 --> 00:17:02,967 HAVE BEEN CORRELATIVE SO WE 439 00:17:02,967 --> 00:17:04,869 WANTED TO LOOK AT CAUSALITY AND 440 00:17:04,869 --> 00:17:05,837 MECHANISM, SO IN ORDER TO DO 441 00:17:05,837 --> 00:17:07,038 THIS WE WANTED TO TURN TO A 442 00:17:07,038 --> 00:17:10,408 MOUSE MODEL WHERE WE COULD 443 00:17:10,408 --> 00:17:13,111 IMPAIR OR DISRUPT X-INACTIVATION 444 00:17:13,111 --> 00:17:13,912 MAINTENANCE AND SO WHAT I WILL 445 00:17:13,912 --> 00:17:15,780 TELL YOU ABOUT TODAY IS THE WORK 446 00:17:15,780 --> 00:17:19,417 OF A VERY TALENTED MD-Ph.D. 447 00:17:19,417 --> 00:17:20,718 STUDENT CLAUDIA LEVEL WHO HAS 448 00:17:20,718 --> 00:17:22,787 BEEN WORKING ON THIS IN MY LAB 449 00:17:22,787 --> 00:17:25,290 AND THIS IS ALL UNPUSH PUBLISHED 450 00:17:25,290 --> 00:17:26,958 AND WE'RE EXCITED TO SHARE THIS 451 00:17:26,958 --> 00:17:28,026 WITH THE COMMUNITY BECAUSE WE 452 00:17:28,026 --> 00:17:29,794 THINK IT'S AN EXCITING NEW 453 00:17:29,794 --> 00:17:30,862 MECHANISM, THAT WILL COMPLEMENT 454 00:17:30,862 --> 00:17:31,796 THE OTHER MECHANISMS THAT WE'RE 455 00:17:31,796 --> 00:17:34,999 GOING TO HEAR ABOUT FROM DIANEA 456 00:17:34,999 --> 00:17:37,969 AND BRENDAN IN THE LATER PART OF 457 00:17:37,969 --> 00:17:39,604 THE SEMINAR. 458 00:17:39,604 --> 00:17:41,573 SO X-INACTIVATION TAKES PLACE IN 459 00:17:41,573 --> 00:17:44,075 THE MOUSE, DURING THE 460 00:17:44,075 --> 00:17:44,876 PREIMPLANTATION STAGE EMBRYO 461 00:17:44,876 --> 00:17:47,445 WHERE 1 X IS RANDOMLY CHOSEN FOR 462 00:17:47,445 --> 00:17:48,413 TRANSCRIPTIONAL SILENCING AND SO 463 00:17:48,413 --> 00:17:52,150 IN ORDER TO MAKE A B-CELL 464 00:17:52,150 --> 00:17:56,287 SPECIFIC EXIST DELETION, WE 465 00:17:56,287 --> 00:17:58,122 MATED XIST 2-LOCK ANIMALS THAT 466 00:17:58,122 --> 00:18:00,325 EXPRESS THE N1 CREE RECOMBIN 467 00:18:00,325 --> 00:18:02,560 ACE, SO THIS,A LOWS FOR 468 00:18:02,560 --> 00:18:03,628 EXPRESSION, SPECIFICALLY DURING 469 00:18:03,628 --> 00:18:05,263 B-CELL DEVELOPMENT STARTING AT 470 00:18:05,263 --> 00:18:08,166 THE PRO B-CELL STAGE, SO WE 471 00:18:08,166 --> 00:18:10,768 GENERATED THROUGH VARIOUS 472 00:18:10,768 --> 00:18:11,803 INTERPROCESSES, HOMOWRIGGOUS 473 00:18:11,803 --> 00:18:14,138 EXIST ANIMALS WHERE EXIST IS 474 00:18:14,138 --> 00:18:15,873 DELETED ON BOTH X-CHROMOSOMES, 475 00:18:15,873 --> 00:18:18,543 AND NEXT WE VERIFIED THAT EXIST 476 00:18:18,543 --> 00:18:21,546 WAS DELETED AND HOMOZYGOUS KNOWN 477 00:18:21,546 --> 00:18:23,881 ANIMALS USING QPC R AND WE ALSO 478 00:18:23,881 --> 00:18:25,883 PERFORM SEQUENTIAL EXIST RNA 479 00:18:25,883 --> 00:18:27,151 FISH FOLLOWED BY IMMUNO 480 00:18:27,151 --> 00:18:29,520 FLUORESCENCE TO LOOK AT 1 481 00:18:29,520 --> 00:18:30,321 HETEROGENEOUS ORY CHROMEATIC 482 00:18:30,321 --> 00:18:36,060 MARK ENRICHED ON THE INACTIVE 483 00:18:36,060 --> 00:18:40,331 X-CHROMOSOME, H2 KA19 UBIQUITIN, 484 00:18:40,331 --> 00:18:43,968 YOU SEE THIS RNA XIST CLOUD THAT 485 00:18:43,968 --> 00:18:46,537 FOCUSED WITH THE H2 K119. 486 00:18:46,537 --> 00:18:47,705 AND THEN HOMOZYGOUS EXIST 487 00:18:47,705 --> 00:18:49,774 DELETED MICE DO NOTEE IT IN 488 00:18:49,774 --> 00:18:52,443 EXIST CLOUD AND ALSO SEE THERE'S 489 00:18:52,443 --> 00:18:55,880 NO FOCUS FOR FHKAUBIQUITIN, THE 490 00:18:55,880 --> 00:18:56,948 NOWLET DELETION OF EXIST HAS 491 00:18:56,948 --> 00:18:58,483 BEEN DONE BY OTHER BROWPS AND 492 00:18:58,483 --> 00:19:01,219 THE DELETION CAN RESULT IN A 493 00:19:01,219 --> 00:19:02,220 RANGE OF DIFFERENT PHENOTYPES 494 00:19:02,220 --> 00:19:03,755 THAT DEPEND ON WHERE AND WHEN 495 00:19:03,755 --> 00:19:06,190 THE DELETION HAS TAKEN PLACE. 496 00:19:06,190 --> 00:19:08,159 SO FOR EXAMPLE, IF YOU DELETE 497 00:19:08,159 --> 00:19:11,529 EXIST, USING A GENERAL DELETER, 498 00:19:11,529 --> 00:19:14,098 FEMALE ANIMALS, EMBRYOS DO NOT 499 00:19:14,098 --> 00:19:15,733 SURVIVE, IT'S EMBRYONIC LETHAL. 500 00:19:15,733 --> 00:19:18,469 AND WHEN XIST IS DELETED IT CAN 501 00:19:18,469 --> 00:19:19,304 IMPACT GENE EXPRESSION 502 00:19:19,304 --> 00:19:22,073 SPECIFICALLY FROM THE INACTIVE 503 00:19:22,073 --> 00:19:23,675 X-CHROMESOME RESULT NOTHING 504 00:19:23,675 --> 00:19:25,743 PARTIAL REACTIVATION OF THIS 505 00:19:25,743 --> 00:19:26,544 CHROMESOME. 506 00:19:26,544 --> 00:19:28,346 HOWEVER, THE NUMBER OF X-LINKED 507 00:19:28,346 --> 00:19:32,050 YEENS AND ALSO THE IDENTITY OF 508 00:19:32,050 --> 00:19:34,752 THESE X-LINKED YEEN SYSTEM CELL 509 00:19:34,752 --> 00:19:36,888 TYPE SPECIFIC DEPENDING ON WHERE 510 00:19:36,888 --> 00:19:38,189 YOUR DELETING HAPPENS, SO 511 00:19:38,189 --> 00:19:40,258 THERE'S A PHENOTYPE THAT RESULTS 512 00:19:40,258 --> 00:19:41,225 FROM THIS DELETION, SO FOR 513 00:19:41,225 --> 00:19:42,527 EXAMPLE, IF YOU DELETE EXIST IN 514 00:19:42,527 --> 00:19:45,630 THE SKIN WITH A KERATIN ARE 14 515 00:19:45,630 --> 00:19:48,266 CREE, THE ANIMALS ARE FINE AND 516 00:19:48,266 --> 00:19:49,934 THERE'S NO NOTABLE PHENOTYPE, IF 517 00:19:49,934 --> 00:19:53,438 YOU DELETE IT IN THE GUT, 518 00:19:53,438 --> 00:19:55,840 THERE'S NO STEADY STATE, HOWEVER 519 00:19:55,840 --> 00:19:57,208 IF YOU INDUCE POLARIZED UP FORM 520 00:19:57,208 --> 00:19:59,077 EGG IN THESE ANIMALS YOU SEE 521 00:19:59,077 --> 00:20:00,945 THERE'S MORE SEVERE DISEASE WHEN 522 00:20:00,945 --> 00:20:04,849 XIST IS DELETED AND THEN FINALLY 523 00:20:04,849 --> 00:20:07,051 DELETION IN HEMATOPOIETIC STEM 524 00:20:07,051 --> 00:20:09,754 CELLS USING A BABCREE, RESULTS 525 00:20:09,754 --> 00:20:11,055 IN FEMALE SPECIFIC BLOOD CANCER 526 00:20:11,055 --> 00:20:13,358 WHERE THERE'S A HUGE EXPANSION 527 00:20:13,358 --> 00:20:14,959 OF THE MYELOID COMPARTMENT AND 528 00:20:14,959 --> 00:20:18,930 THE FEMALE MICE DEVELOP A 529 00:20:18,930 --> 00:20:20,998 MYELOID DRIVEN CANCER 530 00:20:20,998 --> 00:20:21,299 PHENOTYPES. 531 00:20:21,299 --> 00:20:23,201 OKAY, SO WHAT DID WE FIND? 532 00:20:23,201 --> 00:20:25,336 SO WHEN WE DELETE EXIST IN THE 533 00:20:25,336 --> 00:20:28,573 B-CELL COMPART AM, THE FEMALE 534 00:20:28,573 --> 00:20:31,843 HOMOZYGOUS ANIMALS EXHIBIT 535 00:20:31,843 --> 00:20:33,244 EQUIVALENT VIABILITY, SAME LIFE 536 00:20:33,244 --> 00:20:34,579 SPAN AS WILD-TYPE LITTER MATES, 537 00:20:34,579 --> 00:20:35,980 WE SEE THERE'S NORMAL B-CELL 538 00:20:35,980 --> 00:20:38,049 DEVELOPMENT IN THE BONE MARROW, 539 00:20:38,049 --> 00:20:41,152 AND SO, NEXT WE LOOKED IN THE 540 00:20:41,152 --> 00:20:45,556 SPLEEN AND WE SEE THAT FEMALE 541 00:20:45,556 --> 00:20:47,458 EXISTS AND THE FEMALE 6 MONTHS 542 00:20:47,458 --> 00:20:48,726 OF AGE, THE TOTAL NUMBER IN THE 543 00:20:48,726 --> 00:20:50,161 SPLEEN IS NOT AFFECTED, HOWEVER 544 00:20:50,161 --> 00:20:53,498 IF YOU LOOK CAREFULLY ACROSS 545 00:20:53,498 --> 00:20:57,335 B-CELL SUBSETS WE SUE --SEE THEE 546 00:20:57,335 --> 00:20:59,804 ARE SOME ELEVATIONS WITH THE 547 00:20:59,804 --> 00:21:03,241 ACTIVATED GL7 POSITIVE, B-CELLS 548 00:21:03,241 --> 00:21:05,209 WHERE XIST KNOCKOUT MICE ARE 549 00:21:05,209 --> 00:21:05,810 SLIGHTLY HIGHER, SIGNIFICANT, 550 00:21:05,810 --> 00:21:09,046 MORE OF THESE ACTIVATED B-CELLS, 551 00:21:09,046 --> 00:21:11,015 THEY ALSO HAVE MORE SHORT LIVED 552 00:21:11,015 --> 00:21:13,751 PLASMA CELLS AND ALSO MORE CLASS 553 00:21:13,751 --> 00:21:14,886 SWITCH B-CELLS. 554 00:21:14,886 --> 00:21:16,621 NOW, BECAUSE THE EXIST KNOCKOUT 555 00:21:16,621 --> 00:21:19,424 MICE HAD MORE ACTIVATED B-CELLS, 556 00:21:19,424 --> 00:21:23,528 WE MONITORED THE FEMALE MICE, 557 00:21:23,528 --> 00:21:25,797 FOR AUTOANTIBODIES SPECIFIC TO 558 00:21:25,797 --> 00:21:28,800 DOUBLE STRANDED DNA, SO DSDNA, 559 00:21:28,800 --> 00:21:32,203 AND AS A POSITIVE CONTROL WE USE 560 00:21:32,203 --> 00:21:36,774 SERUM 42 FEMALE FDBW MICE WHICH 561 00:21:36,774 --> 00:21:37,542 SPONTANEOUSLY DEVELOP LUPUS LIKE 562 00:21:37,542 --> 00:21:38,409 DISEASE AND THE POSITIVE ARE 563 00:21:38,409 --> 00:21:39,844 SHOWN HERE IN YELLOW AND WE SEE 564 00:21:39,844 --> 00:21:41,712 FOR A RANGE OF AGES OF FEMALE 565 00:21:41,712 --> 00:21:43,147 MICE BETWEEN 6 WEEKS OF AGE AND 566 00:21:43,147 --> 00:21:46,517 12 MONTHS OF AGE, THE MAIORITY 567 00:21:46,517 --> 00:21:48,019 OF XIST HOMOZYGOUS NULL MICE DO 568 00:21:48,019 --> 00:21:52,690 NOT DEVELOP ELEVATED LEVELS OF D 569 00:21:52,690 --> 00:21:52,924 SDNA. 570 00:21:52,924 --> 00:21:57,061 HOWEVER, WHEN WE LOOK AT ANIMALS 571 00:21:57,061 --> 00:21:58,429 BOTH WILD-TYPE AND XIST XOK OUT 572 00:21:58,429 --> 00:21:59,864 MICE THAT WERE 12 MONTHS OF AGE 573 00:21:59,864 --> 00:22:01,599 OR OLDER, WE SEE THERE WERE SOME 574 00:22:01,599 --> 00:22:04,502 MICE THAT DEVELOPED VERY HIGH 575 00:22:04,502 --> 00:22:06,237 LEVELS OF ANTIDSDNA IN THEIR 576 00:22:06,237 --> 00:22:08,673 SERUM, SO WE FOCUSED OUR 577 00:22:08,673 --> 00:22:11,042 ANALYSIS ON AGE MATCHED 578 00:22:11,042 --> 00:22:13,444 WILD-TYPE AND ALSO EXIST 579 00:22:13,444 --> 00:22:15,880 HOMOZYGOUS NULL DELETED FEMALE 580 00:22:15,880 --> 00:22:17,482 MICE AND DISTINGUISHED BETWEEN 581 00:22:17,482 --> 00:22:19,217 XIST KNOCK OUT ANIMALS THAT HAD 582 00:22:19,217 --> 00:22:24,856 EITHER LOW LEVELS OF ANTIDSDNA 583 00:22:24,856 --> 00:22:25,656 AUTOANTIBODIES OR ANIMALS THAT 584 00:22:25,656 --> 00:22:34,165 HAVE HIGH LEVELS OF DSD NA 585 00:22:34,165 --> 00:22:34,565 AUTOANTIBODIES. 586 00:22:34,565 --> 00:22:36,767 HAVE SIGNIFICANTLY MORE NUMBERS 587 00:22:36,767 --> 00:22:38,069 OF DSDNA SECRETING CELLS 588 00:22:38,069 --> 00:22:40,638 COMPARED TO WILD-TYPE CELLS ALSO 589 00:22:40,638 --> 00:22:43,641 EXIST KNOCK OUT LOW MICE, SO 590 00:22:43,641 --> 00:22:45,576 THESE ARE LA-SPOT EXPERIMENTS 591 00:22:45,576 --> 00:22:47,211 WHERE WE QUANTIFIED THE NUMBER 592 00:22:47,211 --> 00:22:49,580 OF POSITIVE CELLS IN THE PLEEN O 593 00:22:49,580 --> 00:22:53,351 SIGHTS THAT WERE RESPONSIBLE FOR 594 00:22:53,351 --> 00:22:54,752 PRODUCING THE DSD NA 595 00:22:54,752 --> 00:22:55,119 AUTOANTIBODIES. 596 00:22:55,119 --> 00:22:57,788 SO NEXT WE WANTED TO ASK WHAT 597 00:22:57,788 --> 00:22:58,356 OTHER AUTOANTIBODIES WERE 598 00:22:58,356 --> 00:22:59,557 PRESENT IN THE SERUM OF THE 599 00:22:59,557 --> 00:23:01,959 KNOCK OUT HIGH AND LOW MICE AND 600 00:23:01,959 --> 00:23:04,262 WE USED AN AUTOANTIBODY 601 00:23:04,262 --> 00:23:06,898 MICROARRAY TO PROFILE ACROSS 120 602 00:23:06,898 --> 00:23:08,266 DIFFERENT AUTOANTIIENS AND WE 603 00:23:08,266 --> 00:23:09,634 FOUND THERE ARE 16 DIFFERENT 604 00:23:09,634 --> 00:23:10,835 AUTOANTIGENS THAT ARE ELEVATED 605 00:23:10,835 --> 00:23:14,372 IN THE SERUM FROM EXIST KNOCKOUT 606 00:23:14,372 --> 00:23:18,609 MICE, HIGH KNOCKOUT MICE, 607 00:23:18,609 --> 00:23:19,744 COMPARED TO LOW KNOCKOUT MICE 608 00:23:19,744 --> 00:23:22,446 AND AS EXPECTED WE SEE THAT 609 00:23:22,446 --> 00:23:25,616 ANTIDNA IS ELEVATED ALONG WITH 610 00:23:25,616 --> 00:23:26,684 ANTISMITH COMPLEX, R& P 611 00:23:26,684 --> 00:23:28,219 PROTEINS WHICH ARE ALSO KNOWN TO 612 00:23:28,219 --> 00:23:32,123 BE ELEVATED IN SLE PATIENTS, WE 613 00:23:32,123 --> 00:23:34,191 ALSO OBSERVED THERE'S OTHER 614 00:23:34,191 --> 00:23:35,293 AUTOANTIGEN THAT ARE STRONGLY 615 00:23:35,293 --> 00:23:37,695 ASSOCIATE WIDE OTHER FEMALE BIAS 616 00:23:37,695 --> 00:23:40,364 AUTOIMMUNE DECEASES SUCH AS MDA 617 00:23:40,364 --> 00:23:42,633 5 AND ALSO ANTIRO. 618 00:23:42,633 --> 00:23:46,837 SO NEXT WE EXAMINED KIDNEYS FROM 619 00:23:46,837 --> 00:23:48,372 XIST KNOCK OUT LOW AND HIGH MICE 620 00:23:48,372 --> 00:23:49,774 TO LOOK FOR EVIDENT OF 621 00:23:49,774 --> 00:23:50,374 PATHOLOGY. 622 00:23:50,374 --> 00:23:52,443 SO WE SUBMITTED THE KIDNEY 623 00:23:52,443 --> 00:23:53,511 SECTIONS FOR PLIENDED 624 00:23:53,511 --> 00:23:58,049 PATHOLOGICAL ASSESSMENT BY THE 625 00:23:58,049 --> 00:23:59,183 PENN VETS COMPARATIVE PATHOLOGY 626 00:23:59,183 --> 00:23:59,550 CORE. 627 00:23:59,550 --> 00:24:01,786 AND OUR PATHOLOGY HALEY FOUND 628 00:24:01,786 --> 00:24:03,554 THAT XIST KNOCK OUT HIGH MICE 629 00:24:03,554 --> 00:24:05,890 HAD HIGHER PATHOLOGY SCORES 630 00:24:05,890 --> 00:24:07,158 COMPARED TO THE XIST KNOCK OUT 631 00:24:07,158 --> 00:24:08,893 LOW MICE AND THIS IS AN EXAMPLE 632 00:24:08,893 --> 00:24:13,164 OF A KIDNEY SECTION RIGHT HERE 633 00:24:13,164 --> 00:24:19,136 SO THIS IS THAT STAINING AT 20 X 634 00:24:19,136 --> 00:24:22,340 RESOLUTION, AND WE ARE SHOWING 3 635 00:24:22,340 --> 00:24:25,743 GLOMULAR MARRIAL EYE I, AND WE 636 00:24:25,743 --> 00:24:28,479 HAVE 3 EPITHELIUM AND ALSO 2 637 00:24:28,479 --> 00:24:33,918 GLOMULAR MERUE LIE THAT ARE 638 00:24:33,918 --> 00:24:37,021 HYPER TROPHIC, THERE'S ALSO MY O 639 00:24:37,021 --> 00:24:38,522 STIRTIAL INFLAMMATION, AND ALSO 640 00:24:38,522 --> 00:24:40,191 EVIDENCE OF TUBEULAR EPITHELIAL 641 00:24:40,191 --> 00:24:42,760 DEGENERATION AND ALSO LOSS WITH 642 00:24:42,760 --> 00:24:43,694 INTERTUBEULAR CAST SHOWN HERE. 643 00:24:43,694 --> 00:24:47,765 SO NEXT WE WANTED TO SHOW WELL 644 00:24:47,765 --> 00:24:50,267 WELL ARE THERE CHANGES TO THE 645 00:24:50,267 --> 00:24:51,936 B-CELL SUBSET IN THE KNOCKOUT 646 00:24:51,936 --> 00:24:53,671 MICE, SO WE ISOLATED SPLEANS AND 647 00:24:53,671 --> 00:24:56,007 BONE MARROW TO DO FLOW CYTOMETRY 648 00:24:56,007 --> 00:24:57,174 AND SO TODAY BECAUSE OF TIME, 649 00:24:57,174 --> 00:24:59,143 I'M JUST GOING TO SHOW YOU THE 650 00:24:59,143 --> 00:25:00,678 RESULTS FROM SPLEN AND TISSUE, 651 00:25:00,678 --> 00:25:02,279 SO WHAT WE FOUND WAS THAT EXIST 652 00:25:02,279 --> 00:25:04,849 KNOCK OUT HIGH MICE, SHOWN HERE 653 00:25:04,849 --> 00:25:09,654 IN THE PURPLE BARS HAVE MORE 654 00:25:09,654 --> 00:25:12,123 SPLEEN X CD11 C AGE ASSOCIATED 655 00:25:12,123 --> 00:25:12,957 B-CELLS BOTH IN FREQUENCY AND 656 00:25:12,957 --> 00:25:16,360 ALSO IN TOTAL NUMBERS. 657 00:25:16,360 --> 00:25:18,796 XIST KNOCK OUT HIGH MICE HAVE 658 00:25:18,796 --> 00:25:20,598 MORE GH7 POSITIVE ACTIVATED 659 00:25:20,598 --> 00:25:22,066 B-CELLS BOG IN FREQUENCY AND 660 00:25:22,066 --> 00:25:25,770 ALSO TOTAL CELL NUMBER. 661 00:25:25,770 --> 00:25:27,304 EXIST KNOCK OUT HIGH MICE ALSO 662 00:25:27,304 --> 00:25:29,407 HAVE SHORT LIVED PLASMA CELLS, 663 00:25:29,407 --> 00:25:31,475 THEY ALSO HAVE HIGHER NUMBERS OF 664 00:25:31,475 --> 00:25:34,478 LONG LIVED PLASMA CELLS, AND 665 00:25:34,478 --> 00:25:37,214 ALSO HIGHER NUMBERS OF CLASS 666 00:25:37,214 --> 00:25:38,749 SWITCHED B-CELLS. 667 00:25:38,749 --> 00:25:44,288 SO, NEXT WE WANTED TO ASK--SO 668 00:25:44,288 --> 00:25:48,392 TAKEN TOGETHER, THE XIST 669 00:25:48,392 --> 00:25:51,662 HOMOZYGOUS B-CELL MICE HAVE MORE 670 00:25:51,662 --> 00:25:52,263 ACTIVATED B-CELLS, SIMILAR TO 671 00:25:52,263 --> 00:25:53,064 THE WILL YOU PLEASEUS PATIENT 672 00:25:53,064 --> 00:25:54,532 ANDS WE WANTED TO ASK HOW IS 673 00:25:54,532 --> 00:25:55,433 GENE EXPRESSION AFFAIRS TEAM 674 00:25:55,433 --> 00:25:56,734 LEADERRERRED IN THESE B-CELL 675 00:25:56,734 --> 00:25:58,436 SUBSETS SO BECAUSE OF TIME I 676 00:25:58,436 --> 00:26:00,705 WILL JUST SHOW YOU THE RNA 677 00:26:00,705 --> 00:26:02,406 SEQUENCING RESULTS FROM 1 SUBSET 678 00:26:02,406 --> 00:26:04,241 THAT EXPANDS AND THE XIST KNOCK 679 00:26:04,241 --> 00:26:07,144 OUT HIGH MICE AND THESE ARE THE 680 00:26:07,144 --> 00:26:08,479 CD11 AND B-ASSOCIATED C-CELLS 681 00:26:08,479 --> 00:26:11,916 AND LOOKING SPECIFICALLY AT THE 682 00:26:11,916 --> 00:26:13,884 X-CHROMESOME WE FOUND THERE ARE 683 00:26:13,884 --> 00:26:18,422 10 X-LINKED GENES THAT ARE 684 00:26:18,422 --> 00:26:19,557 ABERRANTLY UPREGULATED IN THE 685 00:26:19,557 --> 00:26:21,826 MICE, SO 1 THAT CAUGHT OUR 686 00:26:21,826 --> 00:26:23,761 INTEREST IS TASL, IT'S THE 687 00:26:23,761 --> 00:26:26,997 ADAPTER PROTEIN THAT REGULATING 688 00:26:26,997 --> 00:26:30,434 ACTIVATION OF IRF 5 DOWN STREAM 689 00:26:30,434 --> 00:26:32,436 OF TLR8, 7 AND 9 SIGNALING WHICH 690 00:26:32,436 --> 00:26:34,739 RESULTS IN THE PRODUCTION OF 691 00:26:34,739 --> 00:26:36,006 TYPE 1 INTERFERONS CROSS LINKING 692 00:26:36,006 --> 00:26:37,975 SO IT'S KNOWN THAT STIMULATION 693 00:26:37,975 --> 00:26:39,443 OF SIGNALING PATHWAY IS INVOLVED 694 00:26:39,443 --> 00:26:42,213 IN THE PATHOGENESIS OF SLE, O 695 00:26:42,213 --> 00:26:45,549 LOOKING AT AUTOSOMAL GENES WE 696 00:26:45,549 --> 00:26:47,318 OBSERVE XIST KNOCK OUT HIGH MICE 697 00:26:47,318 --> 00:26:48,853 HAVE KNOCKED OUT DIFFERENT 698 00:26:48,853 --> 00:26:49,687 EXPRESSIONS OF AUTOSOMAL GENES 699 00:26:49,687 --> 00:26:50,888 SO THEN TO SUMMARIZE WHAT WE 700 00:26:50,888 --> 00:26:54,125 FOUND IS THAT A B-CELL SPECIFIC 701 00:26:54,125 --> 00:26:57,828 XIST DELETION IN BALB C-MICE CAN 702 00:26:57,828 --> 00:26:59,096 RESULT IN SPONTANEOUS LUPUS LIKE 703 00:26:59,096 --> 00:27:01,098 DEC IN SOME ANIMALS SO ANIMALS 704 00:27:01,098 --> 00:27:04,568 OVER 12 MONTHS OF AGE HAVE 705 00:27:04,568 --> 00:27:06,270 ELEVATED AUTOANTIBODY 706 00:27:06,270 --> 00:27:07,471 PRODUCTION, INCREED GLOMULAR 707 00:27:07,471 --> 00:27:09,173 MARRIAL PATHOLOGY AND ALSO 708 00:27:09,173 --> 00:27:11,609 INCREASED NUMBERS OF ACTIVATED 709 00:27:11,609 --> 00:27:13,344 B-CELLS AND MEMORY ACTIVATED 710 00:27:13,344 --> 00:27:13,577 B-CELLS. 711 00:27:13,577 --> 00:27:17,681 SO NEXT WE WANT TO ASK, WELL 712 00:27:17,681 --> 00:27:19,316 DELETION EXIST IMPACT FEMALE 713 00:27:19,316 --> 00:27:21,152 MICE AND INDUCE MODEL OF LUPUS 714 00:27:21,152 --> 00:27:22,753 LIKE DISEASE, SO BECAUSE THE 715 00:27:22,753 --> 00:27:25,756 DISEASE PEN TRAPTS FOR THE XIST 716 00:27:25,756 --> 00:27:27,391 KNOCKOUT MICE IS LOW YET SIMILAR 717 00:27:27,391 --> 00:27:28,726 TO LUPUS PATIENTS WE WANT TO 718 00:27:28,726 --> 00:27:29,994 LOOK AT MECHANISMS OF DISEASE 719 00:27:29,994 --> 00:27:32,496 DEVELOPMENT SO WE TURN TO THIS 720 00:27:32,496 --> 00:27:36,300 MODEL OF USING PRIVATEAIN, SO 721 00:27:36,300 --> 00:27:44,008 PRIOF THEAIN INJECTIONS IS 722 00:27:44,008 --> 00:27:46,644 ELEVATED LEVELS OF ANTIDSDNA 723 00:27:46,644 --> 00:27:48,012 AUTOANTIBODIES AND ALSO 724 00:27:48,012 --> 00:27:50,281 INCREASED PRODUCTION OF 725 00:27:50,281 --> 00:27:53,951 ACTIVATED B-CELLS AND GLUE 726 00:27:53,951 --> 00:27:55,252 MERULAR NEPHRITIS, THIS SHARES 727 00:27:55,252 --> 00:27:57,121 SOME FEATURES BUT NOT ALL 728 00:27:57,121 --> 00:27:58,088 FEATURES WITH LUPUS PATIENTS SO 729 00:27:58,088 --> 00:28:00,391 WE WANT TO ASK THE QUESTION, HOW 730 00:28:00,391 --> 00:28:01,892 DID THIS DELETION AFFECT THIS 731 00:28:01,892 --> 00:28:03,761 PROCESS, SO FOR THESE 732 00:28:03,761 --> 00:28:05,162 EXPERIMENTS, WE INJECTED VARIOUS 733 00:28:05,162 --> 00:28:07,565 COHORTS OF FEMALE MICE, BOTH 734 00:28:07,565 --> 00:28:09,266 WILD-TYPE AND EXIST KNOCK OUT, 735 00:28:09,266 --> 00:28:12,670 WITH 1 TIME INJECTION OF PRIOF 736 00:28:12,670 --> 00:28:15,206 THEAIN AND THEN WE MONITOR THE 737 00:28:15,206 --> 00:28:16,473 ANIMALS FOR DEVELOPMENT OVER 738 00:28:16,473 --> 00:28:19,443 TIME BY COLLECTING BLOOD AND 739 00:28:19,443 --> 00:28:22,947 URINE, AND AT 3 DIFFERENT TIME 740 00:28:22,947 --> 00:28:23,914 POINTS WE HARVESTED THE KIDNEYS 741 00:28:23,914 --> 00:28:26,016 AND THE BLOOD FROM THE ANIMALS 742 00:28:26,016 --> 00:28:28,085 TO EXAMINE CHANGES WITH THE 743 00:28:28,085 --> 00:28:29,420 B-CELL SUBSETS. 744 00:28:29,420 --> 00:28:32,022 AND SO, FIRST WE LOOKED AT 745 00:28:32,022 --> 00:28:34,191 SERUM, FOR AUTOANTIBODY 746 00:28:34,191 --> 00:28:36,760 PRODUCTION AND AS EXPECTED WE 747 00:28:36,760 --> 00:28:38,863 SEE THAT PRISTANE TREATED 748 00:28:38,863 --> 00:28:41,065 WILD-TYPE ANIMALS PRODUCED MORE 749 00:28:41,065 --> 00:28:43,367 ANTIDSDNA AUTOEABT BODIES OVER 7 750 00:28:43,367 --> 00:28:46,136 MONTHS OF TIME WHEREAS 751 00:28:46,136 --> 00:28:48,372 NONTREATED WILD-TYPE ANIMALS 752 00:28:48,372 --> 00:28:50,207 LACK DETECTION OF ANTIDSDNA. 753 00:28:50,207 --> 00:28:52,376 AND WHAT WE OBSERVED WAS THAT 754 00:28:52,376 --> 00:28:55,079 EXIST KNOCKOUT MICE THAT WERE 755 00:28:55,079 --> 00:28:57,147 TREATED WITH PRISTANE PRODUCED 756 00:28:57,147 --> 00:29:00,050 HIGHER LEVELS OF DSDNA AUTOEABT 757 00:29:00,050 --> 00:29:03,087 BODIES COMPARED TO THE WILD-TYPE 758 00:29:03,087 --> 00:29:04,221 PRISTANE TREATED MICE. 759 00:29:04,221 --> 00:29:07,157 SO NEXT WE EXAMINED THE LEVELS 760 00:29:07,157 --> 00:29:09,760 OF B-CELL SUBSETS OVER TIME AND 761 00:29:09,760 --> 00:29:14,265 WE FOUND THAT PRISTANE TREATED 762 00:29:14,265 --> 00:29:15,699 XIST KNOCKOUT MICE DEVELOPED 763 00:29:15,699 --> 00:29:17,568 MORE AGE ASSOCIATED B-CELLS AT 9 764 00:29:17,568 --> 00:29:19,870 MONTHS OF AGE SHOWN HERE IN THE 765 00:29:19,870 --> 00:29:21,372 BINK BARS AND THEN LOOKING 766 00:29:21,372 --> 00:29:22,873 SPECIFICALLY AT SHORT LIVED 767 00:29:22,873 --> 00:29:27,077 PLASMA CELLS WE SEE THAT EXIST 768 00:29:27,077 --> 00:29:29,446 KNOCKOUT MICE TREATED WITH 769 00:29:29,446 --> 00:29:30,881 PRISTANE AND THESE LEVELS AT 7 770 00:29:30,881 --> 00:29:35,386 MONTH ANDS 9 MONTHS POST 771 00:29:35,386 --> 00:29:36,186 INJECTION. 772 00:29:36,186 --> 00:29:37,554 PRISTANE TREATED XIST KNOCKOUT 773 00:29:37,554 --> 00:29:41,825 MICE HAD HIGHER TOTAL NUMBERS OF 774 00:29:41,825 --> 00:29:44,361 GL7 POSITIVE ACTIVATED B-CELLS 775 00:29:44,361 --> 00:29:47,031 BOTH AT 7-MONTHS AND 9 MONTHS 776 00:29:47,031 --> 00:29:49,366 POST INJECTION. 777 00:29:49,366 --> 00:29:52,002 AND WE ALSO DETECTED INCREASED 778 00:29:52,002 --> 00:29:54,104 NUMBERS OF CLASS SWITCH B-CELLS 779 00:29:54,104 --> 00:29:56,073 FOR EXIST KNOCKOUT MICE THAT 780 00:29:56,073 --> 00:29:57,574 WERE TREATED WITH PRISTANE. 781 00:29:57,574 --> 00:29:59,677 SO TAKEN TOGETHER, PRISTANE 782 00:29:59,677 --> 00:30:01,946 INDUCED DEC REVEALS THAT XIST 783 00:30:01,946 --> 00:30:03,714 DELETION CAN IMPACT B-CELL 784 00:30:03,714 --> 00:30:04,882 NUMBERS AND INCREASE B-CELLS 785 00:30:04,882 --> 00:30:09,620 THAT ARE ACTIVATED AND ALSO THE 786 00:30:09,620 --> 00:30:11,221 B-CELLS THAT ARE RESPONSIBLE FOR 787 00:30:11,221 --> 00:30:11,722 PRODUCING ANTIBODIES. 788 00:30:11,722 --> 00:30:13,891 SO NEXT WE ASKED WHAT X-LINKED 789 00:30:13,891 --> 00:30:15,259 GENES ARE AFFAIRS TEAM 790 00:30:15,259 --> 00:30:17,227 LEADERRERRED IN B-CELLS IN THE 791 00:30:17,227 --> 00:30:18,963 CONTEXT OF PRISTANE INDUCED 792 00:30:18,963 --> 00:30:21,165 DISEASE AND AND I WILL SHOW YOU 793 00:30:21,165 --> 00:30:24,668 THE DATA FOR 2 B-CELL SUBSETS, 794 00:30:24,668 --> 00:30:29,039 ABC CELLS OR ABCS AND ALSO GL7 + 795 00:30:29,039 --> 00:30:30,341 ACTIVATED B-CELLS, SO WOOK 796 00:30:30,341 --> 00:30:32,076 LOOKING AT THE CHROMESOME, WE 797 00:30:32,076 --> 00:30:34,311 SEE THERE ARE 10 X-LINKED GENES 798 00:30:34,311 --> 00:30:36,580 THAT ARE UPREGULATED AND KNOCK 799 00:30:36,580 --> 00:30:38,282 OUT PRISTANE TREATED MICE AND 800 00:30:38,282 --> 00:30:39,783 THIS INCLUDES TASL WHICH WAS 801 00:30:39,783 --> 00:30:41,986 ALSO OVEREXPRESSED IN THE AGE 802 00:30:41,986 --> 00:30:45,055 ASSOCIATED B-CELLS FROM EXIST 803 00:30:45,055 --> 00:30:46,890 KNOCKOUT MICE WITH SPONTANEOUS 804 00:30:46,890 --> 00:30:50,694 LUPUS LIKE DISEASE, AND NOW IN 805 00:30:50,694 --> 00:30:52,563 GL7, POSITIVE ACTIVATED B-CELLS 806 00:30:52,563 --> 00:30:54,398 LOOKING SPECIFICALLY AT THE 807 00:30:54,398 --> 00:30:58,736 X-CHROMESOME, WE ALSO SEE, THAT 808 00:30:58,736 --> 00:31:00,504 TASL IS UPREGULATED ALONG WITH 809 00:31:00,504 --> 00:31:03,741 OTHER X-LINKED YEENS IN THESE 810 00:31:03,741 --> 00:31:04,508 B-CELL SUBSETS. 811 00:31:04,508 --> 00:31:05,943 OKAY, SO TAKEN TOGETHER, I WILL 812 00:31:05,943 --> 00:31:07,578 END WITH THE MODEL HERE, SO, 813 00:31:07,578 --> 00:31:10,414 WHAT WE FOUND IS THAT XIST 814 00:31:10,414 --> 00:31:13,417 DELETION CAN LEAD TO THE 815 00:31:13,417 --> 00:31:15,285 UPREGULATION OF X-LINKED IMMUNE 816 00:31:15,285 --> 00:31:16,320 GENES SPECIFICALLY TASL WHICH WE 817 00:31:16,320 --> 00:31:18,088 THINK CONTRIBUTES TO OUR RESULT 818 00:31:18,088 --> 00:31:21,959 IN PHENOTYPES THAT ARE OBSERVED 819 00:31:21,959 --> 00:31:24,261 IN SLEPATES. 820 00:31:24,261 --> 00:31:26,597 SO WHEN XIST IS DELETE FRIDAY 821 00:31:26,597 --> 00:31:28,665 THE X-CHROMESOME IN B-CELLS 822 00:31:28,665 --> 00:31:30,634 THERE'S A LOT OF FROM THE 823 00:31:30,634 --> 00:31:36,974 X-CHROME COME IS ALSO LOTS OF 824 00:31:36,974 --> 00:31:39,043 HETEROCHROMEATIC MARKS, WE SEE 825 00:31:39,043 --> 00:31:40,811 THERE'S TASL, WE SEE INCREASED 826 00:31:40,811 --> 00:31:42,780 FREQUENCY AND ACTIVATED NUMBER 827 00:31:42,780 --> 00:31:44,782 OF B-CELL SUBSETS AND MEMORY 828 00:31:44,782 --> 00:31:45,582 B-CELL SUBSETS. 829 00:31:45,582 --> 00:31:49,153 WE SEE PRODUCTION OF VARIOUS 830 00:31:49,153 --> 00:31:50,421 AUTOANTIBODIES AND ALSO ON A 831 00:31:50,421 --> 00:31:53,891 NUMBER OF DIFFERENT GLUE MARRIAL 832 00:31:53,891 --> 00:31:55,025 PATHOLOGIES AND IMPORTANTLY 833 00:31:55,025 --> 00:31:56,760 THESE ARE ALL PHENOTYPES THAT 834 00:31:56,760 --> 00:31:58,829 HAVE BEEN OBSERVE INDEED LUPUS 835 00:31:58,829 --> 00:32:01,598 PATIENTS WHICH HAVE DISPURSED 836 00:32:01,598 --> 00:32:04,968 PATTERNS OF RNA LOCALIZED AT THE 837 00:32:04,968 --> 00:32:05,602 INACTIVE X-CHROMESOME SO WITH 838 00:32:05,602 --> 00:32:07,204 THAT I WANT TO TAKE A MOMENT AND 839 00:32:07,204 --> 00:32:12,843 THANK ALL THE PEOPLE IN MY LAB, 840 00:32:12,843 --> 00:32:14,344 ESPECIALLY CLAUDIA WHO HAS 841 00:32:14,344 --> 00:32:15,179 REALLY BEEN SPEARHEADING THIS 842 00:32:15,179 --> 00:32:18,115 PROJECT WHICH HAS BEEN A VERY 843 00:32:18,115 --> 00:32:18,916 TECHNICALLY CHALLENGING PROJECT 844 00:32:18,916 --> 00:32:20,451 AND REALLY REQUIRES A LOT OF 845 00:32:20,451 --> 00:32:23,654 PATIENTS AND DETERMINE NATION 846 00:32:23,654 --> 00:32:25,489 BECAUSE THESE ANIMALS ARE QUITE 847 00:32:25,489 --> 00:32:27,257 AGED WHEN THEY PRESENT WITH 848 00:32:27,257 --> 00:32:28,725 PHENOTYPES. 849 00:32:28,725 --> 00:32:34,398 SO IN PARTICULAR, DR. HALEY 850 00:32:34,398 --> 00:32:36,600 AMERMAN, DOING ALL THE PATHOLOGY 851 00:32:36,600 --> 00:32:39,369 BLINDED FOR THE KIDNEY SECTIONS, 852 00:32:39,369 --> 00:32:40,804 UT SOUTHWESTERN FOR THE GENOMICS 853 00:32:40,804 --> 00:32:44,141 AND MICRO,A RAY, AND FINALLY ALL 854 00:32:44,141 --> 00:32:45,075 THE FUNDINGS SOURCES FOR THE 855 00:32:45,075 --> 00:32:45,442 LAB. 856 00:32:45,442 --> 00:32:55,986 SO WITH THEY WILL STOP SHARING. 857 00:32:56,520 --> 00:32:57,821 >> THANK YOU DOCTOR, FOR ANY WHO 858 00:32:57,821 --> 00:33:00,157 JOINED LATE, WE WILL TAKE 859 00:33:00,157 --> 00:33:01,792 QUESTIONSA THE END AFTER ALL 3 860 00:33:01,792 --> 00:33:02,759 SPEAKER VS SPOKEN, AT THIS TIME 861 00:33:02,759 --> 00:33:05,729 I WOULD LIKE TO INTRODUCE THE 862 00:33:05,729 --> 00:33:12,936 NEXT SPEAKER DR. DIANA DOU, FROM 863 00:33:12,936 --> 00:33:13,637 HARVARD UNIVERSITY. 864 00:33:13,637 --> 00:33:14,004 >> THANK YOU. 865 00:33:14,004 --> 00:33:15,439 LET ME SEE IF I REMEMBER HOW 866 00:33:15,439 --> 00:33:25,616 THORS TO 867 00:33:43,367 --> 00:33:44,067 DO THIS. 868 00:33:44,067 --> 00:33:45,135 ALL RIGHT, YES, THANK YOU FOR 869 00:33:45,135 --> 00:33:46,770 THAT INTRODUCTION AND I AM A 870 00:33:46,770 --> 00:33:49,273 POST DOC IN HOWARD CHANG'S LAB 871 00:33:49,273 --> 00:33:51,675 AT STANFORD AND THANK YOU FOR 872 00:33:51,675 --> 00:33:52,743 INVITING ME TO SPEAK ABOUT THE 873 00:33:52,743 --> 00:33:54,311 ROLES THAT EXIST IN AUTOIMMUNITY 874 00:33:54,311 --> 00:33:55,479 AND SHARE OUR STORY TODAY. 875 00:33:55,479 --> 00:34:00,184 SO I ALWAYS LIKE TO START WITH 876 00:34:00,184 --> 00:34:03,086 THIS CARTOON BECAUSE, WHAT DREW 877 00:34:03,086 --> 00:34:06,190 ME TO HOWARD'S LAB WAS NONCODING 878 00:34:06,190 --> 00:34:10,260 RNAs AND I LOOK THIS ANALOGY 879 00:34:10,260 --> 00:34:13,497 OF LOOKING FOR THESE AT NIGHT, 880 00:34:13,497 --> 00:34:15,232 AND TRADITIONALLY WE'VE ONLY 881 00:34:15,232 --> 00:34:16,733 FOCUSED ON LOOKING FOR THESE DEC 882 00:34:16,733 --> 00:34:19,536 IN THE WELL LIT AREAS OF THE 883 00:34:19,536 --> 00:34:21,038 GENOME, SO PRIMARILY ENCODING 884 00:34:21,038 --> 00:34:22,873 GENES BUT WHEN YOU CONSIDER THAT 885 00:34:22,873 --> 00:34:26,243 IT'S LESS THAN 2% ENCODING WHAT 886 00:34:26,243 --> 00:34:26,944 ALMOST IGNORING 99% OF THE 887 00:34:26,944 --> 00:34:27,878 POSSIBLE PLACES WHERE YOU COULD 888 00:34:27,878 --> 00:34:30,414 HAVE LOST YOUR KEYS OR WHERE 889 00:34:30,414 --> 00:34:33,917 THREEZ IMPORTANT KEYS ARE, SO 890 00:34:33,917 --> 00:34:36,019 THIS IS A GREAT ANIMATION FROM 891 00:34:36,019 --> 00:34:37,187 HUMAN HEALTH AND DEC, SO I THINK 892 00:34:37,187 --> 00:34:40,958 1 OF THE AREAS WHERE THIS 893 00:34:40,958 --> 00:34:42,226 PRESENTS GREAT PROMISE IS THAT 1 894 00:34:42,226 --> 00:34:43,660 OF THE BLACK BOXES OF MEDICINE 895 00:34:43,660 --> 00:34:45,362 THAT WOULD BENEFIT FROM 896 00:34:45,362 --> 00:34:49,299 SEARCHING FOR MORE KEYS ARE 897 00:34:49,299 --> 00:34:49,933 AUTOIMMUNE DISEASES. 898 00:34:49,933 --> 00:34:52,836 SO THIS IS LIKE A BASIC SLIDE, 899 00:34:52,836 --> 00:34:55,005 SHOWING HOW THE IMMUNE SYSTEM IS 900 00:34:55,005 --> 00:34:56,506 VERY COMPLEX, ALWAYS MAINTAIN 901 00:34:56,506 --> 00:34:58,375 THIS BALANCE BETWEEN 902 00:34:58,375 --> 00:34:58,976 SELF-TOLERANCE AND PROTECTION, 903 00:34:58,976 --> 00:35:00,677 IF YOU HAVE TOO MUCH TOLERANCE, 904 00:35:00,677 --> 00:35:06,316 YOU TEND TO NOT CLEAR OUT CELLS 905 00:35:06,316 --> 00:35:08,252 AND YOU GET CANCER WHEREOT OTHER 906 00:35:08,252 --> 00:35:10,020 END OF THE SPECTRUM, IF YOU HAVE 907 00:35:10,020 --> 00:35:11,688 TOO MUCH ACTIVITY AND 908 00:35:11,688 --> 00:35:17,394 PROTECTION, YOU DEVELOP 909 00:35:17,394 --> 00:35:17,728 AUTOIMMUNITY. 910 00:35:17,728 --> 00:35:19,129 AND THE PROBLEM WITH 911 00:35:19,129 --> 00:35:20,897 AUTOIMMUNITY RIGHT MOW IS THAT 912 00:35:20,897 --> 00:35:24,968 IT'S DIFFICULT TO DIAGNOSE AND 913 00:35:24,968 --> 00:35:26,470 LIMITED THERAPIES BECAUSE, AT 914 00:35:26,470 --> 00:35:28,038 LAST YEAR'S SCHEDULED FOUNDATION 915 00:35:28,038 --> 00:35:30,540 MEETING 1 OF THE CLINICIAN 916 00:35:30,540 --> 00:35:31,141 SCIENTISTS MENTIONED SOMETHING 917 00:35:31,141 --> 00:35:33,677 THAT STUCK WITH ME WHICH IS THAT 918 00:35:33,677 --> 00:35:34,378 THE FIELD'S AUTOIMMUNITY SEEMS 919 00:35:34,378 --> 00:35:36,747 TO BE IN THE FIELD OF CANCER 920 00:35:36,747 --> 00:35:38,248 WHERE AROUND 10 YEARS AGO WHERE 921 00:35:38,248 --> 00:35:39,182 EVERYTHING WE'RE DOING 922 00:35:39,182 --> 00:35:40,384 CLINICALLY IS MOSTLY SYMPTOM 923 00:35:40,384 --> 00:35:41,418 BASES BECAUSE WE DON'T REALLY 924 00:35:41,418 --> 00:35:44,221 UNDERSTAND THE CAUSE AND RISK 925 00:35:44,221 --> 00:35:45,589 FACTORS FOR AUTOIMMUNITY 926 00:35:45,589 --> 00:35:47,691 COMPLETELY, SO WHAT ARE THE RISK 927 00:35:47,691 --> 00:35:48,659 FACTORS FOR AUTOIMMUNE DEC THAT 928 00:35:48,659 --> 00:35:49,226 WE KNOW ABOUT. 929 00:35:49,226 --> 00:35:51,361 WELL WE KNOW THERE'S A VERY 930 00:35:51,361 --> 00:35:52,396 STRONG GENETIC COMPONENT BUT 931 00:35:52,396 --> 00:35:54,498 THERE'S ALSO AN ENVIRONMENTAL 932 00:35:54,498 --> 00:35:54,831 COMPONENT. 933 00:35:54,831 --> 00:35:56,700 HOWEVER, THE SINGLE VARIOUS RISK 934 00:35:56,700 --> 00:35:58,101 FACTOR FOR DEVELOPING 935 00:35:58,101 --> 00:35:59,403 AUTOIMMUNITY IS SIMPLY 936 00:35:59,403 --> 00:36:01,371 BIOLOGICAL FEMALES SO 80% OF THE 937 00:36:01,371 --> 00:36:03,440 AUTOIMMUNE POPULATION IS FEMALE, 938 00:36:03,440 --> 00:36:06,176 AND I THINK ALL OF US USE--ALSO 939 00:36:06,176 --> 00:36:08,045 USE SOME OF THE SLIDE FROM THE 940 00:36:08,045 --> 00:36:12,916 SAME REVIEW, IT'S A GREAT 941 00:36:12,916 --> 00:36:13,283 REVIEW. 942 00:36:13,283 --> 00:36:15,018 SO AGAIN HIGHLIGHTING THE RISK 943 00:36:15,018 --> 00:36:19,289 FACTOR FOR DEVELOPING 944 00:36:19,289 --> 00:36:20,957 AUTOIMMUNITY, FEMALES PRESENT A 945 00:36:20,957 --> 00:36:22,659 MUCH HIGHER INCIDENCE AND RISK 946 00:36:22,659 --> 00:36:24,061 FACTOR FOR DEVELOPING IT AND SO 947 00:36:24,061 --> 00:36:30,367 THESE ARE JUST SOME OF THE 948 00:36:30,367 --> 00:36:31,535 FEMALE BIASED IMMUNE DECS, I 949 00:36:31,535 --> 00:36:34,004 WILL SEE IF I CAN GET MY LASER 950 00:36:34,004 --> 00:36:36,673 POINTER UP HERE, YEAH, THE 951 00:36:36,673 --> 00:36:37,774 FEMALE BIASED AUTOIMMUNE DECS 952 00:36:37,774 --> 00:36:46,049 AND 1 OF THE MODELS WE USE IN 953 00:36:46,049 --> 00:36:49,086 MICE, IS THE LUPUS, SO WE 954 00:36:49,086 --> 00:36:51,021 CREATED THIS GREAT INTRODUCTION 955 00:36:51,021 --> 00:36:53,056 WHICH SAVES ME A LOT OF TIME SO 956 00:36:53,056 --> 00:36:54,658 SHE SHARED THAT AUTOIMMUNE 957 00:36:54,658 --> 00:36:56,059 CORRELATES WITH THE DOUBLE 958 00:36:56,059 --> 00:36:58,362 XX COMPLEMENT AND YOU KNOW, YES, 959 00:36:58,362 --> 00:37:00,831 AT THE VERY BASAL LEVEL, THE 960 00:37:00,831 --> 00:37:02,099 DRVESS BETWEEN BIOLOGICAL MALES 961 00:37:02,099 --> 00:37:06,470 AND FEMALES IS THAT FEMALES HAVE 962 00:37:06,470 --> 00:37:11,141 2 X-CHROMESOMES AND WHILE MALES 963 00:37:11,141 --> 00:37:13,577 HAVE 1, AND WHAT'S INTERESTING 964 00:37:13,577 --> 00:37:16,146 IS THAT IN DISEASES LIKE LUPUS, 965 00:37:16,146 --> 00:37:18,815 THE RISK OF DEVELOPING 966 00:37:18,815 --> 00:37:23,553 AUTOIMMUNITY, SUCH AS IN LUPUS 967 00:37:23,553 --> 00:37:26,089 IN [INDISCERNIBLE], THERE'S 1 968 00:37:26,089 --> 00:37:26,857 X-CHROMOSOME INCREASES 969 00:37:26,857 --> 00:37:28,325 DRASTICALLY FOR A LEVEL THAT'S 970 00:37:28,325 --> 00:37:31,328 SIMILAR TO WHAT WE SEE IN THE 971 00:37:31,328 --> 00:37:31,561 FEMALES. 972 00:37:31,561 --> 00:37:33,864 SO WHAT IS IT ABOUT HAVING 2 973 00:37:33,864 --> 00:37:36,266 X-CHROMESOMES THAT IS ABLE TO 974 00:37:36,266 --> 00:37:38,201 ELEVATE THIS RISK, SO 975 00:37:38,201 --> 00:37:39,870 SIGNIFICANTLY IN BOTH MALES AND 976 00:37:39,870 --> 00:37:40,103 FEMALES. 977 00:37:40,103 --> 00:37:42,339 WELL, WE KNOW THAT THE 978 00:37:42,339 --> 00:37:45,008 X-CONTAINS THE LARGEST NUMBER OF 979 00:37:45,008 --> 00:37:45,909 IMMUNE DISEASE, AND KIND OF 980 00:37:45,909 --> 00:37:47,544 BREEZE THROUGH IT AND SO THEY 981 00:37:47,544 --> 00:37:50,147 SHOWED THEIR BEAUTIFUL TODAYS 982 00:37:50,147 --> 00:37:51,448 SHOWING HOW X-GENE EXPRESSION 983 00:37:51,448 --> 00:37:52,983 REALLY NEEDS TO BE TIGHTLY 984 00:37:52,983 --> 00:37:54,851 CONTROLLED, AND THE WAY IT IS 985 00:37:54,851 --> 00:37:57,053 CONTROLLED IS THROUGH THE RNA 986 00:37:57,053 --> 00:37:59,022 CODING, XIST, AND IT SILENCES 1 987 00:37:59,022 --> 00:38:05,395 OF THE 2 X-CHROMESOMES, SO SHE'S 988 00:38:05,395 --> 00:38:08,832 SHOWN HER PATTERNS, IF THERE'S 989 00:38:08,832 --> 00:38:10,300 INCORRECT PATTERNS IT CAN AFFECT 990 00:38:10,300 --> 00:38:11,968 THE GENE EXPRESSION OFF THE 991 00:38:11,968 --> 00:38:13,136 X-CHROMESOME, AND IF YOU GET 992 00:38:13,136 --> 00:38:15,372 THESE YEENS YOU DEVELOP HIGH 993 00:38:15,372 --> 00:38:16,306 AMOUNTS OF AUTOIMMUNITY AND SO 1 994 00:38:16,306 --> 00:38:18,208 OF THE YEENS THAT YOU MENTIONED, 995 00:38:18,208 --> 00:38:20,844 THAT'S AN X-GENE IS TLR 7, 996 00:38:20,844 --> 00:38:24,581 HOWEVER, WHAT OUR WORK WAS 997 00:38:24,581 --> 00:38:26,883 STUDYING IS XIST ITSELF, WHETHER 998 00:38:26,883 --> 00:38:27,918 JUST HAVING XIST, AND THE 999 00:38:27,918 --> 00:38:32,122 PARTICLE THAT IT FORMS IN THE 1000 00:38:32,122 --> 00:38:33,056 FUNCTION, IT'S NONCODING SO IT 1001 00:38:33,056 --> 00:38:35,459 NEEDS TO HAVE ALL THE PROTEINS 1002 00:38:35,459 --> 00:38:37,494 IN THIS COMPLEX TO ACTUALLY HAVE 1003 00:38:37,494 --> 00:38:40,730 AN ABILITY TO FUNCTION AND 1004 00:38:40,730 --> 00:38:42,432 SILENCE THE X-CHROMESOME. 1005 00:38:42,432 --> 00:38:44,167 SO MY FOCUS ON WHETHER THIS 1006 00:38:44,167 --> 00:38:45,535 EXISTS ON THE PARTICLE ITSELF, 1007 00:38:45,535 --> 00:38:47,838 IT IS A FACT THAT INCREASES THE 1008 00:38:47,838 --> 00:38:48,705 AUTOIMMUNE RISK. 1009 00:38:48,705 --> 00:38:50,106 SO THERE IS ACTUALLY PRESENT FOR 1010 00:38:50,106 --> 00:38:55,412 THE CONCEPT OF THE EXIST 1011 00:38:55,412 --> 00:38:58,348 RIBONUCLETIDE AFTER ALL MANY 1012 00:38:58,348 --> 00:39:00,650 RNPs ARE KNOWN AUTOANTIGENS 1013 00:39:00,650 --> 00:39:03,420 AND THE COMPLEXES DO ENGAGE 1014 00:39:03,420 --> 00:39:06,356 TLRs AND AUTOIMMUNE DISEASE, 1015 00:39:06,356 --> 00:39:09,659 FOR EXAMPLE, TLR7 OF ACTIVATION 1016 00:39:09,659 --> 00:39:14,197 OF DENDRITIC CELLS, AND WHAT IS 1017 00:39:14,197 --> 00:39:16,600 IN THE RNF, WELL THE LAB 1018 00:39:16,600 --> 00:39:18,802 DEVELOPED LIKE THIS DIRECT 1019 00:39:18,802 --> 00:39:20,203 PROTEOMICS TECHNIQUE CALLED TRIP 1020 00:39:20,203 --> 00:39:23,607 MS, USED TO PULL DOWN XIST 1021 00:39:23,607 --> 00:39:25,442 COMPLEX AND WE USE IT TO 1022 00:39:25,442 --> 00:39:26,243 IDENTIFY THE PROTEINS. 1023 00:39:26,243 --> 00:39:28,879 SO WHAT'S INTERESTING IS THAT WE 1024 00:39:28,879 --> 00:39:31,181 IDENTIFY 81 UNIQUE BINDING 1025 00:39:31,181 --> 00:39:32,249 PROTEINS IN THE XIST PULL DOWN 1026 00:39:32,249 --> 00:39:35,485 AND A ABOUT A THIRD OF THOSE ARE 1027 00:39:35,485 --> 00:39:36,786 KNOWN AUTOANTIGENS WITH KNOWN 1028 00:39:36,786 --> 00:39:42,759 ASSOCIATIONS WITH AUTOIMMUNE 1029 00:39:42,759 --> 00:39:43,827 DISEASEs, INCLUDING ANTILAW, 1030 00:39:43,827 --> 00:39:46,596 SSB, WHICH BRINGS US TO THE 1031 00:39:46,596 --> 00:39:48,064 HYPOTH THIS THAT THIS EXISTS AND 1032 00:39:48,064 --> 00:39:52,102 IT CAN BE SCAFFOLDING INTO THESE 1033 00:39:52,102 --> 00:39:53,637 LARGE AUTOPOLYMERRIC COMPLEXES 1034 00:39:53,637 --> 00:39:54,437 THAT'S ACTIVATING IMMUNE 1035 00:39:54,437 --> 00:39:56,973 RECEPTORS SO THAT IF YOU GET 1036 00:39:56,973 --> 00:39:59,175 PROLONGED ACTIVATION OF THIS 1037 00:39:59,175 --> 00:40:02,012 IMMUNE SYSTEM, PROLONGED 1038 00:40:02,012 --> 00:40:03,947 INFLAMMATION, YOU CAN DEVELOP 1039 00:40:03,947 --> 00:40:04,714 CHRONIC INFLAMMATION AND 1040 00:40:04,714 --> 00:40:04,948 DISEASE. 1041 00:40:04,948 --> 00:40:06,182 SO IN MY TALK, IT'S KIND OF 1042 00:40:06,182 --> 00:40:08,752 GOING TO BE SEPARATED INTO 1043 00:40:08,752 --> 00:40:11,421 PARTS, THE FIRST OF WHICH IS 1044 00:40:11,421 --> 00:40:13,223 WE'RE LOOKING INTO WHETHER 1045 00:40:13,223 --> 00:40:15,425 EXPRESSION OF THESE XIST RNPs 1046 00:40:15,425 --> 00:40:17,761 ELEVATES THE RISK OF AUTOIMMUNE 1047 00:40:17,761 --> 00:40:20,196 DEC AND FOR THIS WE USE A MOUSE 1048 00:40:20,196 --> 00:40:20,397 MODEL. 1049 00:40:20,397 --> 00:40:22,532 AND THENOT CLINICAL SIDE, WE ASK 1050 00:40:22,532 --> 00:40:26,202 LIKE ARE THE CONPOEMENTS OF THE 1051 00:40:26,202 --> 00:40:30,774 XIST RNP, SERUM AUTO, CAN WE 1052 00:40:30,774 --> 00:40:32,742 DETECT SERUM AUTOANTIBODIES SO 1053 00:40:32,742 --> 00:40:36,379 IS THE EXIST RNP AN ANTIGEN 1054 00:40:36,379 --> 00:40:39,015 COMPLEX, SO WE'RE FORTUNATE TO 1055 00:40:39,015 --> 00:40:48,491 WORK WITH ANTON WOODS IN ZURICH 1056 00:40:48,491 --> 00:40:50,694 AND SHOWING THAT IT BEHAVES 1057 00:40:50,694 --> 00:40:50,961 MODULARLY. 1058 00:40:50,961 --> 00:40:54,064 SO IF YOU TAKE OUT THE FIRST 900 1059 00:40:54,064 --> 00:40:56,299 BASE PAIRS THERE'S A REGION 1060 00:40:56,299 --> 00:40:57,701 CALLED REPEAT A, SO WITHOUT THE 1061 00:40:57,701 --> 00:41:01,338 REGION OF REPEAT A, YOU DON'T 1062 00:41:01,338 --> 00:41:04,474 GET SILENCING OF THE 1063 00:41:04,474 --> 00:41:06,076 S-CHROMESOME, SO IT'S REQUIRED 1064 00:41:06,076 --> 00:41:07,510 FOR YEEN SILENCING IS THAT WE 1065 00:41:07,510 --> 00:41:11,281 DID WITH ANTON WE CREATED THIS 1066 00:41:11,281 --> 00:41:13,216 INDUCIBLE TRANSGENE WITH THIS 1067 00:41:13,216 --> 00:41:17,153 REPEAT A MUTANT EXIST, AND WE 1068 00:41:17,153 --> 00:41:19,723 PUT IT UNDER PET OP PROMOTER SO 1069 00:41:19,723 --> 00:41:20,857 WE CAN CONTROL THE EXPRESSION 1070 00:41:20,857 --> 00:41:23,793 AND PUT IT INTO THE CHROMOSOME 1071 00:41:23,793 --> 00:41:24,027 LISTEN. 1072 00:41:24,027 --> 00:41:25,095 YOU WILL NOTICE THAT IN THIS 1073 00:41:25,095 --> 00:41:30,734 MODEL I PUT IT ON 1 CHROMESOME 1074 00:41:30,734 --> 00:41:33,003 BECAUSE XIST IS JUST ON THE 1075 00:41:33,003 --> 00:41:36,139 XCHROME COME SO TO MIMIC THAT WE 1076 00:41:36,139 --> 00:41:37,107 USED HETEROZYGOTES AND THIS,A 1077 00:41:37,107 --> 00:41:39,376 LOWS US TO STUDY THE FUNCTION OF 1078 00:41:39,376 --> 00:41:42,078 WHAT WAS REALLY A PHENOSPECIFIC 1079 00:41:42,078 --> 00:41:45,382 LINK RNA AND RNA AND RNP COMPLEX 1080 00:41:45,382 --> 00:41:47,350 IN A MALE BACKGROUND INDEPENDENT 1081 00:41:47,350 --> 00:41:53,056 OF HORMONAL CONTRIBUTIONS AND 1082 00:41:53,056 --> 00:41:55,592 DEVELOPMENT TO VERIFY WE WERE 1083 00:41:55,592 --> 00:41:56,259 SEEING INDUCIBLE EXPRESSION IN 1084 00:41:56,259 --> 00:41:57,227 THE SYSTEM. 1085 00:41:57,227 --> 00:42:01,631 WE USE FISH, WE ALSO USE QPC R, 1086 00:42:01,631 --> 00:42:02,465 THROUGH SYSTEMIC ORGANS, MANY 1087 00:42:02,465 --> 00:42:03,967 ORGANS IN THE MOUSE, SO YOU CAN 1088 00:42:03,967 --> 00:42:06,136 SEE IN THE FEMALE CONTROL THAT 1089 00:42:06,136 --> 00:42:09,039 WAS NOT TREATED WITH DOXYPSYCHE 1090 00:42:09,039 --> 00:42:10,974 LINE AND YOU SEE THESE BRIGHT 1091 00:42:10,974 --> 00:42:13,877 TYPES OF THE WILD-TYPE XIST IN 1092 00:42:13,877 --> 00:42:16,279 THE TRANSGENIC ANIMALS THAT WERE 1093 00:42:16,279 --> 00:42:18,915 NOT TREATED WITH PRISTANE, SO 1094 00:42:18,915 --> 00:42:21,284 YOU DON'T SEE IF IN THE NUCLEI, 1095 00:42:21,284 --> 00:42:23,853 HOWEVER, WHEN YOU ADD IT TO THE 1096 00:42:23,853 --> 00:42:25,255 TRANSGENIC MOUSE, NOW YOU'RE 1097 00:42:25,255 --> 00:42:30,560 ABLE TO SEE THESE CLEAR AND 1098 00:42:30,560 --> 00:42:31,127 BRIGHT IMAGES HERE. 1099 00:42:31,127 --> 00:42:32,996 SO WITH THE KEY TAKE AWAY, WE 1100 00:42:32,996 --> 00:42:35,965 ARE ABLE TO GET THE EXIST RNP 1101 00:42:35,965 --> 00:42:37,067 WITHOUT ANY SILENCING AND THIS,A 1102 00:42:37,067 --> 00:42:39,936 LOWS US TO STUDY WHETHER XIST 1103 00:42:39,936 --> 00:42:43,139 EXPRESSION ALONE IS SUFFICIENT 1104 00:42:43,139 --> 00:42:43,973 TO INCREASE AUTOIMMUNITY. 1105 00:42:43,973 --> 00:42:48,044 SO WE CHOSE THE VERY WELL 1106 00:42:48,044 --> 00:42:50,547 STUDIED INDUCED MODEL AND WE 1107 00:42:50,547 --> 00:42:52,515 SHARE MANY ATTRIBUTES OF PEASHTS 1108 00:42:52,515 --> 00:42:54,684 IN LUPUS INCLUDING A FEMALE SEX 1109 00:42:54,684 --> 00:42:56,119 BIAS, SO KIND OF THROWING BACK 1110 00:42:56,119 --> 00:42:57,554 TO THE TRAITS OF LUPUS IN 1111 00:42:57,554 --> 00:43:00,757 PATIENTS, THERE IS A VERY STRONG 1112 00:43:00,757 --> 00:43:02,459 FEMALE, INCIDENCE, IT'S 1113 00:43:02,459 --> 00:43:04,561 MULTIORGAN AS WAY OF THE RANGE 1114 00:43:04,561 --> 00:43:05,628 AND REFLECTED IN THE PRISTANE 1115 00:43:05,628 --> 00:43:11,534 MOUSE MODEL AS WELL, BOTH HUMANS 1116 00:43:11,534 --> 00:43:14,637 AND THIS MOUSE MODEL, IT'S 1117 00:43:14,637 --> 00:43:15,939 INTERFERON AND TLR7 DRIIVE, AND 1118 00:43:15,939 --> 00:43:18,608 TWEPS A WIDE VARIETY OF 1119 00:43:18,608 --> 00:43:18,975 AUTOANTIBODIES. 1120 00:43:18,975 --> 00:43:21,411 SO WITH THIS MODEL WE TESTED IN 1121 00:43:21,411 --> 00:43:22,912 BOTH AUTOIMMUNE RESISTANT AND 1122 00:43:22,912 --> 00:43:23,880 PERMISSIVE BACKGROUND. 1123 00:43:23,880 --> 00:43:25,415 SO WE INITIALLY CONDUCKED OUR 1124 00:43:25,415 --> 00:43:27,117 EXPERIMENTS IN THE BLACK 6 MICE 1125 00:43:27,117 --> 00:43:28,351 BECAUSE IN THE WILD-TYPE STUDIES 1126 00:43:28,351 --> 00:43:30,720 WE KNOW THAT THE MALES NEVER GET 1127 00:43:30,720 --> 00:43:32,122 ANY DISEASE, SO WE THOUGHT IT 1128 00:43:32,122 --> 00:43:34,791 WOULD BE A BIENAR READ OUT, AND 1129 00:43:34,791 --> 00:43:36,426 SO, LATER ON, IN THIS 1130 00:43:36,426 --> 00:43:37,494 PRESENTATION, I WILL EXPLAIN TO 1131 00:43:37,494 --> 00:43:39,362 YOU, YOU WILL SEE WHY IT'S VERY 1132 00:43:39,362 --> 00:43:40,997 IMPORTANT TO HAVE LIKE A 1133 00:43:40,997 --> 00:43:43,500 RHEUMATOLOGIST AS YOUR 1134 00:43:43,500 --> 00:43:43,967 COLLABORATORS. 1135 00:43:43,967 --> 00:43:48,705 SO THIS IS KIND OF BASIC SLIDES 1136 00:43:48,705 --> 00:43:50,006 JUST SHOWING YOU THE PATHWAYS 1137 00:43:50,006 --> 00:43:52,475 AND IMMUNE CELLS THAT ARE 1138 00:43:52,475 --> 00:43:54,110 INVOFFED IN AUTOIMMUNE SIGNALING 1139 00:43:54,110 --> 00:43:56,312 AND HOW IT CAN PROCEED 2 WAYS 1140 00:43:56,312 --> 00:43:58,114 TRADITIONALLY WITH THE B-CELLS 1141 00:43:58,114 --> 00:43:59,382 PRESENTING AND ACTIVATING THE 1142 00:43:59,382 --> 00:44:02,385 T-CELLS AND ALSO PRODUCED 1143 00:44:02,385 --> 00:44:03,787 ANTIBODIES, T-CELLS WILL YOU 1144 00:44:03,787 --> 00:44:06,923 KNOW ACTIVATE THE CD8 T-CELLS, 1145 00:44:06,923 --> 00:44:08,057 PRODUCE CYTOKINES BUT THIS 1146 00:44:08,057 --> 00:44:10,026 PATHWAY COULD ALSO BE MORE 1147 00:44:10,026 --> 00:44:12,028 LIKELY CELL OR INITIATED OR 1148 00:44:12,028 --> 00:44:12,695 DRIVEN AND PRESENTATION CAN 1149 00:44:12,695 --> 00:44:13,897 OCCUR FROM THE DRAINAGE CELLS 1150 00:44:13,897 --> 00:44:16,866 AND SO THIS SLIDE REALLY IS 1151 00:44:16,866 --> 00:44:18,268 EMPHASIZED THAT OUR INITIAL 1152 00:44:18,268 --> 00:44:21,271 STUDIES WERE CONDUCTED WITH THE 1153 00:44:21,271 --> 00:44:23,640 CD4 T-CELL, BECAUSE YOU CAN SEE 1154 00:44:23,640 --> 00:44:26,042 THE T-REGS ARE INVOF INDEED 1155 00:44:26,042 --> 00:44:27,544 SUPPRESSING THESE AUTOIMMUNE 1156 00:44:27,544 --> 00:44:29,112 PATHWAYS AND THE T-EFFECTOR 1157 00:44:29,112 --> 00:44:29,979 CELLS SEEM TO BE RIGHT IN THE 1158 00:44:29,979 --> 00:44:32,282 MITSD OF IT SO WHAT WE SAW WAS 1159 00:44:32,282 --> 00:44:34,317 THAT THE CD4 T-CELLS SEEM TO BE 1160 00:44:34,317 --> 00:44:35,852 THE HUB OF AUTOIMMUNE SIGNALING 1161 00:44:35,852 --> 00:44:37,987 SO OUR INITIAL SEQUENCING 1162 00:44:37,987 --> 00:44:38,621 EXPERIMENTS AND EVALLIA YOU 1163 00:44:38,621 --> 00:44:40,023 GUYSS WERE DONE ON THIS, I USED 1164 00:44:40,023 --> 00:44:42,025 TO GET THE QUESTION A LOT AND I 1165 00:44:42,025 --> 00:44:46,229 ON GO WHAT ABOUT B-CELLS AND 1166 00:44:46,229 --> 00:44:47,063 DENDRITIC CELLS, IT STARTED LIKE 1167 00:44:47,063 --> 00:44:48,731 THIS BECAUSE IT LOOKED LIKE THE 1168 00:44:48,731 --> 00:44:49,999 HUB WHERE MOST ACTIVITY WAS 1169 00:44:49,999 --> 00:44:51,768 HAPPENING SO LET'S GO BACK, 1170 00:44:51,768 --> 00:44:53,670 STARTING WITH THE RESISTANT 1171 00:44:53,670 --> 00:44:55,238 BACKGROUND, YOU NOTICE I SAID 1172 00:44:55,238 --> 00:44:57,307 HERE 52 WEEKS SO AFTER TREATMENT 1173 00:44:57,307 --> 00:44:59,709 WITH PRISTANE AND 1 TIME 1174 00:44:59,709 --> 00:45:00,510 INJECTION WITH PRISTANE, 52 1175 00:45:00,510 --> 00:45:02,178 WEEKS LATER I COLLECTED THE 1176 00:45:02,178 --> 00:45:05,215 SPLEEN AND ISOLATED OUT THE CD4 1177 00:45:05,215 --> 00:45:06,583 T-CELLS AND CONDUCTED BOTH 1178 00:45:06,583 --> 00:45:09,152 ATTACK SEQ ON THE CELLS FROM THE 1179 00:45:09,152 --> 00:45:10,220 SPLEEN 52 WEEKS AFTER TREATMENT, 1180 00:45:10,220 --> 00:45:11,721 AND SO HERE IS A POSITIVE 1181 00:45:11,721 --> 00:45:14,157 CONTROL, IT WAS THE FEMALE, THAT 1182 00:45:14,157 --> 00:45:15,225 WAS TREATED WITH PRISTANE AND 1183 00:45:15,225 --> 00:45:20,430 YOU CAN SEE THE ATTACK SEQ 1184 00:45:20,430 --> 00:45:23,066 SPLITS INTO 2 DISTINCT CLUSTERS 1185 00:45:23,066 --> 00:45:24,901 AND HERE ARE MALE CONTROL 1186 00:45:24,901 --> 00:45:25,735 GROUPS, SO THESE MALE CONTROL 1187 00:45:25,735 --> 00:45:27,337 GROUPS THIS IS THE WILD-TYPE 1188 00:45:27,337 --> 00:45:28,872 THAT WAS TREATED WITH PRISTANE 1189 00:45:28,872 --> 00:45:30,707 AND HERE'S A TRANSGENIC MOUSE 1190 00:45:30,707 --> 00:45:32,876 THAT WAS TREATED FOR STAIN BUT 1191 00:45:32,876 --> 00:45:35,311 NO DOXYPSYCHEY PSYCHE LINE, SO 1192 00:45:35,311 --> 00:45:37,180 THERE'S NO TRANSGENE IN THESE 1193 00:45:37,180 --> 00:45:38,681 HIGHER POPULATIONS AND SAME HERE 1194 00:45:38,681 --> 00:45:40,750 IS THE MALE, SO IN ALL THESE 1195 00:45:40,750 --> 00:45:43,987 MALE CONTROL MALE ANIMALS YOU 1196 00:45:43,987 --> 00:45:45,255 CAN SEE THE 2 DISTINCT CLUSTERS 1197 00:45:45,255 --> 00:45:47,123 HERE AND YOU CAN SEPARATE IT TO 1198 00:45:47,123 --> 00:45:48,658 NOW WHAT'S MORE OPEN IN THE 1199 00:45:48,658 --> 00:45:50,894 CLUSTER AND WHAT'S MORE OPEN IN 1200 00:45:50,894 --> 00:45:52,862 THE FEMALES, SO, WHERE DOES OUR 1201 00:45:52,862 --> 00:45:54,264 ACTUAL TEST SUBJECT FALL? 1202 00:45:54,264 --> 00:45:57,233 WELL WE'RE VERY EXCITED TO SEE 1203 00:45:57,233 --> 00:45:58,968 THAT AT THE EPIGENETIC PROFILE 1204 00:45:58,968 --> 00:46:00,403 LEVEL IN THESE T-CELLS, THESE 1205 00:46:00,403 --> 00:46:02,906 MICE THAT HAD BOTH THE 1206 00:46:02,906 --> 00:46:04,841 CHALLENGES PRISTANE TO INDUCE 1207 00:46:04,841 --> 00:46:08,378 THE DISEASE AND ALSO INDUCTION 1208 00:46:08,378 --> 00:46:10,747 OF THE TRANSGENIC XIST SEEM TO 1209 00:46:10,747 --> 00:46:12,382 FALL MORE INTO THE FEMALE 1210 00:46:12,382 --> 00:46:14,350 PROFILE, SO EVEN THOUGH AFTER 52 1211 00:46:14,350 --> 00:46:17,353 WEEKS, WE DEPARTMENT SEE ANY 1212 00:46:17,353 --> 00:46:17,954 PHYSICAL DISEASE 1213 00:46:17,954 --> 00:46:20,757 CHARACTERISTICS, WE DO SEE THAT 1214 00:46:20,757 --> 00:46:24,661 EXPRESSION OF XIST IMPOSES A 1215 00:46:24,661 --> 00:46:27,330 FEMALE LIKE EPIGENETIC PROFILE 1216 00:46:27,330 --> 00:46:28,731 IN THESE MALE CELLS THAT WE 1217 00:46:28,731 --> 00:46:30,266 ASSESS, WHAT IS IN CLUSTER 2 1218 00:46:30,266 --> 00:46:32,001 THAT WE TERM THE FEMALE, LIKE 1219 00:46:32,001 --> 00:46:33,770 THE ACCESS IBLGHT CLUSTER, WELL, 1220 00:46:33,770 --> 00:46:35,705 IN CLUSTER 2 ITSELF, WE SEE A 1221 00:46:35,705 --> 00:46:39,075 LOT OF TLRs AND MYD88 CASCADES 1222 00:46:39,075 --> 00:46:41,210 WHICH ARE VERY IMPORTANT IN 1223 00:46:41,210 --> 00:46:42,879 LUPUS AND LUPUS PATHOGENESIS, 1224 00:46:42,879 --> 00:46:46,115 AND NOW SHOWING THE RNA SEQ DATA 1225 00:46:46,115 --> 00:46:48,084 AND IT'S QUITE SIMILAR TO THIS 1226 00:46:48,084 --> 00:46:51,154 IS, IT'S LESS, IT'S LESS SORT OF 1227 00:46:51,154 --> 00:46:52,889 DISTINCT BUT THE TREND IS VERY 1228 00:46:52,889 --> 00:46:53,323 SIMILAR. 1229 00:46:53,323 --> 00:46:55,291 SO THIS GAVE US INCENTIVE TO 1230 00:46:55,291 --> 00:47:00,063 CONTINUE TO A DIFFERENT MODEL, 1231 00:47:00,063 --> 00:47:03,132 AND SO, THE AUTOMODEL WE WENT 1232 00:47:03,132 --> 00:47:07,303 WITH WAS SJLJ, THIS WAS JIM 1233 00:47:07,303 --> 00:47:09,272 LAMBERT, SO IN BOTH THIS MODEL 1234 00:47:09,272 --> 00:47:10,907 BOTH MALES AND FEMALES WILL 1235 00:47:10,907 --> 00:47:12,675 DEVELOP THE DISEASE BUT THE 1236 00:47:12,675 --> 00:47:14,043 FEMALES WILL DEVELOP MORE SEVERE 1237 00:47:14,043 --> 00:47:17,347 AND MUCH HIGHER LETHALITY OF 1238 00:47:17,347 --> 00:47:19,315 THIS PRISTANE INDUCED LUPUS. 1239 00:47:19,315 --> 00:47:22,585 AND SO THESE ARE OUR COHORTS 1240 00:47:22,585 --> 00:47:25,021 AGAIN, SO WE HAVE--THIS TIME WE 1241 00:47:25,021 --> 00:47:27,523 USE THE WILD-TYPE FEMALE AND THE 1242 00:47:27,523 --> 00:47:29,058 WILE TYPE MALE AND AGAIN WE HAVE 1243 00:47:29,058 --> 00:47:30,460 THESE TEST GROUPS AND SO OUR 1244 00:47:30,460 --> 00:47:34,764 TEST GROUP IS AGAIN, THE MALE 1245 00:47:34,764 --> 00:47:36,599 TRANSGENIC MOUSE WITH BOTH 1246 00:47:36,599 --> 00:47:38,534 INDUCTION OF THE TRANSYEEN AND 1247 00:47:38,534 --> 00:47:40,670 THE CHALLENGE WITH PRISTANE AND 1248 00:47:40,670 --> 00:47:42,205 HERE JUST TO SHARE THERE ARE MOW 1249 00:47:42,205 --> 00:47:43,172 DIFFERENCES WE SHARED THIS 1250 00:47:43,172 --> 00:47:44,474 TREATMENT IN THE MODEL WILD-TYPE 1251 00:47:44,474 --> 00:47:46,542 AS WELL, OR JUST TO CONTRAST THE 1252 00:47:46,542 --> 00:47:47,677 DIFFERENCES WE DID THE SAME 1253 00:47:47,677 --> 00:47:48,978 TREATMENT IN THE WILD-TYPE MODEL 1254 00:47:48,978 --> 00:47:50,313 AS WELL, AND YOU CAN SEE HERE 1255 00:47:50,313 --> 00:47:52,281 THAT THE FEMALES START DYING 1256 00:47:52,281 --> 00:47:54,784 AROUND 16 WEEKS AND THIS 1257 00:47:54,784 --> 00:47:56,419 WILD-TYPE SURVIVAL CURVE, SO WE 1258 00:47:56,419 --> 00:47:59,155 CHOSE THE TERMINAL POINT OF 16 1259 00:47:59,155 --> 00:48:01,090 WEEKS POST INDUCTION, POST 1260 00:48:01,090 --> 00:48:02,158 INJECTION, TO AVOID LOSING ANY 1261 00:48:02,158 --> 00:48:04,794 MICE BECAUSE WE WANT TO SEQUENCE 1262 00:48:04,794 --> 00:48:07,530 THESE MICE WORKING WITH DISEASE 1263 00:48:07,530 --> 00:48:11,601 TISSUE, WOULD BE--WOULD NOT BE 1264 00:48:11,601 --> 00:48:12,035 IDEAL. 1265 00:48:12,035 --> 00:48:13,836 SO FINALLY IN THIS PERMISSIVE 1266 00:48:13,836 --> 00:48:16,105 MODEL, WE'RE ABLE TO SEE A VERY 1267 00:48:16,105 --> 00:48:17,740 CLEAR OF ALL THE AUTOANTIBODIES 1268 00:48:17,740 --> 00:48:20,276 IN THE MALES WITH A TRANSGENIC 1269 00:48:20,276 --> 00:48:21,878 EXPRESSION AND ALSO CHALLENGE 1270 00:48:21,878 --> 00:48:24,180 WITH PRISTANE AND JUST 16 WEEKS 1271 00:48:24,180 --> 00:48:26,082 POST INDUCTION, SO AGAIN, WE HAD 1272 00:48:26,082 --> 00:48:28,885 TO WAIT 52 WEEKS IN THE BLACK 6 1273 00:48:28,885 --> 00:48:35,391 AND WE REALLY WEREN'T SEEING ANY 1274 00:48:35,391 --> 00:48:36,225 SIGNIFICANCE, WE DIDN'T SEE 1275 00:48:36,225 --> 00:48:39,562 TRENDS BUT WE DID SEE 1276 00:48:39,562 --> 00:48:40,496 SIGNIFICANCE, AND AGAIN THIS WAS 1277 00:48:40,496 --> 00:48:47,770 DONE WITH OUR COLLABORATOR 1278 00:48:47,770 --> 00:48:49,439 PJ UTZ, AND HE WAS GREAT IN 1279 00:48:49,439 --> 00:48:50,840 CONSULTING THE PANELS FOR US ON 1280 00:48:50,840 --> 00:48:53,242 THE PHOSPHORYLATED MODELING SIZE 1281 00:48:53,242 --> 00:48:54,944 AND THE RHEUMATOLOGY SIDE AND 1282 00:48:54,944 --> 00:48:57,280 HE'S ALSO THE 1 WHO POINTED OUT 1283 00:48:57,280 --> 00:48:59,348 BLACK 6 IS AUTOIMMUNE RESISTANT 1284 00:48:59,348 --> 00:49:03,519 SO VERY IMPORTANT TO HAVE GREAT 1285 00:49:03,519 --> 00:49:05,254 COLLABORATORS EMPLOY SO ON THE 1286 00:49:05,254 --> 00:49:06,722 PATHOLOGY END, AGAIN WITH BLACK 1287 00:49:06,722 --> 00:49:08,791 6 AT 52 WEEKS WE WEREN'T REALLY 1288 00:49:08,791 --> 00:49:10,993 SEEING ANY PATHOLOGY WE COULD 1289 00:49:10,993 --> 00:49:12,695 SAY DISTINCTLY WAS RELATED TO 1290 00:49:12,695 --> 00:49:13,996 DISEASE BUT HERE AT JUST 16 1291 00:49:13,996 --> 00:49:19,001 WEEKS WE CAN SEE THAT IN THE 1292 00:49:19,001 --> 00:49:21,037 KIDNEY OF THESE PRISTANE TREATED 1293 00:49:21,037 --> 00:49:23,139 MICE, WE CAN SEE THICKENING IN 1294 00:49:23,139 --> 00:49:24,674 THE DEPOSITS IN THE KIDNEY AND 1295 00:49:24,674 --> 00:49:27,110 ALSO DAMAGE TO LIVERS OF THESE 1296 00:49:27,110 --> 00:49:30,179 EXPRESSING MICE, SO HERE'S A 1297 00:49:30,179 --> 00:49:31,080 WILD-TYPE FEMALE, WILD-TYPE MALE 1298 00:49:31,080 --> 00:49:33,616 WITH THE TREATMENT CONTROL AND 1299 00:49:33,616 --> 00:49:35,418 THIS IS THE TRANSGENIC WITH THE 1300 00:49:35,418 --> 00:49:36,586 FULL TREATMENT AS WELL. 1301 00:49:36,586 --> 00:49:38,688 AND SO THIS TOTAL PATHOLOGY 1302 00:49:38,688 --> 00:49:43,860 SCORE IS ACTUALLY COMPOSITE 1303 00:49:43,860 --> 00:49:45,161 SCORE FOR THE SUM TOTAL OF 1304 00:49:45,161 --> 00:49:47,830 DAMAGE FROM THE KIDNEY, THE 1305 00:49:47,830 --> 00:49:50,600 LIVER, THE SPLEEN, ADIPOST, LUNG 1306 00:49:50,600 --> 00:49:52,001 AND LIVE LYMPHNODES AND SO THESE 1307 00:49:52,001 --> 00:49:57,440 ARE ALL IMPACTED IN PATIENT 1308 00:49:57,440 --> 00:49:58,441 LUPUS, AS WELL. 1309 00:49:58,441 --> 00:50:01,811 SO FROM HERE, I ALSO HARVEST THE 1310 00:50:01,811 --> 00:50:02,745 SPLEEN SAMPLES FOR SEQUENCING 1311 00:50:02,745 --> 00:50:04,280 AND THIS TIME, YOU KNOW HOWARD 1312 00:50:04,280 --> 00:50:05,681 WAS LIKE, YES, NOW YOU CAN DO 1313 00:50:05,681 --> 00:50:08,117 SINGLE CELL AND THIS IS ALSO 1314 00:50:08,117 --> 00:50:09,886 WHERE I ENCOUNTERED THE 1315 00:50:09,886 --> 00:50:11,154 LIMITATIONS OF HHMI FUNDING 1316 00:50:11,154 --> 00:50:13,456 BECAUSE I DID ASK HOWARD IF WE 1317 00:50:13,456 --> 00:50:14,724 COULD SEQUENCE LIKE ALL 60 MICE 1318 00:50:14,724 --> 00:50:17,093 WE DID AND SHE SAID NO, THAT IS 1319 00:50:17,093 --> 00:50:18,394 WAY TOO EXPENSIVE, YOU WILL JUST 1320 00:50:18,394 --> 00:50:25,268 HAVE TO PICK, A FEW FROM EACH 1321 00:50:25,268 --> 00:50:25,935 SIGNIFICANT EACH REPRESENTATIVE 1322 00:50:25,935 --> 00:50:29,305 GROUP AND GO FROM THERE IFLET 1323 00:50:29,305 --> 00:50:30,473 MULTIOME SEQUENCING, SO WHAT WE 1324 00:50:30,473 --> 00:50:32,575 SAW HERE WAS THE PATHOLOGY SCORE 1325 00:50:32,575 --> 00:50:35,611 WAS NEVER LOWER THAN 10, SO 10 1326 00:50:35,611 --> 00:50:38,347 WAS THE SCORE, SO WE TURN THIS 1327 00:50:38,347 --> 00:50:39,949 DEC SEVERE AND INTERESTING 1328 00:50:39,949 --> 00:50:41,450 ENOUGH WITH THE WILD-TYPE MALES 1329 00:50:41,450 --> 00:50:48,191 WE KNEW WE WOULD SEE SOME 1330 00:50:48,191 --> 00:50:50,126 DISEASE IN THE WILD-TYPE MALES 1331 00:50:50,126 --> 00:50:52,862 AND WHAT'S INTERESTING IS THAT 1332 00:50:52,862 --> 00:50:55,364 THE WILD-TYPE SCORE REACHES 10, 1333 00:50:55,364 --> 00:50:57,567 SO WE TERM IT FEMALE LIKE OR LOW 1334 00:50:57,567 --> 00:51:00,870 LIKE SO LOW SLEEZE AND SORT OF 1335 00:51:00,870 --> 00:51:02,271 HIGH DISEASE AND I ALSO POINTED 1336 00:51:02,271 --> 00:51:04,540 OUT THAT IT'S INTERESTING THAT 1337 00:51:04,540 --> 00:51:05,641 WE HAVE THESE BIFURCATION OF 1338 00:51:05,641 --> 00:51:09,045 THESE 2 IN OUR TREATMENT GROUP. 1339 00:51:09,045 --> 00:51:10,780 SO TO ASSESS THIS AGAIN, HOWARD, 1340 00:51:10,780 --> 00:51:12,548 YOU DIDN'T LET ME SEQUENCE EVERY 1341 00:51:12,548 --> 00:51:14,850 SINGLE MOUSE BUT WE DID TAKE A 1342 00:51:14,850 --> 00:51:16,719 FEW MICE FROM EACH OF THESE 1343 00:51:16,719 --> 00:51:18,654 HIGHLIGHTED GROUP, SO THAT WE 1344 00:51:18,654 --> 00:51:25,428 COULD SEE THE DIFFERENCES AND 1345 00:51:25,428 --> 00:51:27,063 WHAT'S GOING ON THERE AND SO I'M 1346 00:51:27,063 --> 00:51:32,001 JUST SHOWING THIS SLIDE, THIS IS 1347 00:51:32,001 --> 00:51:33,869 IMPORTANT FOR KIND OF STAGING OR 1348 00:51:33,869 --> 00:51:34,937 THE DISEASE PROGRESS, SO ON THE 1349 00:51:34,937 --> 00:51:38,140 PLAQUE 6 WHERE WE SAW CLEAR 1350 00:51:38,140 --> 00:51:40,977 DISTINCT PATTERNS DISTINGUISHING 1351 00:51:40,977 --> 00:51:44,580 EXIST EXPRESSING AND AND 1352 00:51:44,580 --> 00:51:45,615 NONEXIST EXPRESSING MICE, I 1353 00:51:45,615 --> 00:51:48,451 DIDN'T REALLY SEE THAT HERE SO 1354 00:51:48,451 --> 00:51:52,054 EACH WHEN I GROUP THE MALE LOW 1355 00:51:52,054 --> 00:51:53,456 SLEEZE TOGETHER FOR A HIGHER 1356 00:51:53,456 --> 00:51:57,326 POWER FOR THE COMPARISON 1357 00:51:57,326 --> 00:51:58,661 PURPOSES, BETWEEN THE WILD-TYPE 1358 00:51:58,661 --> 00:52:00,596 TO THE COMPARISONS I DIDN'T SEE 1359 00:52:00,596 --> 00:52:04,667 VERY MANY DIFFERENCES BETWEEN 1360 00:52:04,667 --> 00:52:05,935 THE SEXES, AND THIS FINALLY MADE 1361 00:52:05,935 --> 00:52:07,370 SENSE TO ME BECAUSE OF COURSE, 1362 00:52:07,370 --> 00:52:09,438 IT SEEMS LIKE THE EPIGENETIC 1363 00:52:09,438 --> 00:52:10,873 MODELS HAS ALREADY HAPPENED SO 1364 00:52:10,873 --> 00:52:13,075 WE REALLY HAD TO GO INTO THE 1365 00:52:13,075 --> 00:52:14,110 YEEN EXPRESSION LEVEL, SO 1366 00:52:14,110 --> 00:52:15,278 STARTING AT THE GENE EXPRESSION 1367 00:52:15,278 --> 00:52:17,113 LEVELS WHERE WE TART TO SEE 1368 00:52:17,113 --> 00:52:18,481 THOSE DIFFERENCES AND WE SEE 1369 00:52:18,481 --> 00:52:23,019 HERE ON THE MAP, PRETTY CLEAN, 1370 00:52:23,019 --> 00:52:24,220 CELL TYPE CLUSTERS SO THIS IS 1371 00:52:24,220 --> 00:52:26,322 JUST TO SHOW THAT HERE, WITH THE 1372 00:52:26,322 --> 00:52:28,791 TGM WITH THE HIGH DEC, EXISTS 1373 00:52:28,791 --> 00:52:30,760 EXPRESSING MALES WITH THE HIGH 1374 00:52:30,760 --> 00:52:32,194 DISEASE AND THE WILD-TYPE 1375 00:52:32,194 --> 00:52:33,663 FEMALES ARE SORT OF CLUSTERING 1376 00:52:33,663 --> 00:52:34,997 TOGETHER, SO YOU'RE SEEING THE 1377 00:52:34,997 --> 00:52:38,734 OVERLAY OF THE RED AND THE 1378 00:52:38,734 --> 00:52:38,934 GREEN. 1379 00:52:38,934 --> 00:52:42,104 SO AGAIN AS I MENTIONED WITH THE 1380 00:52:42,104 --> 00:52:43,706 SINGLE CELL MULTIDATA SET, WE 1381 00:52:43,706 --> 00:52:45,775 DIDN'T SEE ANY CHANGES BETWEEN 1382 00:52:45,775 --> 00:52:46,475 THE MISTINE CHALLENGE MOUSE 1383 00:52:46,475 --> 00:52:48,110 GROUPS AND THIS MAKES SENSE IN 1384 00:52:48,110 --> 00:52:49,512 TERMS OF TIME BECAUSE THESE MICE 1385 00:52:49,512 --> 00:52:52,381 IN CONTRAST TO THE BLACK 6 ARE 1386 00:52:52,381 --> 00:52:53,082 DISPLAYING PHYSIOLOGICAL SENSE 1387 00:52:53,082 --> 00:52:54,917 OF DISEASE, AND THE CHROMATIN 1388 00:52:54,917 --> 00:52:56,185 REMODELING HAS ALREADY HAPPENED 1389 00:52:56,185 --> 00:52:59,622 AND STABILIZED BUT THE SEVERITY 1390 00:52:59,622 --> 00:53:02,725 IS STILL INCAPSULATED IN THE 1391 00:53:02,725 --> 00:53:04,460 TRANSCRIPTOME, SO, LOCATING 1392 00:53:04,460 --> 00:53:06,062 WITHIN THESE POPULATIONS, SORT 1393 00:53:06,062 --> 00:53:08,397 OF THE--SO WE HAVE THESE B-CELL 1394 00:53:08,397 --> 00:53:10,266 GROUPS AND B-CELL GROUPS SO 1395 00:53:10,266 --> 00:53:12,101 LOOKING BROADLY INTO THESE 1396 00:53:12,101 --> 00:53:13,169 B-CELL GROUPS WE SEE MARKERS 1397 00:53:13,169 --> 00:53:15,137 THAT ARE AGAIN ASSOCIATE WIDE 1398 00:53:15,137 --> 00:53:17,239 LIKE AGE RELATED B-CELLS OR 1399 00:53:17,239 --> 00:53:18,307 ATYPICAL B-CELLS AS WE TERM THEM 1400 00:53:18,307 --> 00:53:22,311 SO YOU SEE THE ELEVATION OF ZEB2 1401 00:53:22,311 --> 00:53:23,279 AND ASSOCIATE WIDE DOUBLE B 1402 00:53:23,279 --> 00:53:25,114 CELLS AND WE ALSO SEE THE 1403 00:53:25,114 --> 00:53:27,983 DECREASE IN THE T-CELL 1404 00:53:27,983 --> 00:53:30,386 POPULATION OF THESE IMMUNO 1405 00:53:30,386 --> 00:53:32,922 MODULARY SIGNAL SO NRCC1 IS 1406 00:53:32,922 --> 00:53:38,127 INVOLVED IN THE T-CELL INFLAMM 1407 00:53:38,127 --> 00:53:40,663 EGG, CD54 IS A IMMUNE REGULATOR 1408 00:53:40,663 --> 00:53:45,167 AND CD37 IS A COMPLEMENT 1409 00:53:45,167 --> 00:53:46,635 MEDIATED INTERACTIVE T-CELLS, SO 1410 00:53:46,635 --> 00:53:47,903 ZOOMING INTO 1 OF THE CLUSTERS 1411 00:53:47,903 --> 00:53:49,505 WHERE WE SEE PRIMARILY JUST 1412 00:53:49,505 --> 00:53:50,840 OVERLAW OF THE RED AND THE 1413 00:53:50,840 --> 00:53:52,875 GREEN, SO THE TRANSGENIC MALE, 1414 00:53:52,875 --> 00:53:55,244 WITH THE HIGH DISEASE AND THE 1415 00:53:55,244 --> 00:53:56,145 FEMALE, WILD-TYPE POSITIVE 1416 00:53:56,145 --> 00:53:58,247 CONTROLS, WE SEE THAT THIS KIND 1417 00:53:58,247 --> 00:54:00,182 OF CORRELATES WITH B-CELL 1418 00:54:00,182 --> 00:54:02,084 CLUSTER 3, SO, IN B-CELL CLUSTER 1419 00:54:02,084 --> 00:54:04,086 3, THERE ARE VERY CLEARLY 1420 00:54:04,086 --> 00:54:07,056 B-CELLS BECAUSE THERE'S HIGH 1421 00:54:07,056 --> 00:54:10,493 CD19 SIGNATURES BUT WE ALSO SAW 1422 00:54:10,493 --> 00:54:14,330 THIS MASSIVE INCREASE IN THESE 1423 00:54:14,330 --> 00:54:15,765 OTHER 2 TRANSCRIPTS AND CONCUR 1424 00:54:15,765 --> 00:54:17,867 EPTLY WE SAW THE DOWN REGULATION 1425 00:54:17,867 --> 00:54:19,835 OF CR2 WHICH INCORRODES CD21 AND 1426 00:54:19,835 --> 00:54:23,372 IN A DOWN REGULATION OF CDR5, 1427 00:54:23,372 --> 00:54:28,110 BOTH OF WHICH ARE HALLMARKS OF 1428 00:54:28,110 --> 00:54:30,746 ATYPICAL B-CELLS IN LUPUS 1429 00:54:30,746 --> 00:54:31,147 PATIENTS. 1430 00:54:31,147 --> 00:54:34,016 SO CD21 NEGATIVE AND CD27 DOUBLE 1431 00:54:34,016 --> 00:54:35,751 NEGATIVE POPULATIONS ARE TYPICAL 1432 00:54:35,751 --> 00:54:37,953 OF THE SIGNATURES OF B-CELLS, 1433 00:54:37,953 --> 00:54:40,423 AND IN A HALLMARK OF ATYPICAL 1434 00:54:40,423 --> 00:54:41,924 B-CELLS IN THE PATHOGENESIS OF 1435 00:54:41,924 --> 00:54:43,159 THIS, AND THIS IS EXCITING FOR 1436 00:54:43,159 --> 00:54:44,193 US TO SEE THAT THERE IS 1437 00:54:44,193 --> 00:54:45,461 SOMETHING WE CAN FIND REFLECT 1438 00:54:45,461 --> 00:54:46,762 INDEED THE PATIENT POPULATION AS 1439 00:54:46,762 --> 00:54:47,229 WELL. 1440 00:54:47,229 --> 00:54:49,865 SO THAT KIND OF CONCLUDES THE 1441 00:54:49,865 --> 00:54:52,401 PART OF OUR MOUSE MODEL PART 1442 00:54:52,401 --> 00:54:56,472 WHERE WE SHOWED THAT IF WE KIND 1443 00:54:56,472 --> 00:55:00,009 OF INDUCE, EXIST RMPs IN A 1444 00:55:00,009 --> 00:55:00,743 MALE BACKGROUND, ANIMAL 1445 00:55:00,743 --> 00:55:03,746 BACKGROUND WE'RE ABLE TO PROMOTE 1446 00:55:03,746 --> 00:55:04,747 FEMALE BIASED AUTOIMMUNITY IN 1447 00:55:04,747 --> 00:55:06,282 THESE MALES. 1448 00:55:06,282 --> 00:55:10,619 SO PHYSIOLOGICALLY WE'RE ABLE TO 1449 00:55:10,619 --> 00:55:11,787 DETECT INCREASED AUTOANTIBODY 1450 00:55:11,787 --> 00:55:17,793 PRODUCTION AS WELL AS MORE 1451 00:55:17,793 --> 00:55:20,996 SEVERE DISEASE ORGANS AND 1452 00:55:20,996 --> 00:55:21,464 AUTOIMMUNITY. 1453 00:55:21,464 --> 00:55:22,431 AND SO, THIS KIND OF BRINGS US 1454 00:55:22,431 --> 00:55:24,433 TO THE NEXT PART, LIKE WHAT IS 1455 00:55:24,433 --> 00:55:28,471 THE CLINICAL IMPACT OF THE XIST 1456 00:55:28,471 --> 00:55:30,973 ARM PIECE? 1457 00:55:30,973 --> 00:55:32,608 ARE AUTOIMMUNE PATIENTS ACTUALLY 1458 00:55:32,608 --> 00:55:37,580 REACTIVE TO COMPONENTS WITHIN 1459 00:55:37,580 --> 00:55:38,280 THE XIST RMP? 1460 00:55:38,280 --> 00:55:39,615 SO THIS LEADS US TO THE NEXT 1461 00:55:39,615 --> 00:55:41,417 PART OF THE TALK, SO THIS KIND 1462 00:55:41,417 --> 00:55:43,118 OF A BASIC SLIDE, YOU KNOW JUST 1463 00:55:43,118 --> 00:55:45,754 REMINDING US OF THE IMPORTANCE 1464 00:55:45,754 --> 00:55:47,056 OF AUTOANTIBODIES AND 1465 00:55:47,056 --> 00:55:50,626 AUTOANTIGENS IN THE CONTEXT OF 1466 00:55:50,626 --> 00:55:51,627 AUTOIMMUNE DEC AND DIAGNOSIS, 1467 00:55:51,627 --> 00:55:53,362 AND THEY ARE PRODUCED AGAIN, AND 1468 00:55:53,362 --> 00:55:55,798 HOW THE CELL ANTIGENS DURING 1469 00:55:55,798 --> 00:55:57,099 CELL DAMAGE OR INFLAMMATION, CAN 1470 00:55:57,099 --> 00:55:58,968 YOU GET THE RELEASE OF CELL 1471 00:55:58,968 --> 00:56:00,269 ANTIIENS AND THEY COULD BE 1472 00:56:00,269 --> 00:56:02,137 CLEAVED BO THIS UNRECOGNIZED 1473 00:56:02,137 --> 00:56:04,006 ANTIGENS WHICH THEN THE 1474 00:56:04,006 --> 00:56:06,175 SELF-RECOGNIZES AS FOREIGN, 1475 00:56:06,175 --> 00:56:10,346 INCORRECTLY, OR THEY COULD LOOK 1476 00:56:10,346 --> 00:56:13,516 VERY SIMILAR TO AUTOANTIGENS 1477 00:56:13,516 --> 00:56:15,618 THAT ARE ALREADY--THEY COULD 1478 00:56:15,618 --> 00:56:17,119 CROSS REACT WITH AUTOEABT BODIES 1479 00:56:17,119 --> 00:56:18,487 THAT EXIST BETWEEN PATHOGENS 1480 00:56:18,487 --> 00:56:21,590 MEAN THEY LOOK VERY SIMILAR TO 1481 00:56:21,590 --> 00:56:21,857 PATHOGENS. 1482 00:56:21,857 --> 00:56:24,627 AND THEY ACT AS CLINICAL 1483 00:56:24,627 --> 00:56:25,828 BIOMARKERS FOR AUTOIMMUNE 1484 00:56:25,828 --> 00:56:28,063 DISEASE AND IT'S AGAIN, 1485 00:56:28,063 --> 00:56:29,498 AUTOIMMUNE DECS CAN BE DIFFICULT 1486 00:56:29,498 --> 00:56:32,234 TO DIAGNOSE BECAUSE OF THE 1487 00:56:32,234 --> 00:56:33,769 HETEROGENEITY AND OVERLAPPING 1488 00:56:33,769 --> 00:56:34,937 SYMPTOMS VERY EARLY ON SO IT'S 1489 00:56:34,937 --> 00:56:37,473 IMPORTANT TO FIND AS MANY 1490 00:56:37,473 --> 00:56:41,343 CLINICAL BIOMARKER AS WE CAN TO 1491 00:56:41,343 --> 00:56:43,078 HELP DORPH SPECIFIC AUTOANTIIEN 1492 00:56:43,078 --> 00:56:46,482 PROFILES IMPROVE DIAGNOSIS AND 1493 00:56:46,482 --> 00:56:46,749 TREATMENT. 1494 00:56:46,749 --> 00:56:48,417 AND SO, ON THE CLINICAL 1495 00:56:48,417 --> 00:56:49,952 RELEVANCE SIDE, HERE IS WHERE WE 1496 00:56:49,952 --> 00:56:52,588 COLLABORATE WITH THE HUMAN 1497 00:56:52,588 --> 00:56:54,657 PROTEIN ATLAS PROJECT IN SWEDEN 1498 00:56:54,657 --> 00:56:57,426 WHO HELPED US DESIGN AN 1499 00:56:57,426 --> 00:56:58,260 ASSOCIATED PROTEIN ANTIGEN 1500 00:56:58,260 --> 00:57:02,231 ARRAY, AND PROTEINS WE IDENTIFY 1501 00:57:02,231 --> 00:57:03,499 THROUGH THE TRIPMIS, PULL DOWN 1502 00:57:03,499 --> 00:57:05,834 ASSAY I MENTIONED EARLIER. 1503 00:57:05,834 --> 00:57:07,336 YOU KNOW INITIALLY WE DORPHED 81 1504 00:57:07,336 --> 00:57:09,204 IN THE EXPERIMENTS AND WE GOT 1505 00:57:09,204 --> 00:57:10,773 SERUM SAMPLES FROM MULTIPLE LABS 1506 00:57:10,773 --> 00:57:19,415 AT JOHNS HOPKINS AND STANFORD, 1507 00:57:19,415 --> 00:57:25,254 WITH 3 DIFFERENT DISEASES WITH 1508 00:57:25,254 --> 00:57:27,656 SCLERODERMA AND OTHERS AND WE 1509 00:57:27,656 --> 00:57:29,224 EXAMINED THEM WITH THE SERUM WE 1510 00:57:29,224 --> 00:57:31,126 GOT PRACTICES THE STANFORD 1511 00:57:31,126 --> 00:57:31,994 DONATION CENTER AND WE SAW THERE 1512 00:57:31,994 --> 00:57:33,629 WERE 9 THAT WERE SHARED BETWEEN 1513 00:57:33,629 --> 00:57:34,763 ALL 3 DISEASE GROUPS AND THE 1514 00:57:34,763 --> 00:57:38,300 REST SEEM TO BE KIND OF DISTINCT 1515 00:57:38,300 --> 00:57:39,001 TO EACH DISEASE. 1516 00:57:39,001 --> 00:57:41,637 AND AT THE TIME OF THE 1517 00:57:41,637 --> 00:57:45,040 PUBLICATION OF THE MANUSCRIPT OF 1518 00:57:45,040 --> 00:57:47,443 THE 79 AUTOANTIGENS WE KIND OF 1519 00:57:47,443 --> 00:57:49,745 IDENTIFY IN THIS ARRAY, 28 OF 1520 00:57:49,745 --> 00:57:53,415 THEM WERE NOT DESCRIBED IN THE 1521 00:57:53,415 --> 00:57:54,950 LITERATURE AS ANTIGEN, SO THIS 1522 00:57:54,950 --> 00:57:58,587 OPENED THE PROFILES FROM 1523 00:57:58,587 --> 00:57:59,755 INCREASED SPECIFICITY AND KIAG 1524 00:57:59,755 --> 00:58:00,789 NUMBER OF THETICS. 1525 00:58:00,789 --> 00:58:03,525 AND SO, THIS IS KIND OF THE 1526 00:58:03,525 --> 00:58:07,730 OVERVIEW OF THE MODEL OF HOW WE 1527 00:58:07,730 --> 00:58:09,798 PROPOSE XIST LINK RNA CAN BE 1528 00:58:09,798 --> 00:58:13,235 FUNCTIONING SORT OF A TRIGGER 1529 00:58:13,235 --> 00:58:14,236 FOR INFERIOR BIASED 1530 00:58:14,236 --> 00:58:14,870 AUTOIMMUNITY. 1531 00:58:14,870 --> 00:58:15,938 SO IN THE PHOSPHORYLATED MODEL 1532 00:58:15,938 --> 00:58:18,507 IN THE FIRST PART OF THE TALK, 1533 00:58:18,507 --> 00:58:20,909 THE INCREASE EXPRESSION PROMOTES 1534 00:58:20,909 --> 00:58:22,211 AUTOIMMUNITY IN THE MOUSE MODEL. 1535 00:58:22,211 --> 00:58:24,113 WE SAW THIS BOTH EPIGENETICALLY 1536 00:58:24,113 --> 00:58:26,615 AND ON THE GENE EXPRESSION LEVEL 1537 00:58:26,615 --> 00:58:28,250 THERE WAS INCREASE 1538 00:58:28,250 --> 00:58:30,219 IMPEDIMENTSUNE ACTIVATION AND 1539 00:58:30,219 --> 00:58:31,220 DECREASED IMMUNE MODULATION. 1540 00:58:31,220 --> 00:58:33,789 WE ALSO SAW THIS INCREASED 1541 00:58:33,789 --> 00:58:34,423 AUTOANTIBODY PRODUCTION, SO CAN 1542 00:58:34,423 --> 00:58:36,825 YOU KIND OF SEE THE STAGING OF 1543 00:58:36,825 --> 00:58:39,595 DEC, THE TLB CELL, CHROMATIN 1544 00:58:39,595 --> 00:58:40,429 REMODELING WILL OCCUR FIRST 1545 00:58:40,429 --> 00:58:42,431 BEFORE YOU HAVE ANY CHANGES IN 1546 00:58:42,431 --> 00:58:46,402 THE EXPRESSION. 1547 00:58:46,402 --> 00:58:48,337 AND THEN USUALLY THERE'S ANOTHER 1548 00:58:48,337 --> 00:58:49,171 CHECK POINT, NEVER PROGRESS TO 1549 00:58:49,171 --> 00:58:50,472 THE DISEASE BECAUSE THERE ARE 1550 00:58:50,472 --> 00:58:53,475 CHECK POINTS THERE, HOWEVER, IN 1551 00:58:53,475 --> 00:58:56,078 OUR MODEL, AS WE SEE ALSO, MORE 1552 00:58:56,078 --> 00:58:57,913 SEVERE ORGAN DISEASE PENETRANTS 1553 00:58:57,913 --> 00:59:00,649 AND SEVERITY ASSOCIATED WITH THE 1554 00:59:00,649 --> 00:59:03,852 EXPRESSION IN OUR MALE ANIMALS 1555 00:59:03,852 --> 00:59:04,353 AS WELL. 1556 00:59:04,353 --> 00:59:06,655 AND ON A CLINICAL END, WE SHOWED 1557 00:59:06,655 --> 00:59:11,427 THAT AUTOIMMUNE DEC PATIENTS ARE 1558 00:59:11,427 --> 00:59:13,062 ACTUALLY SERO-REACTIVE TO THE 1559 00:59:13,062 --> 00:59:14,830 XIST RMP, AND HOPEFULLY ALL THIS 1560 00:59:14,830 --> 00:59:17,166 RESEARCH WILL HELP US IMPROVE 1561 00:59:17,166 --> 00:59:18,701 THERAPIES AND DIAGNOSTICS AS WE 1562 00:59:18,701 --> 00:59:22,304 CONTINUE EXPLORING THIS ANGLE OF 1563 00:59:22,304 --> 00:59:24,773 HOW XIST, THE PARTICLE WORKS AND 1564 00:59:24,773 --> 00:59:27,076 INFLUENCES THE IMMUNE SYSTEM OR 1565 00:59:27,076 --> 00:59:28,010 INTERACTING WITH THE IMMUNE 1566 00:59:28,010 --> 00:59:29,878 SYSTEM TO PROMOTE THIS 1567 00:59:29,878 --> 00:59:31,180 BACKGROUND OF INCREASED 1568 00:59:31,180 --> 00:59:32,581 AUTOIMMUNITY IN FEMALES, SO, AT 1569 00:59:32,581 --> 00:59:34,650 THIS POINT, I WOULD LIKE TO 1570 00:59:34,650 --> 00:59:35,884 ACKNOWLEDGE THE MANY PEOPLE 1571 00:59:35,884 --> 00:59:38,087 WITHOUT WHOM THIS WORK WOULD NOT 1572 00:59:38,087 --> 00:59:39,154 HAVE BEEN POSSIBLE, SO EVERYONE 1573 00:59:39,154 --> 00:59:41,690 IN THE CHANG LAB AND ESPECIALLY 1574 00:59:41,690 --> 00:59:42,024 HOWARD. 1575 00:59:42,024 --> 00:59:44,526 SO AS YOU CAN PROBABLY TELL FROM 1576 00:59:44,526 --> 00:59:46,328 THE SLIDES, THERE WAS A LOT OF 1577 00:59:46,328 --> 00:59:48,497 MOUSE WORK INVOLVED, A LOT OF 1578 00:59:48,497 --> 00:59:51,166 CROSSING, A LOT OF GENETIC 1579 00:59:51,166 --> 00:59:52,434 STUDIES AND SEQUENCING, EVEN 1580 00:59:52,434 --> 00:59:53,902 THOUGH HOWARD DIDN'T LET ME 1581 00:59:53,902 --> 00:59:55,604 SEQUENCE ALL 60 MICE, IT WAS 1582 00:59:55,604 --> 00:59:57,439 STILL VERY EXPENSIVE TO DO ALL 1583 00:59:57,439 --> 00:59:58,741 THE SEQUENCING AND HE WAS VERY 1584 00:59:58,741 --> 00:59:59,074 PATIENT. 1585 00:59:59,074 --> 01:00:01,276 THIS WAS A VERY LONG PROGEC, 1586 01:00:01,276 --> 01:00:04,980 AND, YOU KNOW HE WAS A GREAT 1587 01:00:04,980 --> 01:00:06,148 CHEERLEADER, AND VERY GOOD 1588 01:00:06,148 --> 01:00:06,381 MENTOR. 1589 01:00:06,381 --> 01:00:09,585 AND HE PAID FOR EVERYTHING, SO 1590 01:00:09,585 --> 01:00:10,619 THANK YOU HOWARD. 1591 01:00:10,619 --> 01:00:12,588 AND ON OUR VETERINARIAN SIDE, 1592 01:00:12,588 --> 01:00:15,257 KERRY WAS THE 1 WHO DID A LOT OF 1593 01:00:15,257 --> 01:00:17,993 THE NECROPSY END POINT WORK FOR 1594 01:00:17,993 --> 01:00:23,198 US, AND READ THE HISTOLOGY, AND 1595 01:00:23,198 --> 01:00:23,832 OUR CLINICAL COLLABORATORS WHO 1596 01:00:23,832 --> 01:00:26,135 CONTRIBUTED TO THE SERUM TO THE 1597 01:00:26,135 --> 01:00:29,204 STUDY, AGAIN, A PGA, THE PGA IS 1598 01:00:29,204 --> 01:00:30,839 ACTUALLY THE CO MENTOR FOR THE 1599 01:00:30,839 --> 01:00:33,942 K99 AND HE PROVIDED A LOT OF THE 1600 01:00:33,942 --> 01:00:34,576 RHEUMATOLOGY EXPERTISE, AND HE 1601 01:00:34,576 --> 01:00:36,445 LET ME GO TO HIS LAB AND HE WILL 1602 01:00:36,445 --> 01:00:39,748 PRESENT AND GAVE ME GREAT 1603 01:00:39,748 --> 01:00:41,116 FEEDBACK, OUR ADMIN WITHOUT WHOM 1604 01:00:41,116 --> 01:00:44,553 NOTHING WOULD REALLY GET DONE 1605 01:00:44,553 --> 01:00:46,722 AND ALSO SCILIFE LAB IN SWEDEN 1606 01:00:46,722 --> 01:00:49,258 WHO DESIGNED THE ARRAY AND 1607 01:00:49,258 --> 01:00:51,693 ALLOWED US TO HAVE STOCK UPS TO 1608 01:00:51,693 --> 01:00:52,561 THE HUMAN AT PLACENTAS PROTEINS 1609 01:00:52,561 --> 01:00:54,763 WHICH IS A LOT AND ALSO OF 1610 01:00:54,763 --> 01:00:56,198 COURSE, THE FUNDING, THE PROJECT 1611 01:00:56,198 --> 01:00:59,034 WAS LARGELY FUNDED BY THE 1612 01:00:59,034 --> 01:00:59,735 SCLERODERMA RESEARCH FOUNDATION 1613 01:00:59,735 --> 01:01:01,170 BUT I WAS ACTUALLY PERSONALLY 1614 01:01:01,170 --> 01:01:05,140 FUNDED BY THE NIH, NIAMS, SO I 1615 01:01:05,140 --> 01:01:07,442 WAS ON A TRAINING GRANT WITH 1616 01:01:07,442 --> 01:01:09,077 THEM INITIALLY WHEN I START MY 1617 01:01:09,077 --> 01:01:14,550 POST DOC AND I GOT THE K99 1618 01:01:14,550 --> 01:01:16,151 R00 TRANSITION FROM THE SAME 1619 01:01:16,151 --> 01:01:18,720 INSTITUTE SO THANK YOU VERY MUCH 1620 01:01:18,720 --> 01:01:20,355 NIH AND NIAMS AND I WOULD LIKE 1621 01:01:20,355 --> 01:01:21,423 TO CONCLUDE ON THIS SLIDE WHICH 1622 01:01:21,423 --> 01:01:26,829 IS A SUMMARY OF THE PAPER THAT 1623 01:01:26,829 --> 01:01:29,598 I--THE WORK I JUST PRESENTED WAS 1624 01:01:29,598 --> 01:01:31,800 THE CELL PAPER WE JUST PRESENTED 1625 01:01:31,800 --> 01:01:32,868 IN FEBRUARY, AND AGAIN WE WANT 1626 01:01:32,868 --> 01:01:34,770 TO HIGHLIGHT THAT THE END GOAL 1627 01:01:34,770 --> 01:01:38,407 IS TO IMPROVE THERAPIES AND 1628 01:01:38,407 --> 01:01:39,374 DIAGNOSTICS, SO IF YOU HAVE 1629 01:01:39,374 --> 01:01:41,777 SERUM AND WOULD LIKE TO BE PART 1630 01:01:41,777 --> 01:01:43,946 OF THESE STUDIES PLEASE GET IN 1631 01:01:43,946 --> 01:01:45,247 TOUCH WITH ME, IT WOULD BE VERY 1632 01:01:45,247 --> 01:01:54,289 COOL IF WE COULD ALSO FIND LIKE 1633 01:01:54,289 --> 01:01:57,326 SOME CLIENTELE SERUM AND CHANGES 1634 01:01:57,326 --> 01:01:59,094 TO THE XIST EXPRESSION OR 1635 01:01:59,094 --> 01:02:01,196 INCREASE DOSAGE OF XIMPEDIMENTS 1636 01:02:01,196 --> 01:02:04,366 PACTS AUTOIMMUNITY AS WELL, AND 1637 01:02:04,366 --> 01:02:06,368 KIND OF A SELF-PLUG HERE. 1638 01:02:06,368 --> 01:02:07,970 IF YOU'RE INTERESTED, I THINK I 1639 01:02:07,970 --> 01:02:11,173 CAN SAY PRETTY CONFIDENTLY THAT 1640 01:02:11,173 --> 01:02:13,809 THE DOU LAB WILL PROBABLY BE 1641 01:02:13,809 --> 01:02:15,210 OPENING IN FALL 2024, KIND OF 1642 01:02:15,210 --> 01:02:19,381 NARROW DOWN THE LOCATION RIGHT 1643 01:02:19,381 --> 01:02:20,582 NOW SO, YEAH, KEEP YOUR EYES 1644 01:02:20,582 --> 01:02:30,993 PEELED AND THANK YOU FOR 1645 01:02:31,827 --> 01:02:32,160 LISTENING. 1646 01:02:32,160 --> 01:02:33,862 >> THANK YOU SO MUCH DR. DOU. 1647 01:02:33,862 --> 01:02:41,970 WE WOULD LIKE TO INTRODUCE THE 1648 01:02:41,970 --> 01:02:44,106 NEXT SPEAKER DR. ANDIOS,. 1649 01:02:44,106 --> 01:02:45,607 >> THANK YOU, THANK YOU FOR THE 1650 01:02:45,607 --> 01:02:47,576 INVITATION TO BE A PART OF THIS 1651 01:02:47,576 --> 01:02:49,645 EVENT AND THANK TO YOU YOUR TEAM 1652 01:02:49,645 --> 01:02:51,179 FOR ORCHESTRATING 1 OF THE MORE 1653 01:02:51,179 --> 01:02:52,014 COMPLEX VOOM INTERACTIONS THAT I 1654 01:02:52,014 --> 01:02:53,882 HAVE BEEN A PART OF AND I JUST 1655 01:02:53,882 --> 01:03:04,426 WANT TO CONFIRM HERE THAT I CAN 1656 01:03:06,061 --> 01:03:08,096 SHARE MY SCREEN. 1657 01:03:08,096 --> 01:03:12,734 ALL RIGHT, OKAY, SO THANK YOU 1658 01:03:12,734 --> 01:03:14,703 AGAIN, I'M BRENDAN, I'M WITH THE 1659 01:03:14,703 --> 01:03:15,871 RHEUMATOLOGY DIVISION AT JOHNS 1660 01:03:15,871 --> 01:03:18,073 HOPKINS AND MY GOAL TODAY IS TO 1661 01:03:18,073 --> 01:03:20,709 REVIEW FOR YOU THE FINDINGS OF A 1662 01:03:20,709 --> 01:03:23,478 MANUSCRIPT THAT OUR GROUP 1663 01:03:23,478 --> 01:03:24,446 PUBLISHED LAST FALL. 1664 01:03:24,446 --> 01:03:26,181 THIS PAPER MADE 2 CONCLUSIONS 1665 01:03:26,181 --> 01:03:28,150 THAT I'M GOING TO HIGHLIGHT 1666 01:03:28,150 --> 01:03:32,154 WHICH ARE 1, WE IDENTIFIED XIST 1667 01:03:32,154 --> 01:03:35,490 AS AN ENDOGENOUS SOURCE OF RNA 1668 01:03:35,490 --> 01:03:37,259 LIGANDS THAT ACTIVATE TLR7 WHICH 1669 01:03:37,259 --> 01:03:39,428 FRAMES EXIST AS A DAMP AND TO 1670 01:03:39,428 --> 01:03:41,363 OUR KNOWLEDGE IS REALLY THE ONLY 1671 01:03:41,363 --> 01:03:44,399 EXAMPLE OF A FEMALE SCIENTIFIC 1672 01:03:44,399 --> 01:03:46,068 DAMP IDENTIFIED TO DATE. 1673 01:03:46,068 --> 01:03:50,272 THE OTHER MAIN FINDING TO REPORT 1674 01:03:50,272 --> 01:03:52,007 HERE IS THAT XIST UPREGULATION 1675 01:03:52,007 --> 01:03:54,042 OF CELLS IN PETRESSABLE MALE 1676 01:03:54,042 --> 01:03:55,377 PATIENTS WITH LUPUS IN 1677 01:03:55,377 --> 01:03:58,180 COMPARISON TO HEALTHY FEMALE 1678 01:03:58,180 --> 01:03:58,447 CONTROLS. 1679 01:03:58,447 --> 01:04:01,316 SO, TO INTRODUCE THIS TOPIC AND 1680 01:04:01,316 --> 01:04:04,853 REALLY EXPLAIN WHY WE CHOSE TO 1681 01:04:04,853 --> 01:04:06,388 FOCUS ON TLR 7, I AM GOING TO 1682 01:04:06,388 --> 01:04:09,925 FIRST REVIEW SOME OF THE DATA 1683 01:04:09,925 --> 01:04:11,793 BEHIND TLR 7 AS BEING A KEY 1684 01:04:11,793 --> 01:04:13,128 CONTRIBUTOR TO THE PATHOLOGY 1685 01:04:13,128 --> 01:04:14,663 OBSERVED IN SLE, SO THIS MAY BE 1686 01:04:14,663 --> 01:04:16,398 A REVIEW FOR SOME OF OUR 1687 01:04:16,398 --> 01:04:17,899 AUDIENCE BUT IT'S IMPORTANT TO 1688 01:04:17,899 --> 01:04:19,601 REVIEW THIS KIND OF FRAME WHY 1689 01:04:19,601 --> 01:04:22,771 THIS QUESTION WAS POSED IN THE 1690 01:04:22,771 --> 01:04:23,739 FIRST PLACE. 1691 01:04:23,739 --> 01:04:25,140 OKAY, SO, THESE CONCEPTS REALLY 1692 01:04:25,140 --> 01:04:27,109 DON'T NEED TO BE INTRODUCED NOW, 1693 01:04:27,109 --> 01:04:28,477 WE'RE HERE BECAUSE OF THE FACT 1694 01:04:28,477 --> 01:04:35,417 THAT WE KNOW THAT FEMALES, 1695 01:04:35,417 --> 01:04:35,984 EXPERIENCE, AUTOIMMUNITY 1696 01:04:35,984 --> 01:04:37,486 DISPROPORTIONATELY COMPARED TO 1697 01:04:37,486 --> 01:04:39,221 MALES, I WILL POINT OUT I HAVE 1698 01:04:39,221 --> 01:04:42,457 THE SAME DATA AS MY 2 1699 01:04:42,457 --> 01:04:43,492 PREDECESSORS, BUT SHOWING 1700 01:04:43,492 --> 01:04:44,159 DIFFERENT REVIEW ARTICLES WHICH 1701 01:04:44,159 --> 01:04:46,361 IS SHOWING THAT THE BULK OF IT 1702 01:04:46,361 --> 01:04:48,363 LIES WITH FEMALE ANDS THAT 1703 01:04:48,363 --> 01:04:49,731 INCLUDES ORGAN SPECIFIC 1704 01:04:49,731 --> 01:04:50,832 AUTOIMMUNITY, BUT ALSO SYSTEMIC 1705 01:04:50,832 --> 01:04:56,405 DISEASES THAT WE SEE IN 1706 01:04:56,405 --> 01:04:58,140 RHEUMATOLOGY, SUCH AS LUPUS AND 1707 01:04:58,140 --> 01:05:00,208 CLER DERMA AND OTHERS, AS HAS 1708 01:05:00,208 --> 01:05:02,511 BEEN MENTIONED IN LUPUS AND THE 1709 01:05:02,511 --> 01:05:03,678 BEST KNOWN RISK FACTOR FOR 1710 01:05:03,678 --> 01:05:06,214 HAVING LUPUS IS SIMPLY BEING 1711 01:05:06,214 --> 01:05:09,217 FEMALE WITH 9 TO 10 MORE TIMES, 1712 01:05:09,217 --> 01:05:10,385 AND THIS INTERESTING DOSE 1713 01:05:10,385 --> 01:05:13,388 RESPONSE RELATED TO THE 1714 01:05:13,388 --> 01:05:16,024 X-CHROMOSOME, AND MEN WITH 1715 01:05:16,024 --> 01:05:16,825 [INDISCERNIBLE], VERSUS WOMEN 1716 01:05:16,825 --> 01:05:19,261 WITH TURNER SIN TROAM, AND @ THE 1717 01:05:19,261 --> 01:05:20,896 SAME TIME AS HAS BEEN MENTIONED 1718 01:05:20,896 --> 01:05:22,230 THERE HAVE BEEN DIFFERENCES IN 1719 01:05:22,230 --> 01:05:23,432 THE HOST IMMUNE RESPONSES 1720 01:05:23,432 --> 01:05:24,699 BETWEEN FEMALES AND MALES, IT'S 1721 01:05:24,699 --> 01:05:27,135 SOMETHING THAT'S NOT EMILY THED 1722 01:05:27,135 --> 01:05:28,870 TO HUMANS, IT'S AVAILABLE IN 1723 01:05:28,870 --> 01:05:30,338 OTHER SPECIES BUT WHAT'S KNOWN 1724 01:05:30,338 --> 01:05:32,474 IN WOMEN IS THAT THERE'S 1725 01:05:32,474 --> 01:05:33,275 ENHANCED TYPE 1 INTERFERON 1726 01:05:33,275 --> 01:05:35,777 SIGNALING AS WELL AS ENHANCED 1727 01:05:35,777 --> 01:05:36,845 ANTIBODY RESPONSES, SO 1728 01:05:36,845 --> 01:05:37,546 DIFFERENCES IN THE INTERFERON 1729 01:05:37,546 --> 01:05:39,514 SYSTEM AND THE B-CELL 1730 01:05:39,514 --> 01:05:41,817 COMPARTMENT, WHICH GIVE FEMALES 1731 01:05:41,817 --> 01:05:43,685 AN ADVANTAGE IN SOME SCENARIOS, 1732 01:05:43,685 --> 01:05:46,154 AND SO THE WITH KNOWLEDGE THAT 1733 01:05:46,154 --> 01:05:47,122 THESE IMMUNE RESPONSES DIFFER 1734 01:05:47,122 --> 01:05:48,423 BASED ON SEX, THIS RAISES A 1735 01:05:48,423 --> 01:05:50,392 QUESTION WHETHER THERE ARE 1736 01:05:50,392 --> 01:05:51,893 SPECIFIC IMMUNE PATHWAYS THAT 1737 01:05:51,893 --> 01:05:53,962 COULD GIVE FEMALES AN ADVANTAGE 1738 01:05:53,962 --> 01:05:57,399 IN HOST DEFENSE BUT WHEN 1739 01:05:57,399 --> 01:05:59,134 DISREGULATED OR EXACERBATED, 1740 01:05:59,134 --> 01:06:00,836 COULD CONTRIBUTE TO AUTOIMMUNITY 1741 01:06:00,836 --> 01:06:03,371 AND THESE SEX BIASED RHEUMATIC 1742 01:06:03,371 --> 01:06:07,209 DISEASES THAT WE'RE ALL FAMILIAR 1743 01:06:07,209 --> 01:06:07,909 WITH IN RHEUMATOLOGY. 1744 01:06:07,909 --> 01:06:09,544 SO TO APPROACH THIS QUESTION IN 1745 01:06:09,544 --> 01:06:13,348 LUPUS, WE CHOSE TO FOCUS ON TLR 1746 01:06:13,348 --> 01:06:13,715 7. 1747 01:06:13,715 --> 01:06:16,017 SO TOLL-LIKE RECEPTOR 7 IS AN 1748 01:06:16,017 --> 01:06:17,352 INNATE PATTERN RECOGNITION 1749 01:06:17,352 --> 01:06:20,622 RECEPTOR THAT IS FOUND IN IMMUNE 1750 01:06:20,622 --> 01:06:23,225 CELLS, PARTICULARLY B-CELLS, 1751 01:06:23,225 --> 01:06:27,562 ANDA ANTIGEN PRESENTING CELLS OR 1752 01:06:27,562 --> 01:06:31,099 PDCs, TLR7 IS A SENSOR OF RNA 1753 01:06:31,099 --> 01:06:32,834 AND RNA DEGRADATION PRODUCTS 1754 01:06:32,834 --> 01:06:35,470 DETEBT INDEED THE ENDOSOME, AND 1755 01:06:35,470 --> 01:06:37,706 TLR 7LICATION IN B-CELLS 1756 01:06:37,706 --> 01:06:40,442 ACTIVATES PROLIFERATION IN 1757 01:06:40,442 --> 01:06:42,043 ANTIBODY RESPONSES, TLR 1758 01:06:42,043 --> 01:06:43,912 REGULATION IN DENDRITIC CELLS 1759 01:06:43,912 --> 01:06:45,213 TRIGGERRINGS TYPE 1 INTERFERON 1760 01:06:45,213 --> 01:06:48,116 PRODUCTION AND WE KNOW BOTH OF 1761 01:06:48,116 --> 01:06:49,851 THESE FETTURES DISREGULATED IN 1762 01:06:49,851 --> 01:06:51,586 PATIENTS WITH LUPUS, WELL KNOWN 1763 01:06:51,586 --> 01:06:55,056 THESE PATIENTS PRODUCE AN A 1764 01:06:55,056 --> 01:06:55,557 RANGE OF AUTOANTIBODIES. 1765 01:06:55,557 --> 01:06:57,993 WE HEARD ABOUT THE ATYPICAL 1766 01:06:57,993 --> 01:06:59,127 B-CELLS THAT RESPONSIBLE FOR 1767 01:06:59,127 --> 01:07:00,562 THAT, WHICH LIE DOWN STREAM OF 1768 01:07:00,562 --> 01:07:04,132 TLR SIGNALING AND THERE IS THIS 1769 01:07:04,132 --> 01:07:05,033 LONG RECOGNIZED INTERFERON 1770 01:07:05,033 --> 01:07:07,636 SIGNATURE PRESENT IN PATIENTS 1771 01:07:07,636 --> 01:07:11,206 WITH LUPUS AND PLASMA 1772 01:07:11,206 --> 01:07:12,140 SIGNIFYATOID DENDRITIC CELLS ARE 1773 01:07:12,140 --> 01:07:13,708 A CONTRIBUTOR TO THE SIGNALING, 1774 01:07:13,708 --> 01:07:16,011 THE ONLY CELL TYPE OF INTEREST 1775 01:07:16,011 --> 01:07:17,045 IN THAT INTERFERON SIGNATURE IS 1776 01:07:17,045 --> 01:07:19,214 INTERESTING IN THAT IT'S 1777 01:07:19,214 --> 01:07:20,615 UBIQUITOUS, IT'S PRESENT IN THE 1778 01:07:20,615 --> 01:07:21,783 BLOOD AND TARGET ORELIMINATEDIGE 1779 01:07:21,783 --> 01:07:24,653 AS WELL, SO IT'S KNOWN IS THAT 1780 01:07:24,653 --> 01:07:26,054 TLR 7 CAN CONTRIBUTE TO BOTH 1781 01:07:26,054 --> 01:07:27,355 THESE FEATURES OF THE DISEASE 1782 01:07:27,355 --> 01:07:29,424 AND THAT'S BEEN SHOWN BOTH IN 1783 01:07:29,424 --> 01:07:32,794 MOUSE MODELS AS WELL MORE 1784 01:07:32,794 --> 01:07:34,196 RECENTLY IN POLYMORPHISMS 1785 01:07:34,196 --> 01:07:36,298 DESCRIBED IN HUMANS WITH SLE, SO 1786 01:07:36,298 --> 01:07:37,933 JUST TO QUICKLY REVIEW THESE 1787 01:07:37,933 --> 01:07:41,469 CONCEPTS AGAIN, THERE ARE MANY 1788 01:07:41,469 --> 01:07:43,772 MOUSE MODELS OF SLE AND SEVERAL 1789 01:07:43,772 --> 01:07:48,043 OF THEM ARE TLR DEPENDENT, THE 1790 01:07:48,043 --> 01:07:49,878 YAA MODEL LONG STANDING USED 1791 01:07:49,878 --> 01:07:52,347 MODEL OF LUPUS RESULTS IN THE 1792 01:07:52,347 --> 01:07:55,283 DUPLICATION OF TLR7 ON A PORTION 1793 01:07:55,283 --> 01:07:57,118 OF THE X-CHROMESOME CONTAINING 1794 01:07:57,118 --> 01:07:59,955 TISSUING LR7 ON TO THE Y-GIVING 1795 01:07:59,955 --> 01:08:03,058 THIS THE TLR 7 LINKED PHENOTYPE, 1796 01:08:03,058 --> 01:08:04,893 THE PRISTANE MODEL IS ANOTHER 1797 01:08:04,893 --> 01:08:07,963 EXAMPLE OF A MOUSE MODEL THAT 1798 01:08:07,963 --> 01:08:09,097 GENERATES AUTOANTIBODIES, TYPE 1 1799 01:08:09,097 --> 01:08:10,632 INTERFERON AND END ORGAN DAMAGE 1800 01:08:10,632 --> 01:08:13,201 THAT MIMICS THE HUMAN DEC, 1801 01:08:13,201 --> 01:08:14,669 STUDIES IN TLR 7 KNOCK OUT MOUSE 1802 01:08:14,669 --> 01:08:17,005 HAVE SHOWN THAT IT TLR 7 SIGNAL 1803 01:08:17,005 --> 01:08:18,273 SUGGEST KEY FOR INDUCING 1804 01:08:18,273 --> 01:08:20,508 PATHOLOGY SEEN IN THAT MODEL. 1805 01:08:20,508 --> 01:08:22,043 AND MORE RECENTLY, KIND OF A 1806 01:08:22,043 --> 01:08:24,512 SIMPLER MODEL OF LUPUS HAS BEEN 1807 01:08:24,512 --> 01:08:28,116 DERIVED BY SIMPLY DIRECTLY 1808 01:08:28,116 --> 01:08:29,884 ACTIVATING TLR7 IN WILD-TYPE 1809 01:08:29,884 --> 01:08:31,820 MICE USING THESE ANALOGUES AND 1810 01:08:31,820 --> 01:08:33,255 THESE MICE ALSO DEVELOP 1811 01:08:33,255 --> 01:08:34,656 ANTIBODIES AND AGER AN DAMAGE 1812 01:08:34,656 --> 01:08:37,158 THAT MIMICS THE HUMAN DISEASE 1813 01:08:37,158 --> 01:08:40,829 EMPLOY SO SEVERAL EXAMPLES OF 1814 01:08:40,829 --> 01:08:42,497 MICE OF ENDOPATHOLOGY AND 1815 01:08:42,497 --> 01:08:43,598 AUTOANTIBODY PROFILES THAT 1816 01:08:43,598 --> 01:08:44,799 RESEMBLE THE HUMAN ILLNESS THAT 1817 01:08:44,799 --> 01:08:50,772 ARE ALL LINKED TO TLR SIGNAL 7 1818 01:08:50,772 --> 01:08:51,072 SIGNALING. 1819 01:08:51,072 --> 01:08:52,407 THE SAME TIME MORE RECENTLY 1820 01:08:52,407 --> 01:08:53,275 THERE'S BEEN EVIDENCE GAIN 1821 01:08:53,275 --> 01:08:55,810 INDEED HUMANS THAT GAIN OF 1822 01:08:55,810 --> 01:08:57,078 FUNCTION MUTATIONS IN TON LR 7 1823 01:08:57,078 --> 01:09:04,886 CAN BE FOUND IN PATES WITH ADULT 1824 01:09:04,886 --> 01:09:06,955 ONSET, SLE, SO THIS GROUP 2 1825 01:09:06,955 --> 01:09:07,689 YEARS AGO PUBLISHED THIS ON 1826 01:09:07,689 --> 01:09:08,690 ACTIVITIES AND PROJECTS INITIAL 1827 01:09:08,690 --> 01:09:10,225 CASE OF YOUNG PATIENT WITH 1828 01:09:10,225 --> 01:09:12,027 CLINICAL FEATURES OF LUPUS THAT 1829 01:09:12,027 --> 01:09:13,528 IDENTIFIED THAT MUTATION IN TLR 1830 01:09:13,528 --> 01:09:18,733 7 AS BEING RESPONSIBLE FOR THE 1831 01:09:18,733 --> 01:09:21,836 PHENOTYPE, THEY WENT TO TO 1832 01:09:21,836 --> 01:09:23,371 IDENTIFY 2 UNRELATED PHENOTYPES 1833 01:09:23,371 --> 01:09:25,540 IN PATIENTS WHO HAD EARLY SEVERE 1834 01:09:25,540 --> 01:09:26,941 SLE, NOW WHAT THESE PATIENTS HAD 1835 01:09:26,941 --> 01:09:29,611 IN COMMON IS THAT THEY LOWERED 1836 01:09:29,611 --> 01:09:33,148 THE THRESHOLD FOR T LR 1837 01:09:33,148 --> 01:09:34,215 ACTIVATION IN THE CELL SYSTEM, 1838 01:09:34,215 --> 01:09:35,750 THEY WEPT ON TO PUT 1 OF THESE 1839 01:09:35,750 --> 01:09:37,085 IN THE MOUSE AND GENERATED 1840 01:09:37,085 --> 01:09:40,789 ANOTHER MOUSE MODEL OF SLE, THE 1841 01:09:40,789 --> 01:09:41,823 FEATURED AUTOANTIBODIES IN ORGAN 1842 01:09:41,823 --> 01:09:44,726 DAMAGE THAT MIMIC THE HUMAN 1843 01:09:44,726 --> 01:09:44,959 DISEASE. 1844 01:09:44,959 --> 01:09:46,127 I WILL POINT OUT THAT MORE 1845 01:09:46,127 --> 01:09:48,096 RECENTLY JUST WITHIN THE LAST 2 1846 01:09:48,096 --> 01:09:52,734 MONTHS, A GROUP IN GERMANY HAS 1847 01:09:52,734 --> 01:09:54,736 DESCRIBED ARK DITIONAL MUTATIONS 1848 01:09:54,736 --> 01:09:58,306 NOT IN TLR 7 ITSELF, AND IN A 1849 01:09:58,306 --> 01:09:59,841 YEEN ENCODING TLR7 TURNOVER IN 1850 01:09:59,841 --> 01:10:01,543 THE ENDOSOME, SO THOSE MUTATIONS 1851 01:10:01,543 --> 01:10:03,111 WERE IDENTIFIED ALSO IN PATIENTS 1852 01:10:03,111 --> 01:10:04,646 WITH EARLY ONSET SEVERE SLE, 1853 01:10:04,646 --> 01:10:08,116 WITH WITH THESE MUTATIONS DO IS 1854 01:10:08,116 --> 01:10:09,851 TO PROLONG TLR 7 SIGNALING IN 1855 01:10:09,851 --> 01:10:12,987 THE ENDOSOME BY BLOCKING 1856 01:10:12,987 --> 01:10:17,158 DEGRADATION AND TURNOVER IN THE 1857 01:10:17,158 --> 01:10:18,026 SENSOR COMPARTMENT. 1858 01:10:18,026 --> 01:10:19,427 SO OBSERVATIONS MADE BOTH IN 1859 01:10:19,427 --> 01:10:21,196 HUMANS WITH THE DISEASE AND IN 1860 01:10:21,196 --> 01:10:23,932 MICE, GOING TO TLR 7, THE OTHER 1861 01:10:23,932 --> 01:10:26,334 POINT I WANTED TO MAKE ON THIS 1862 01:10:26,334 --> 01:10:28,870 SLIDE IS THAT IN THE PAST 10-20 1863 01:10:28,870 --> 01:10:31,072 YEARS THERE ARE BEEN MANY 1864 01:10:31,072 --> 01:10:31,673 POLYMORPHISMS IDENTIFIED IN 1865 01:10:31,673 --> 01:10:34,542 GENES IN THE INNATE IMMUNE 1866 01:10:34,542 --> 01:10:37,779 SYSTEM, WHICH CAN BE ASSOCIATED 1867 01:10:37,779 --> 01:10:39,280 WITH STERILE INFLAMMATORY 1868 01:10:39,280 --> 01:10:43,918 SYNDROMES, NOT ALL OF THOSE 1869 01:10:43,918 --> 01:10:45,220 MUTATIONS GENERATE CLINICAL 1870 01:10:45,220 --> 01:10:47,188 PHENOTYPES THAT PERFECTLY MIMIC 1871 01:10:47,188 --> 01:10:48,356 OUR RHEUMATIC DISEASES, SO FOR 1872 01:10:48,356 --> 01:10:50,291 EXAMPLE, GAIN OF FUNCTIONS IN 1873 01:10:50,291 --> 01:10:53,194 STING, A KEY COMPONENT OF THE 1874 01:10:53,194 --> 01:10:54,028 CELL INTRINSIC RESPONSE, IS 1875 01:10:54,028 --> 01:10:54,996 ASSOCIATE WIDE A CLINICAL 1876 01:10:54,996 --> 01:10:56,598 SYNDROME THAT HAS FEATURES OF 1877 01:10:56,598 --> 01:10:58,099 OUR DISEASES BUT DOES NOT LOOK 1878 01:10:58,099 --> 01:11:00,902 LIKE WHAT WE THINK OF AS 1879 01:11:00,902 --> 01:11:02,637 RHEUMATOLOGISTS AS IDIO TAGHTIC 1880 01:11:02,637 --> 01:11:03,972 SLE AND WHAT IS REALLY 1881 01:11:03,972 --> 01:11:05,607 COMPELLING ABOUT THESE MUTATION 1882 01:11:05,607 --> 01:11:07,542 SYSTEM THAT THEY'RE IDENTIFIED 1883 01:11:07,542 --> 01:11:09,978 IN PATIENTS, WHO HAVE FEATURED 1884 01:11:09,978 --> 01:11:11,613 THAT LOOK LIKE THE CLASSICALLY 1885 01:11:11,613 --> 01:11:14,582 THOUGHT OF IDIO PATHIC DISEASE. 1886 01:11:14,582 --> 01:11:17,018 SO WHAT WE SET OUT TO DO HERE 1887 01:11:17,018 --> 01:11:19,387 WAS RECOGNIZING THE FACT THAT 1888 01:11:19,387 --> 01:11:22,891 TLR 7 IS HEAVILY IMPLICATED IN 1889 01:11:22,891 --> 01:11:24,025 LUPUS PATHOGENESIS, AND 1890 01:11:24,025 --> 01:11:25,860 RECOGNIZING THIS FACT THAT LUPUS 1891 01:11:25,860 --> 01:11:28,630 IS SO HIGHLY FEMALE BIASED, 1892 01:11:28,630 --> 01:11:29,964 LET'S POSE THE QUESTION OF 1893 01:11:29,964 --> 01:11:32,901 WHETHER THERE ARE ENDOGENOUS RNA 1894 01:11:32,901 --> 01:11:35,136 LIGANDS THAT ARE FEMALE ENRICHED 1895 01:11:35,136 --> 01:11:37,806 OR FEMALE SPECIFIC THAT COULD BE 1896 01:11:37,806 --> 01:11:39,674 RESPONSIBLE FOR ACTIVATION OF 1897 01:11:39,674 --> 01:11:41,543 THE SENSOR IN THIS DISEASE. 1898 01:11:41,543 --> 01:11:44,679 AND SO THIS QUESTION IS KIND OF 1899 01:11:44,679 --> 01:11:46,781 POSED WITHIN A LARGER FRAMEWORK, 1900 01:11:46,781 --> 01:11:48,516 WITHIN THE LAST FEW YEARS, 1901 01:11:48,516 --> 01:11:50,652 INTEREST IN UNDERSTANDING 1902 01:11:50,652 --> 01:11:53,455 WHETHER THERE ARE SPECIFIC 1903 01:11:53,455 --> 01:11:54,823 ENDOGENOUS NUCLEIC ASITS THAT 1904 01:11:54,823 --> 01:11:56,391 DRIF THE IMMUNE PATHOLOGY THAT 1905 01:11:56,391 --> 01:11:59,194 DRIVE WHAT WE SEE IN SLE AND 1906 01:11:59,194 --> 01:12:00,962 OTHER INTERFERON LINKED DECS, 1907 01:12:00,962 --> 01:12:04,032 NUCLEIC ACIDS ARE POTENT LIGANDS 1908 01:12:04,032 --> 01:12:05,233 FOR ACTIVATING VARIOUS 1909 01:12:05,233 --> 01:12:06,000 COMPONENTS OF THE INTERFERON 1910 01:12:06,000 --> 01:12:08,269 SYSTEM, SO FOR EXAMPLE, 1911 01:12:08,269 --> 01:12:09,070 MITOCHONDRIA DNETWORKA IS A 1912 01:12:09,070 --> 01:12:11,973 SOURCE OF DOUBLE STRANDED DNA 1913 01:12:11,973 --> 01:12:14,843 THAT CAN ACTIVATE CGAS, 1914 01:12:14,843 --> 01:12:15,643 CYTOSTOOL DNAIC SENSOR, THIS HAS 1915 01:12:15,643 --> 01:12:17,846 BEEN OF INTEREST IN THE SLE 1916 01:12:17,846 --> 01:12:20,548 TODAY IN RECENT YEARS, THERE IS 1917 01:12:20,548 --> 01:12:23,218 A GAIN OF FUNCTION MUTATION, 1918 01:12:23,218 --> 01:12:25,653 DESCRIBED IN MDA 5 WHICH IS A 1919 01:12:25,653 --> 01:12:27,388 CYTOSOLIC SENSOR OF DOUBLE 1920 01:12:27,388 --> 01:12:28,690 STRANDED RNA, AN EFFORT TO 1921 01:12:28,690 --> 01:12:30,592 UNDERSTAND WHAT YOU THIS CLAYIC 1922 01:12:30,592 --> 01:12:32,460 ACIDS ARE RESPONSIBLE FOR 1923 01:12:32,460 --> 01:12:35,864 ACTIVATING THIS GAIN OF 5, THIS 1924 01:12:35,864 --> 01:12:37,599 MDA GAIN OF 5 FUNCTION MUTANT IN 1925 01:12:37,599 --> 01:12:40,768 PATIENTS WHO HAVE THIS IN THE 1926 01:12:40,768 --> 01:12:42,537 SETTING OF GENETICALLY DRIVEN 1927 01:12:42,537 --> 01:12:48,710 SLE, LED TO IDENTISK OF ALU, 1928 01:12:48,710 --> 01:12:50,545 CELLULAR DUPLEXS AS A SOURCE 1929 01:12:50,545 --> 01:12:51,913 THAT MDA 5 LIGAND. 1930 01:12:51,913 --> 01:12:54,582 SO THESE DIEWP PLEXS ARE 1931 01:12:54,582 --> 01:12:55,483 CAPABILITY OF ACTIVATING THIS 1932 01:12:55,483 --> 01:12:58,319 GAIN OF FUNCTION MUTANT BUT NOT 1933 01:12:58,319 --> 01:13:01,022 CAPABILITY OF ACTIVATING THE 1934 01:13:01,022 --> 01:13:02,590 WILD-TYPE AND THIS MUTATION WAS 1935 01:13:02,590 --> 01:13:06,895 IDENTIFIED IN PATIENT WHO IS HAD 1936 01:13:06,895 --> 01:13:07,095 SLE. 1937 01:13:07,095 --> 01:13:08,263 A THIRD REFERENCE THAT I'LL 1938 01:13:08,263 --> 01:13:10,965 POINT OUT IS THIS PAPER FROM 1939 01:13:10,965 --> 01:13:13,034 SOME YEARS AGO, THOUGHT TO 1940 01:13:13,034 --> 01:13:15,570 IDENTIFY SPECIFIC RNAs TO 1941 01:13:15,570 --> 01:13:17,305 INTERACT WITH RO 60 WHICH IS THE 1942 01:13:17,305 --> 01:13:19,741 HALLMARK ANTIIENS THAT ARE 1943 01:13:19,741 --> 01:13:20,842 FEATURED IN RHEUMATIC DECS, AND 1944 01:13:20,842 --> 01:13:22,510 HERE AGAIN, IT WAS IDENTIFIED AS 1945 01:13:22,510 --> 01:13:25,280 A SOURCE OF RNA FOUND IN 1946 01:13:25,280 --> 01:13:28,449 COMPLEXES WITH ROW 60, AND THE 1947 01:13:28,449 --> 01:13:30,852 MODEL HERE IS THAT 1948 01:13:30,852 --> 01:13:32,387 AUTOANTIBODIES CAN CONVEY 1949 01:13:32,387 --> 01:13:34,489 TAKEN--THEY ALU RNA TO ASPECT 1950 01:13:34,489 --> 01:13:35,957 GEN PRESENTING CELLS TO THE 1951 01:13:35,957 --> 01:13:36,624 IMMUNE COMPLEX. 1952 01:13:36,624 --> 01:13:39,494 SO EXAMPLES OF EFFORTS TO 1953 01:13:39,494 --> 01:13:40,562 IDENTIFY SPECIFIC NUCLEIC ACIDS 1954 01:13:40,562 --> 01:13:41,963 THAT CAN ACTIVATE THE INTERFERON 1955 01:13:41,963 --> 01:13:43,731 SYSTEM, BUT HERE WE WANT TO 1956 01:13:43,731 --> 01:13:46,701 APPLY THIS FILTER OF SEX BIAS, 1957 01:13:46,701 --> 01:13:49,237 AND THERE'S AN OPPORTUNITY TO DO 1958 01:13:49,237 --> 01:13:50,505 THAT, WITH TLR 7 BECAUSE IN 1959 01:13:50,505 --> 01:13:52,740 CONTRAST TO THESE OTHER SENSORS 1960 01:13:52,740 --> 01:13:55,944 I JUST MENTIONED, TLR 7 SHOWS 1961 01:13:55,944 --> 01:13:57,812 SOME SEQUENCE SPECIFICITY IN ITS 1962 01:13:57,812 --> 01:14:04,052 MODE OF ACTIVATION, SO, TLR 7 AS 1963 01:14:04,052 --> 01:14:11,526 2 BINDING SITES, 1 THAT IS BOUND 1964 01:14:11,526 --> 01:14:13,628 BY GUANA SIGN AND A SECOND SPIKE 1965 01:14:13,628 --> 01:14:15,930 IN THE SINGLE RNA FRAGMENTS AND 1966 01:14:15,930 --> 01:14:17,699 1 COMPONENT THAT'S BEEN IDENTIFY 1967 01:14:17,699 --> 01:14:21,302 INDEED GENERATING A POTENT 1968 01:14:21,302 --> 01:14:23,037 LIGAND TO ACTIVATE TLR7 AT THIS 1969 01:14:23,037 --> 01:14:29,711 SITE IS THE PRESENCE OF 1970 01:14:29,711 --> 01:14:32,447 UU SPECIFICITY AND THESE ARE IN 1971 01:14:32,447 --> 01:14:35,650 CONTRAST TO THE 2 OTHER SENSORS 1972 01:14:35,650 --> 01:14:37,051 I JUST MENTIONED, CGAS WHICH 1973 01:14:37,051 --> 01:14:39,554 RECK NICES THE SHAPE OF DOUBLE 1974 01:14:39,554 --> 01:14:44,125 STRAND THE DNA IN A INDEPENDENT 1975 01:14:44,125 --> 01:14:45,927 FASHION AND NDMA 5 THAT IS 1976 01:14:45,927 --> 01:14:46,894 DOUBLE STRANDED ON THE WAY TO 1977 01:14:46,894 --> 01:14:49,897 THE MOLECULE AND NOT THE 1978 01:14:49,897 --> 01:14:51,065 NUCLEOTIDE SEQUENCE, SO 1979 01:14:51,065 --> 01:14:53,267 UU RICHNESS IS A FACTOR WE CHOSE 1980 01:14:53,267 --> 01:14:56,738 TO FOCUS ON, WHEN LOOKING FOR 1981 01:14:56,738 --> 01:15:00,408 POTENTIAL ENDOGENOUS TLR 7 1982 01:15:00,408 --> 01:15:02,443 LIGANDS, THERE IS ANOTHER 1983 01:15:02,443 --> 01:15:05,880 EXAMPLE TO INDICATE THAT THE 1984 01:15:05,880 --> 01:15:09,183 DINUCLEOTIDES ALONE ARE NOT THE 1985 01:15:09,183 --> 01:15:11,986 SOLE DETERMINANT OF AN RNA'S 1986 01:15:11,986 --> 01:15:13,287 ABILITY TO ACTIVATE RNA7 BUT 1987 01:15:13,287 --> 01:15:14,722 THAT THE SURROUNDING MOTIFS MAY 1988 01:15:14,722 --> 01:15:16,858 INFLUENCE THAT AS WELL, SO THIS 1989 01:15:16,858 --> 01:15:18,126 A PUBLICATION PUBLISHED SEVERAL 1990 01:15:18,126 --> 01:15:21,029 YEARS AGO NOW FROM A GROUP THAT 1991 01:15:21,029 --> 01:15:22,530 WAS USING SiRNA TO KNOCK DOWN 1992 01:15:22,530 --> 01:15:24,966 GENE TARGETS IN THE ANTIGEN 1993 01:15:24,966 --> 01:15:26,934 PRESENTING CELLS AND FOUND 1994 01:15:26,934 --> 01:15:28,569 UNEXPECTEDLY THAT THESE COULD 1995 01:15:28,569 --> 01:15:31,639 TRIGGER INTERFERON PRODUCTION IN 1996 01:15:31,639 --> 01:15:32,707 PLASMA SIGNIFYATOID DENDRITIC 1997 01:15:32,707 --> 01:15:35,476 CELLS AND THEY MAPPED THEM OUT 1998 01:15:35,476 --> 01:15:36,778 AND IDENTIFIED SEQUENCES 1999 01:15:36,778 --> 01:15:38,780 INCLUDING THE 9 BASE SEQUENCE 2000 01:15:38,780 --> 01:15:41,215 WHICH THEY REFERRED TO AS 2001 01:15:41,215 --> 01:15:42,750 SiRNA 9.2 AND I WILL REFER TO 2002 01:15:42,750 --> 01:15:44,952 THIS AS WE MOVE AHEAD IN OUR DAT 2003 01:15:44,952 --> 01:15:46,754 AND THIS IS 2 FEATURES WE CHOSE 2004 01:15:46,754 --> 01:15:50,658 TO UTILIZE IN LOOKING FOR 2005 01:15:50,658 --> 01:15:53,261 POTENTIAL ENDOGENOUS TLR 7 2006 01:15:53,261 --> 01:15:53,861 LIGANDS. 2007 01:15:53,861 --> 01:15:55,363 SO THE STARTING POINT HERE WAS 2008 01:15:55,363 --> 01:15:59,033 GENE EXPRESSION DATA FROM THE 2009 01:15:59,033 --> 01:16:00,768 G-TEXT DATABASE, THIS IS DATA 2010 01:16:00,768 --> 01:16:01,636 DERIVE FRIDAY HEALTHY CONTROLS 2011 01:16:01,636 --> 01:16:05,339 AND WHAT WE DID WAS TO FIRST 2012 01:16:05,339 --> 01:16:07,008 LOOK FOR RNA MOLECULES THAT WERE 2013 01:16:07,008 --> 01:16:08,509 RICH IN THESE UU DISCIPLINARY 2014 01:16:08,509 --> 01:16:13,881 YOU DINUCLEOTIDE 2015 01:16:13,881 --> 01:16:14,782 REPEATS, WITH THE EXPRESSION 2016 01:16:14,782 --> 01:16:16,484 BIAS SO WE SEE ON THE PLATIS 2017 01:16:16,484 --> 01:16:17,985 THAT TRANSCRIPT ITS THE RIGHT 2018 01:16:17,985 --> 01:16:19,854 ARE FEMALE SPECIFIC AND EXIST, 2019 01:16:19,854 --> 01:16:21,789 HERE AN OUTLIER IN BEING 2020 01:16:21,789 --> 01:16:23,458 ENTIRELY FEMALE SPECIFIC AND 2021 01:16:23,458 --> 01:16:28,496 CONTAINING A LARGE NUMBER OF 2022 01:16:28,496 --> 01:16:28,930 THESE UU REPEATS. 2023 01:16:28,930 --> 01:16:30,164 WE CONSIDER THE FACT THAT THE 2024 01:16:30,164 --> 01:16:32,133 LINK OF AN RNA WOULD INFLUENCE 2025 01:16:32,133 --> 01:16:35,703 ITS ABILITY TO CONTAIN THESE 2026 01:16:35,703 --> 01:16:38,172 UU-DINUCLEOTIDES AND THAT 2027 01:16:38,172 --> 01:16:39,340 PERHAPS SMALLER RNAs THAT 2028 01:16:39,340 --> 01:16:41,109 CONTAIN A HIGH DENSITY OF THOSE 2029 01:16:41,109 --> 01:16:42,643 REPEATS MIGHT BE MORE POTENT 2030 01:16:42,643 --> 01:16:44,045 THAN A REALLY LONG RNA WITH 2031 01:16:44,045 --> 01:16:46,347 JUDGE UOF THE A FEW SCATTERED 2032 01:16:46,347 --> 01:16:49,150 OVER A GREAT REGION AND SO WE 2033 01:16:49,150 --> 01:16:50,218 CALCULATED MAXIMUM UU RICHNESS 2034 01:16:50,218 --> 01:16:52,553 WHICH WAS THE MAXIMUM NUMBER OF 2035 01:16:52,553 --> 01:16:53,755 THESE MOTIFS PRESCRIBINGENT 2036 01:16:53,755 --> 01:16:56,958 WITHIN A 500 BASE REEJ OF ANY 2037 01:16:56,958 --> 01:16:58,726 RNA TRANSCRIPT AND AGAIN WHEN 2038 01:16:58,726 --> 01:17:00,661 COMPARED TO FEMALE VERSUS MALE 2039 01:17:00,661 --> 01:17:02,163 EXPRESSION, EXIST IS NOTABLE IN 2040 01:17:02,163 --> 01:17:03,097 BEING FEMALE SPECIFIC AND 2041 01:17:03,097 --> 01:17:05,199 CONTAINING A LOT OF THESE OR A 2042 01:17:05,199 --> 01:17:09,604 HIGH DEGREE OF UU RICHNESS. 2043 01:17:09,604 --> 01:17:11,272 WE THEN LOOK FOR TRANSCRIPTS 2044 01:17:11,272 --> 01:17:13,674 THAT CONTAIN THE 9 BASE SEQUENCE 2045 01:17:13,674 --> 01:17:15,543 THAT HAD BEEN PREVIOUSLY 2046 01:17:15,543 --> 01:17:18,279 IDENTIFIED AS A TLR7 AGONIST AND 2047 01:17:18,279 --> 01:17:19,113 WE IDENTIFY ROUGHLY 300 RNAs 2048 01:17:19,113 --> 01:17:21,449 IN THE DATA SET THAT CONTAIN THE 2049 01:17:21,449 --> 01:17:24,752 MOTIF AND ONLY 1 OF THEM WAS 2050 01:17:24,752 --> 01:17:29,991 FEMALE SPECIFIC AND THAT WAS 2051 01:17:29,991 --> 01:17:32,160 XIST, NOW I DON'T NEED TO REVIEW 2052 01:17:32,160 --> 01:17:33,461 WHAT XIST WE'VE BEEN TALKING 2053 01:17:33,461 --> 01:17:34,962 ABOUT IT FOR OVER AN HOUR BUT I 2054 01:17:34,962 --> 01:17:37,398 WILL POINT OUT YES THIS, IS THE 2055 01:17:37,398 --> 01:17:39,500 SAME XIST MOLECULE THAT'S BEEN 2056 01:17:39,500 --> 01:17:40,234 IMPLICATE INDEED AUTOIMMUNITY 2057 01:17:40,234 --> 01:17:41,302 FOR THE 2 REASONS WE JUST HEARD 2058 01:17:41,302 --> 01:17:43,204 ABOUT AND WHEN WE WERE IN THE 2059 01:17:43,204 --> 01:17:44,405 EARLY STAGES OF THIS WORK, WE 2060 01:17:44,405 --> 01:17:45,773 WERE SURPRISED TO SEE THIS 2061 01:17:45,773 --> 01:17:47,074 COMING UP IN THE SCREEN BECAUSE 2062 01:17:47,074 --> 01:17:48,910 THERE WERE ALREADY REASONS TO 2063 01:17:48,910 --> 01:17:52,079 IMPLICATE EXIST IN THE TWEPMENT 2064 01:17:52,079 --> 01:17:55,516 OF AUTOIMMUNITY. 2065 01:17:55,516 --> 01:17:56,784 SPECIFICALLY, 2066 01:17:56,784 --> 01:17:59,921 DR. [INDISCERNIBLE]'S WORK 2067 01:17:59,921 --> 01:18:00,755 SHOWING THAT BIOALLELIC 2068 01:18:00,755 --> 01:18:03,457 EXPRESSION COULD BE DRIIVE BY 2069 01:18:03,457 --> 01:18:05,827 LOSS OF SILENCING ENACTIVATE X 2070 01:18:05,827 --> 01:18:07,595 WHICH COULD CONTRIBUTE TO 2071 01:18:07,595 --> 01:18:08,863 UPREGULATION OF THE THE SENSOR 2072 01:18:08,863 --> 01:18:11,799 SO IN THIS MODEL WHERE TLR 7 2073 01:18:11,799 --> 01:18:13,634 COULD BE UPREGULATED IN PATIENTS 2074 01:18:13,634 --> 01:18:14,268 WITH AUTOIMMUNITY. 2075 01:18:14,268 --> 01:18:15,203 WE FOUND EXIST COMING TO THE POP 2076 01:18:15,203 --> 01:18:17,405 OF THIS LIST OF POTENTIAL 2077 01:18:17,405 --> 01:18:19,040 CANDIDATES OF BEING THE LIGAND 2078 01:18:19,040 --> 01:18:21,475 FOR THAT VERY SAME SENSOR. 2079 01:18:21,475 --> 01:18:26,013 AS WAS MENTIONED, BY DR. DOU, 2080 01:18:26,013 --> 01:18:28,983 DR. CHANG'S LAB HAD PUBLISHED A 2081 01:18:28,983 --> 01:18:30,785 DESCRIPTION OF PROTEIN 2082 01:18:30,785 --> 01:18:31,519 INTERACTORS WITH SEVERAL 2083 01:18:31,519 --> 01:18:33,521 AUTOANTIGENS ON THAT LIST, SO 2084 01:18:33,521 --> 01:18:34,755 THERE ARE REASON ALREADY TO 2085 01:18:34,755 --> 01:18:38,192 EXIST EXIST AS A CONTRIBUTOR TO 2086 01:18:38,192 --> 01:18:39,827 AUTOIMMUNITY BUT HERE FINDING IT 2087 01:18:39,827 --> 01:18:41,729 WHEN APPROACHING THIS QUESTION 2088 01:18:41,729 --> 01:18:47,268 FROM A DIFFERENT ANGLE. 2089 01:18:47,268 --> 01:18:48,769 SO NEXT WE CONSIDERED THE 2090 01:18:48,769 --> 01:18:50,371 OVERALL EXPRESSION LEVELS THAT 2091 01:18:50,371 --> 01:18:53,374 WOULD BE A SIGNIFICANT FACTOR IN 2092 01:18:53,374 --> 01:18:54,175 GIVING AN RNA MOLECULE 2093 01:18:54,175 --> 01:18:57,178 OPPORTUNITY TO KROWBT TO TLR 7 2094 01:18:57,178 --> 01:18:58,913 SIGNALING SO THESE ARE PLOTS 2095 01:18:58,913 --> 01:19:03,117 LOOKING JUST IN FEMALES IN THE 2096 01:19:03,117 --> 01:19:05,086 SAME PERIPHERAL BLOOD SATTA SET, 2097 01:19:05,086 --> 01:19:07,555 WE'RE LOOKING AT THE COMBINATION 2098 01:19:07,555 --> 01:19:10,157 LEVELS VERSUS THE PRESENCE OF 2099 01:19:10,157 --> 01:19:12,460 THESE UU REPEATS, AND FIND AGAIN 2100 01:19:12,460 --> 01:19:13,060 THAT WHEN ANALYZING THE DAILY 2101 01:19:13,060 --> 01:19:14,729 BASIS AT THIS WAY, EXIST 2102 01:19:14,729 --> 01:19:18,432 REMAINSA THE TOP OF THE LIST OF 2103 01:19:18,432 --> 01:19:20,034 CANDIDATE TLR 7 LIGANDS SO 2104 01:19:20,034 --> 01:19:21,669 HIGHLY EXPRESSED AND CONTAINS 2105 01:19:21,669 --> 01:19:26,073 THESE MOTIFS OF INTEREST. 2106 01:19:26,073 --> 01:19:28,709 SO THEN FINALLY WE DEVELOP WHAT 2107 01:19:28,709 --> 01:19:30,544 WE TERMED A TLR7 LIGATION SCORE 2108 01:19:30,544 --> 01:19:33,047 WHERE WE TAKE INTO ACCOUNT THESE 2109 01:19:33,047 --> 01:19:37,018 FEATURES, TOTAL FEMALE BIAS, THE 2110 01:19:37,018 --> 01:19:38,152 MAXIMUM UU RICHNESS AND 2111 01:19:38,152 --> 01:19:39,086 EXPRESSION LEVELS AND LOOK NOT 2112 01:19:39,086 --> 01:19:41,289 ONLY IN BLOOD BUT OF OTHER 2113 01:19:41,289 --> 01:19:43,824 TISSUES OF AND ALL TISSUES 2114 01:19:43,824 --> 01:19:44,992 PRESENT IN THE DATABASE AND YOU 2115 01:19:44,992 --> 01:19:47,795 CAN SEE HERE IN LOOKING ACROSS 2116 01:19:47,795 --> 01:19:49,363 ALL TISSUES REMAINS AN OUTLIER, 2117 01:19:49,363 --> 01:19:50,631 IT HAS THESE FEATURES THAT COULD 2118 01:19:50,631 --> 01:19:54,302 MAKE IT A FEMALE SPECIFIC TLR 7 2119 01:19:54,302 --> 01:20:00,241 LIGAND AND VERY UBIQUITOUSLY 2120 01:20:00,241 --> 01:20:00,508 EXPRESSED. 2121 01:20:00,508 --> 01:20:02,710 SO WE THEN WANTED TO FIGURE OUT 2122 01:20:02,710 --> 01:20:04,345 WHAT PORTIONS OF THE MOLECULE WE 2123 01:20:04,345 --> 01:20:07,682 COULD FOCUS ON, SO THIS IS A 2124 01:20:07,682 --> 01:20:09,750 PLOT OF THE UU RICHNESS ACROSS 2125 01:20:09,750 --> 01:20:11,485 THE MOLECULE, AND WHAT YOU CAN 2126 01:20:11,485 --> 01:20:14,388 SEE HERE IS THE DOTTED LINE THIS 2127 01:20:14,388 --> 01:20:16,724 IS THE AVERAGE UU RICHNESS OF 2128 01:20:16,724 --> 01:20:18,159 ALL TRANSCRIPTS PRESENT IN THE 2129 01:20:18,159 --> 01:20:20,728 DATABASE, SO KIND OF AN AVERAGE 2130 01:20:20,728 --> 01:20:22,163 UU RICHNESS, AND EXIST IS 2131 01:20:22,163 --> 01:20:24,565 REMARKABLE AND BASICALLY THE 2132 01:20:24,565 --> 01:20:25,866 ENTIRE MOLECULE LIES ABOVE THAT 2133 01:20:25,866 --> 01:20:28,169 LINE, THERE ARE 2 PARTS THAT 2134 01:20:28,169 --> 01:20:30,604 REALLY STAND OUT, THIS A-REPEAT 2135 01:20:30,604 --> 01:20:31,772 REAMINGION WHICH IS PARTICULARLY 2136 01:20:31,772 --> 01:20:34,875 DENSE WITH THE UU MOTIFS AND A 2137 01:20:34,875 --> 01:20:37,511 MORE DISTAL COMPONENT IN THE 2138 01:20:37,511 --> 01:20:39,547 VICINITY OF THE REPEAT. 2139 01:20:39,547 --> 01:20:42,483 HERE ON XIST 1 IS A FRAGMENT WE 2140 01:20:42,483 --> 01:20:45,720 CHOSE TO LOOK AT BASED ON PRIOR 2141 01:20:45,720 --> 01:20:47,121 IDENTIFICATION OF THIS ON A 2142 01:20:47,121 --> 01:20:50,691 PRIOR LIGAND, THAT WAS ON TLR 1, 2143 01:20:50,691 --> 01:20:53,260 AND WE TERM THIS XIST 1.1 AND WE 2144 01:20:53,260 --> 01:20:55,329 DO THESE INVITRO TO LOOK AT 2145 01:20:55,329 --> 01:20:57,698 THESE 2 PORTIONS OF THE MOLECULE 2146 01:20:57,698 --> 01:20:59,867 TO PROVE THESE AREAS OF EXIST 2147 01:20:59,867 --> 01:21:03,771 ARE CAPABLE OF ACTIVATING TLR 7. 2148 01:21:03,771 --> 01:21:07,241 SO WE STARTED WITH THIS 2149 01:21:07,241 --> 01:21:10,511 FRAGMENT, WE ISOLATED 20 BASE 2150 01:21:10,511 --> 01:21:13,647 SECTION SURROUNDING THIS 9 MER, 2151 01:21:13,647 --> 01:21:16,083 USE THE CONTROL POSITIVE 2 WHICH 2152 01:21:16,083 --> 01:21:17,918 HAD BEEN BREFIOUSLY PUBLISHED AS 2153 01:21:17,918 --> 01:21:20,688 WELL AS ANTISENSE AND POLY-A AS 2154 01:21:20,688 --> 01:21:22,990 WELL AS NEGATIVE CONTROLS. 2155 01:21:22,990 --> 01:21:26,060 PUTTING THESE IN HEALTHY DONOR 2156 01:21:26,060 --> 01:21:29,163 PLASMA SIGHT DENDRITIC CELLS, WE 2157 01:21:29,163 --> 01:21:32,266 SHOWED THIS XIST WAS ABLE TO 2158 01:21:32,266 --> 01:21:33,200 ACTIVATE INTERFERON EXPRESSION 2159 01:21:33,200 --> 01:21:35,936 BY USING PDCs AND WE USE THE 2160 01:21:35,936 --> 01:21:36,937 SAME FRAGMENTS IN A REPORTER 2161 01:21:36,937 --> 01:21:38,873 CELL LINE AND YOU CAN SEE IN 2162 01:21:38,873 --> 01:21:40,841 THIS DOSE RESPONSE EXPERIMENT, 2163 01:21:40,841 --> 01:21:42,109 IS THAT THE EXIST FREG 2164 01:21:42,109 --> 01:21:43,944 MENTORSHIP SKILL AND THIS 2165 01:21:43,944 --> 01:21:45,079 POSITIVE CONTROL BEHAVE 2166 01:21:45,079 --> 01:21:45,346 SIMILARLY. 2167 01:21:45,346 --> 01:21:48,983 THEN WE WANTED TO CONFIRM, A 2168 01:21:48,983 --> 01:21:50,151 DIRECT INTERACTION INVITRO WAS 2169 01:21:50,151 --> 01:21:51,085 RESPONSIBLE FOR THESE FINDINGS 2170 01:21:51,085 --> 01:21:53,421 IN CELLS SO WE USE FLUORESCENCE 2171 01:21:53,421 --> 01:21:55,823 WHICH WOULD BE BASED LIGAND 2172 01:21:55,823 --> 01:21:57,091 BINDING ASSAY THAT HOE THAT 2173 01:21:57,091 --> 01:22:01,996 EXIST IN THIS POSITIVE CONTROL 2174 01:22:01,996 --> 01:22:02,830 OLIGIO-INTERACT DIRECTLY WITH 2175 01:22:02,830 --> 01:22:04,598 THE FASHION IN SIMILAR AFFINITYS 2176 01:22:04,598 --> 01:22:06,667 SO INDEED THIS PART OF EXIST, 2177 01:22:06,667 --> 01:22:09,370 APPEARS CAPABLE OF BINDING TO 2178 01:22:09,370 --> 01:22:11,038 AND ACTIVATING TLR 7 IN PRIMARY 2179 01:22:11,038 --> 01:22:15,843 CELLS AND A REPORTER CELL 2180 01:22:15,843 --> 01:22:16,210 SYSTEM. 2181 01:22:16,210 --> 01:22:19,213 SO THEN WE LOOKED AT THE 2182 01:22:19,213 --> 01:22:22,049 A-REPEAT, WE ISOLATED A ROUGHLY 2183 01:22:22,049 --> 01:22:23,451 800 BASE FRAGMENT, FROM THAT 2184 01:22:23,451 --> 01:22:26,087 REGION OF EXIST, WHICH WAS THE 2185 01:22:26,087 --> 01:22:29,056 MOST UU DENSE PORTION OF THE 2186 01:22:29,056 --> 01:22:29,323 MOLECULE. 2187 01:22:29,323 --> 01:22:32,460 USED A CONTROL RNA AND AGAIN 2188 01:22:32,460 --> 01:22:33,828 WENT BACK TO OUR REPORTER CELLS 2189 01:22:33,828 --> 01:22:35,763 AND SHOWED THAT WE COULD 2190 01:22:35,763 --> 01:22:37,631 ACTIVATE TLR 7 IN THIS REPORTER 2191 01:22:37,631 --> 01:22:43,971 CELL SYSTEM, PUT THE A-REPEAT 2192 01:22:43,971 --> 01:22:45,473 INTO PRIMARY PDCs AND SHOWED 2193 01:22:45,473 --> 01:22:48,409 WE COULD GENERATE A PRIMARY 2194 01:22:48,409 --> 01:22:50,044 INTERFERON RESPONSE AND BY USING 2195 01:22:50,044 --> 01:22:51,479 HYDROXY CHLOR O QUINAND 2196 01:22:51,479 --> 01:22:52,613 INHIBITORS SHOWED THIS EFFECT 2197 01:22:52,613 --> 01:22:54,915 WAS INDEED DUE TO TLR 7 2198 01:22:54,915 --> 01:22:55,850 ACTIVATION. 2199 01:22:55,850 --> 01:22:59,720 SO THE A-REPEAT, IN ADDITION TO 2200 01:22:59,720 --> 01:23:01,956 THIS FRAGMENT ALSO APPEARS 2201 01:23:01,956 --> 01:23:03,824 CAPABLE OF ACTIVATING TLR 7 BOTH 2202 01:23:03,824 --> 01:23:06,660 IN THE REPORTER CELL SYSTEM AND 2203 01:23:06,660 --> 01:23:07,194 PRIMARY CELLS. 2204 01:23:07,194 --> 01:23:10,197 WE THEN WANTED TO KNOW WHAT WAS 2205 01:23:10,197 --> 01:23:12,266 THE RELATIVE CONTRIBUTION OF 2206 01:23:12,266 --> 01:23:13,701 EACH OF THESE COMPONENTS IN 2207 01:23:13,701 --> 01:23:20,875 TERMS OF POTENCY IN BEING A TLR7 2208 01:23:20,875 --> 01:23:23,577 LIGAND OR SOURCE OF TLR7. 2209 01:23:23,577 --> 01:23:29,817 SO WE EXAMINED THIS USING PICO 2210 01:23:29,817 --> 01:23:31,318 MOLAR EXAMINATIONS AND YOU COULD 2211 01:23:31,318 --> 01:23:33,587 SEE AS YOU WOULD EXPECT THAT THE 2212 01:23:33,587 --> 01:23:36,023 A-REPEAT IS FULL OF THESE 2213 01:23:36,023 --> 01:23:38,759 DINUCLEOTIDE MOTIFS IS A MORE 2214 01:23:38,759 --> 01:23:41,495 POTENT AGONIST, AND IN MORE 2215 01:23:41,495 --> 01:23:44,265 CAPABLE OF GENERATING AN 2216 01:23:44,265 --> 01:23:47,368 INTERFERON RESPONSE OF PDCs IN 2217 01:23:47,368 --> 01:23:48,435 A LOWER CONCENTRATION, SO THE 2218 01:23:48,435 --> 01:23:54,074 EVIDENCE THAT THE UU-ENRICHMENT 2219 01:23:54,074 --> 01:23:58,746 IS MORE IMPORTANT THAN THE 9-MER 2220 01:23:58,746 --> 01:24:00,314 SEQUENCE, SOAZ THESE WERE 2221 01:24:00,314 --> 01:24:02,950 SEQUENCES DONE INVITRO, WHERE WE 2222 01:24:02,950 --> 01:24:05,152 HAD ISOLATED PORTIONS OF THE 2223 01:24:05,152 --> 01:24:06,253 XIST MOLECULE ANDY WOO WANT TO 2224 01:24:06,253 --> 01:24:08,522 PUT IT IN CONTEXT AND ASK THE 2225 01:24:08,522 --> 01:24:10,724 QUESTION OF WHERE DOES XIST SIT 2226 01:24:10,724 --> 01:24:12,493 IN THE ENTIRE TRANSCRIPTOME OF A 2227 01:24:12,493 --> 01:24:15,696 FEMALE CELL IN TERMS OF THE 2228 01:24:15,696 --> 01:24:17,731 RELATIVE CONTRIBUTION TO TLR 7 2229 01:24:17,731 --> 01:24:20,901 ACTIVATION, SO TO DO THAT, WE 2230 01:24:20,901 --> 01:24:23,103 USED A FEMALE DERIVED 2231 01:24:23,103 --> 01:24:25,406 IMMORTALIZED CELL LINE WHICH IS 2232 01:24:25,406 --> 01:24:27,841 EXIST POSITIVE A431 CELL LINE 2233 01:24:27,841 --> 01:24:30,411 AND USE CRSPR EDITING TO DELETE 2234 01:24:30,411 --> 01:24:32,379 EXIST, WE FIRST GENERATED SOME 2235 01:24:32,379 --> 01:24:34,215 POPULATIONS OF CELLS THAT WERE 2236 01:24:34,215 --> 01:24:38,919 EITHER WILD-TYPE OR EXIST 2237 01:24:38,919 --> 01:24:40,087 NULLLIN VARYING DEGREES AND 2238 01:24:40,087 --> 01:24:41,855 ISOLATE FRIDAY THAT A CLONAL 2239 01:24:41,855 --> 01:24:44,858 POPULATION OF COMPLETE KNOCK OUT 2240 01:24:44,858 --> 01:24:45,926 CELLS, SO GENERATE--WE USE THESE 2241 01:24:45,926 --> 01:24:48,429 CELLS AS A SOURCE OF WHOLE 2242 01:24:48,429 --> 01:24:51,899 CELLULAR RNA WHICH WE THEN 2243 01:24:51,899 --> 01:24:53,100 ISOLATED AND FRAGMENTED INVITRO 2244 01:24:53,100 --> 01:24:55,135 DOWN TO THE LENGTH OF SEVERAL 2245 01:24:55,135 --> 01:24:57,338 DOZEN BASE PAIRS TO KIND OF 2246 01:24:57,338 --> 01:25:00,307 SIMULATE THE ENVIRONMENT OF THE 2247 01:25:00,307 --> 01:25:03,577 ENDOSOME WHERE TLR 7 WILL BE 2248 01:25:03,577 --> 01:25:04,812 EBCOUNTERRING RNA DEGRADATION 2249 01:25:04,812 --> 01:25:07,381 PRODUCTS AND WHAT YOU CAN SEE IN 2250 01:25:07,381 --> 01:25:08,882 THE TLR7 REPORTER CELL LINE HERE 2251 01:25:08,882 --> 01:25:10,517 IS THAT IN COMPARISON TO THE 2252 01:25:10,517 --> 01:25:12,386 WILD-TYPE AND THE CRSPER 2253 01:25:12,386 --> 01:25:13,754 CONTROL, THERE IS A DOSE EFFECT 2254 01:25:13,754 --> 01:25:15,623 BASED ON THE DEGREE TO WHICH 2255 01:25:15,623 --> 01:25:17,625 XIST HAS BEEN REMOVED FROM THE 2256 01:25:17,625 --> 01:25:19,827 TRANSCRIPTOME OF THESE CELLS, 2257 01:25:19,827 --> 01:25:22,263 AND THEN COMPARING RNA FROM THE 2258 01:25:22,263 --> 01:25:23,230 WILD-TYPE CELLS VERSUS COMPLETE 2259 01:25:23,230 --> 01:25:24,898 KNOCK OUT, WHAT WE SAW ON THE 2260 01:25:24,898 --> 01:25:27,101 REPORTER CELLS WAS GREATER THAN 2261 01:25:27,101 --> 01:25:29,270 50% REDUCTION IN THE ABILITY OF 2262 01:25:29,270 --> 01:25:31,472 THIS FRAGMENTED WHOLE CELLULAR 2263 01:25:31,472 --> 01:25:36,076 RNA TO ACTIVATE TLR 7 WHICH WAS 2264 01:25:36,076 --> 01:25:38,445 SURPRISING IN ITS MAGNITUDE, 2265 01:25:38,445 --> 01:25:39,580 REMOVING 1 RNA CAN CONTRIBUTE SO 2266 01:25:39,580 --> 01:25:41,482 MUCH TO THE ABILITY OF WHOLE 2267 01:25:41,482 --> 01:25:44,551 CELLULAR RNA TO ACTIVATE THE 2268 01:25:44,551 --> 01:25:44,885 SENSOR. 2269 01:25:44,885 --> 01:25:49,923 SO WE WANTED TO CONFIRM, THAT 2270 01:25:49,923 --> 01:25:51,325 THROUGH CRSPER EDITING WE HADN'T 2271 01:25:51,325 --> 01:25:52,960 KNOCKED DOWN ANY OTHER RNAs 2272 01:25:52,960 --> 01:25:55,629 WHICH MIGHT BE IMPORTANT SOURCES 2273 01:25:55,629 --> 01:25:58,232 OF TLR 7 LIGANDS SO WE USED RNA 2274 01:25:58,232 --> 01:26:00,401 SEQ TO LOOK AT CHANGES IN OUR 2275 01:26:00,401 --> 01:26:01,935 KNOCK OUT POOL VERSUS THE WILE 2276 01:26:01,935 --> 01:26:05,806 TYPE, WE IDENTIFIED TRANSCRIPTS 2277 01:26:05,806 --> 01:26:07,408 THAT WERE SIPPING 95 CANTILY 2278 01:26:07,408 --> 01:26:10,277 DOWN REGULATED AND THEN LOOKED 2279 01:26:10,277 --> 01:26:12,146 AT L UU CONTENT VERSUS 2280 01:26:12,146 --> 01:26:13,213 EXPRESSION LEVELS IF IN THE 2281 01:26:13,213 --> 01:26:15,149 WILD-TYPE CELLS TO TRY TO 2282 01:26:15,149 --> 01:26:16,317 DETERMINE WHETHER WE KNOCKED OUT 2283 01:26:16,317 --> 01:26:17,718 ANYTHING ELSE THAT MIGHT BE AN 2284 01:26:17,718 --> 01:26:21,355 IMPORTANT SOURCE OF THESE 2285 01:26:21,355 --> 01:26:21,722 UU FEATURES. 2286 01:26:21,722 --> 01:26:25,492 AND YOU CAN SEE IT IN FACT XIST 2287 01:26:25,492 --> 01:26:28,228 APPEARS TO BE THE MOST IMPORTANT 2288 01:26:28,228 --> 01:26:31,932 POTENTIAL SOURCE OF TLR7 LIGANDS 2289 01:26:31,932 --> 01:26:33,100 THAT WE'VE REMOVED BASED ON WHAT 2290 01:26:33,100 --> 01:26:36,704 WE'RE LOOKING AT HERE, BASED ON 2291 01:26:36,704 --> 01:26:38,339 THE UU-REPEATS, IT CONTAINS THE 2292 01:26:38,339 --> 01:26:40,174 NUMBER AS WELL, BUT YOU CAN SEE 2293 01:26:40,174 --> 01:26:41,475 IT'S EXPRESSED AT A MUCH LOWER 2294 01:26:41,475 --> 01:26:43,344 LEVEL THAN THE WILD-TYPE CELLS. 2295 01:26:43,344 --> 01:26:45,779 SO IN FACT IF LOOKED LIKE WE HAD 2296 01:26:45,779 --> 01:26:47,648 LOOKED LIKE WE REMOVED WHAT 2297 01:26:47,648 --> 01:26:49,983 SEEMED TO BE THE MOST IMPORTANT 2298 01:26:49,983 --> 01:26:52,986 SOURCE OF LIGAND SOUL CELLS, SO 2299 01:26:52,986 --> 01:26:54,822 HAVING SEEN THIS UNEXPECTED 2300 01:26:54,822 --> 01:26:56,123 RESULT, IT EXIST ITSELF LOOKS 2301 01:26:56,123 --> 01:26:59,426 LIKE IT CAN BE SUCH AN IMPORTANT 2302 01:26:59,426 --> 01:27:02,062 RESERVOIR FOR THESE TLR 7 2303 01:27:02,062 --> 01:27:02,896 ACTIVATING MOTIFS, WE THEN ASK 2304 01:27:02,896 --> 01:27:04,398 THE QUESTION OF WHAT EXIST 2305 01:27:04,398 --> 01:27:08,969 EXPRESSION LEVELS LOOK LIKE IN 2306 01:27:08,969 --> 01:27:12,373 LUPUS SUBJECTS, THE TLR7 DRIVEN 2307 01:27:12,373 --> 01:27:15,142 DEC EMPLOY SO TO DO THIS WE USED 2308 01:27:15,142 --> 01:27:16,910 AN RNAFLOW 7 ASSAY AND COMPARED 2309 01:27:16,910 --> 01:27:19,346 THESE FROM THE CENTER HERE AT 2310 01:27:19,346 --> 01:27:21,548 YAWNS HOPKINS VERSUS HEALTHY 2311 01:27:21,548 --> 01:27:23,050 CONTROL FEMALE DONORS, AND WHAT 2312 01:27:23,050 --> 01:27:26,053 YOU WILL SEE WHAT YOU CAN SEE IS 2313 01:27:26,053 --> 01:27:28,522 THAT IN PBMCs WE FOUND HIGHER 2314 01:27:28,522 --> 01:27:30,591 EXPRESSION LEVELS OF XIST IN THE 2315 01:27:30,591 --> 01:27:32,326 LUPUS COHORT COMPARED TO 2316 01:27:32,326 --> 01:27:33,127 CONTROLS. 2317 01:27:33,127 --> 01:27:34,762 AND THIS DIFFERENCE WAS MOST 2318 01:27:34,762 --> 01:27:36,530 EXAGGERATED IN THE B-CELL 2319 01:27:36,530 --> 01:27:37,664 COMPARTMENT, NOW, THOSE OF YOU 2320 01:27:37,664 --> 01:27:39,733 WHO ARE JUST LISTENING TO WHAT 2321 01:27:39,733 --> 01:27:41,602 THE DOCTOR TOLD US AT THE ONSET 2322 01:27:41,602 --> 01:27:44,571 HERE ABOUT WHAT HAPPENS WHEN YOU 2323 01:27:44,571 --> 01:27:46,673 DELETE XIST FROM A B-CELL, YOU 2324 01:27:46,673 --> 01:27:48,108 MAY BE SCRATCHING YOUR HEADS AND 2325 01:27:48,108 --> 01:27:50,310 SAYING HOW DOES THIS ALL ADD UP, 2326 01:27:50,310 --> 01:27:52,780 AND I'M NOT SURE I HAVE ALL THE 2327 01:27:52,780 --> 01:27:53,881 ANSWERS FOR YOU BUT HERE LOOKING 2328 01:27:53,881 --> 01:27:57,751 AT EXPRESSION LEVELS WE WERE NOT 2329 01:27:57,751 --> 01:27:59,052 O'CLOCKING AT XIST LOCALIZATION 2330 01:27:59,052 --> 01:28:00,320 EMPLOY I THINK IT WOULD BE 2331 01:28:00,320 --> 01:28:01,522 INTERESTING TO BE ABLE TO DO 2332 01:28:01,522 --> 01:28:03,190 THAT IT WILL BE NICE TO HAVE 2333 01:28:03,190 --> 01:28:04,925 THIS INITIAL ANALYSIS BUT IN 2334 01:28:04,925 --> 01:28:06,226 THINKING ABOUT THE XIST TO DO 2335 01:28:06,226 --> 01:28:09,263 LIST, I THINK THAT RECONCILING 2336 01:28:09,263 --> 01:28:10,330 EXPRESSION LEVELS VERSUS EXIST 2337 01:28:10,330 --> 01:28:11,131 LOCALIZATION IS SOMETHING THAT 2338 01:28:11,131 --> 01:28:12,866 COULD HELP US PUT THIS INTO 2339 01:28:12,866 --> 01:28:19,072 CONTEXT AND UNDERSTAND WHAT IT 2340 01:28:19,072 --> 01:28:19,573 MEANS. 2341 01:28:19,573 --> 01:28:20,941 IN T-CELLS AND MONOCYTES THERE 2342 01:28:20,941 --> 01:28:22,242 WAS A TREND TOWARDS HIGHER 2343 01:28:22,242 --> 01:28:23,710 EXPRESSION AS WELL BUT THAT 2344 01:28:23,710 --> 01:28:25,646 DIFFERENCE WAS MOST DRAMATIC 2345 01:28:25,646 --> 01:28:28,415 REDUCTIONTATTIC ON THE B-CELL 2346 01:28:28,415 --> 01:28:30,384 COMPARTMENT, USING THIS COHORT, 2347 01:28:30,384 --> 01:28:31,985 WE WERE USING THIS RELATION 2348 01:28:31,985 --> 01:28:32,820 BETWEEN EXPRESSION AND DISEASE 2349 01:28:32,820 --> 01:28:35,489 ACTIVITY AND THERE ARE 2 2350 01:28:35,489 --> 01:28:37,891 COMMONLY USED CLINICAL INDICES 2351 01:28:37,891 --> 01:28:39,092 FOR LUPUS ACTIVITY WE HAD ACCESS 2352 01:28:39,092 --> 01:28:41,161 TO AS A PART OF OUR COHORT WHICH 2353 01:28:41,161 --> 01:28:45,065 ARE PART OF THE THE PHYSICIAN'S 2354 01:28:45,065 --> 01:28:46,366 ASSESSMENT AND THE LEAD ON YOU 2355 01:28:46,366 --> 01:28:49,236 CAN SEE THERE'S A TREND TOWARDS 2356 01:28:49,236 --> 01:28:51,738 HIGHER XIST EXPRESSION AMONG 2357 01:28:51,738 --> 01:28:53,974 PBMCs AMONG THE EXPRESSIONS 2358 01:28:53,974 --> 01:28:54,842 WITH ACTIVE DEC CORRELATED POSE 2359 01:28:54,842 --> 01:28:56,610 TO THOSE WHO ARE CLINICALLY 2360 01:28:56,610 --> 01:28:59,012 QUESTIONNAIRES XET THERE'S A 2361 01:28:59,012 --> 01:29:02,049 POSITIVE CORRELATION BETWEEN 2362 01:29:02,049 --> 01:29:04,284 XIST EXPRESSION AND SLEDAI SEEN 2363 01:29:04,284 --> 01:29:05,285 IN THE COHORT. 2364 01:29:05,285 --> 01:29:07,154 SO THE FINDINGS HERE ARE THAT 2365 01:29:07,154 --> 01:29:10,757 EXIST LOOK TO BE UPREGULATED IN 2366 01:29:10,757 --> 01:29:12,826 THE PERIPHERAL BLOOD OF PATIENTS 2367 01:29:12,826 --> 01:29:14,361 AS COMPARED TO CONTROLS AND 2368 01:29:14,361 --> 01:29:17,931 AGAIN THERE'S A POSITIVE DISEASE 2369 01:29:17,931 --> 01:29:19,066 RELATIONSHIP ACTIVITY WITH THE 2370 01:29:19,066 --> 01:29:20,667 SINGLE POINT TIME ANALYSIS. 2371 01:29:20,667 --> 01:29:23,770 SO WE WANTED TO APPROACH THIS 2372 01:29:23,770 --> 01:29:27,641 USING ANOTHER DATA SET, AND ALSO 2373 01:29:27,641 --> 01:29:30,777 LOOK AT THE RELATIONSHIP BETWEEN 2374 01:29:30,777 --> 01:29:32,079 XIST EXPRESSION LEVELS AND 2375 01:29:32,079 --> 01:29:34,748 INTERFERON AND SO TO DO THAT, WE 2376 01:29:34,748 --> 01:29:38,285 USE THE AMP DATA SET WHICH IS A 2377 01:29:38,285 --> 01:29:40,754 MULTISITE STUDY WHICH COLLECTED 2378 01:29:40,754 --> 01:29:42,689 RENAL BIOPSY SAMPLES FROM 2379 01:29:42,689 --> 01:29:44,992 PATIENTS WITH LUPUS NEPHRITIS 2380 01:29:44,992 --> 01:29:47,694 AND PERFORMED SINGLE CELL 2381 01:29:47,694 --> 01:29:50,597 ANALYSIS ON IMMUNE CELLS 2382 01:29:50,597 --> 01:29:51,398 INFILTRATING THOSE RENAL 2383 01:29:51,398 --> 01:29:52,533 BIOPSIES AND 1 OF THE FINDINGS 2384 01:29:52,533 --> 01:29:55,769 OF THAT STUDY WAS THAT THERE IS 2385 01:29:55,769 --> 01:29:57,037 THIS POSITIVE RELATIONSHIP 2386 01:29:57,037 --> 01:29:57,971 BETWEEN INTERFERON EXPRESSION IN 2387 01:29:57,971 --> 01:29:59,606 THE TARGET ORGAN HERE BEING THE 2388 01:29:59,606 --> 01:30:01,241 KIDNEY AS WELL AS PERIPHERAL 2389 01:30:01,241 --> 01:30:01,842 BLOOD. 2390 01:30:01,842 --> 01:30:06,213 SO IN AN ANALYSIS OF THIS DATA 2391 01:30:06,213 --> 01:30:09,182 SET WE FOUND A STRONG POSITIVE 2392 01:30:09,182 --> 01:30:10,684 CORRELATION BETWEEN XIST AND 2393 01:30:10,684 --> 01:30:11,718 INTERFERON EXPRESSION AND AGAIN 2394 01:30:11,718 --> 01:30:13,287 IN THESE IMMUNE CELLS THAT IN 2395 01:30:13,287 --> 01:30:15,489 THIS ANALYSIS ARE IN THE TARGET 2396 01:30:15,489 --> 01:30:17,090 OREGON AFFECTED BY THE DISEASE 2397 01:30:17,090 --> 01:30:19,192 AS OPPOSE TO THE PERIPHERAL 2398 01:30:19,192 --> 01:30:19,560 BLOOD. 2399 01:30:19,560 --> 01:30:21,361 SO THAT'S AN INTRIGUING FINDING 2400 01:30:21,361 --> 01:30:22,930 AND 1 OF THE POTENTIAL 2401 01:30:22,930 --> 01:30:23,864 EXPLANATIONS WHICH WILL BE 2402 01:30:23,864 --> 01:30:26,133 PRETTY STRAIGHT FORWARD WILL BE 2403 01:30:26,133 --> 01:30:28,502 IF IT EXISTS ITSELF OR SIMPLY AN 2404 01:30:28,502 --> 01:30:31,471 INTERFERON INDUCED YEEN AND THAT 2405 01:30:31,471 --> 01:30:32,839 HADN'T BEEN PREVIOUSLY FORWARDED 2406 01:30:32,839 --> 01:30:35,375 BUT WE WANTED TO CONFIRM THIS 2407 01:30:35,375 --> 01:30:37,644 RELATIONSHIP WASN'T DUE TO THE 2408 01:30:37,644 --> 01:30:40,847 FACT THAT XIST ITSELF WAS 2409 01:30:40,847 --> 01:30:42,583 INTERFERON EXISTABLE AND WE TOOK 2410 01:30:42,583 --> 01:30:46,853 CELL LINES THAT EXPRESS EXIST, 2411 01:30:46,853 --> 01:30:49,289 PRIMARY PBMCs AND PRIMARY 2412 01:30:49,289 --> 01:30:51,692 KERATINOCYTES AND TREATED THEM 2413 01:30:51,692 --> 01:30:53,460 WITH INTERFERONS INVITRO AND 2414 01:30:53,460 --> 01:30:55,195 CONFIRMED WE'RE GENERATING 2415 01:30:55,195 --> 01:30:56,229 UPREGULATION OF INTERFERON 2416 01:30:56,229 --> 01:30:57,197 STIMULATED GENES IN THESE CELLS 2417 01:30:57,197 --> 01:31:00,200 AND SAW THAT THERE WAS NO CHANGE 2418 01:31:00,200 --> 01:31:02,869 IN EXIST LEVELS. 2419 01:31:02,869 --> 01:31:04,404 --XIST LEVELS, SOMETHING I WILL 2420 01:31:04,404 --> 01:31:05,439 NOTE THAT WASN'T INCLUDED HERE 2421 01:31:05,439 --> 01:31:08,208 THAT WE'VE DONE SENSE IS TO 2422 01:31:08,208 --> 01:31:09,476 STIMULATE THESE SAME XIST 2423 01:31:09,476 --> 01:31:10,644 EXPRESSING CELLS WITH OTHER 2424 01:31:10,644 --> 01:31:13,947 LIGANDS THAT WILL BE UPSTREAM OF 2425 01:31:13,947 --> 01:31:17,718 INTERFERONS SO FOR EXAMPLE, 2426 01:31:17,718 --> 01:31:20,921 USING POLYAIC OR ACTIVATING CELL 2427 01:31:20,921 --> 01:31:21,888 INTRINSIC ACTIVATING AND WE 2428 01:31:21,888 --> 01:31:22,923 HAVEN'T SEEN ANY RESPONSE IN 2429 01:31:22,923 --> 01:31:25,559 EXIST EITHER GOING UP OR DOWN, 2430 01:31:25,559 --> 01:31:27,527 IN RESPONSE TO THOSE STIMULI. 2431 01:31:27,527 --> 01:31:30,497 SO WE CONCLUDED FROM THIS, IS 2432 01:31:30,497 --> 01:31:32,499 THAT XIST ITSELF IS NOT 2433 01:31:32,499 --> 01:31:35,335 INFLUENCED BY INTERFERON, AND 2434 01:31:35,335 --> 01:31:36,737 THAT IN EXPLAINING THIS 2435 01:31:36,737 --> 01:31:38,438 RELATIONSHIP, POSITIVE 2436 01:31:38,438 --> 01:31:39,773 RELATIONSHIP BETWEEN INTERFERON 2437 01:31:39,773 --> 01:31:42,242 AND XIST EXPRESSION WE SAW IN 2438 01:31:42,242 --> 01:31:43,310 RENAL BIOPSIES, XIST IS MORE 2439 01:31:43,310 --> 01:31:46,913 LIKELY A DRIVER OF THAT THAN A 2440 01:31:46,913 --> 01:31:52,653 DOWN STREAM CONSEQUENCE OF THAT. 2441 01:31:52,653 --> 01:31:55,188 SO THAT BRINGS US TO OUR MODEL 2442 01:31:55,188 --> 01:31:58,892 WHICH AGAIN CENTERS ON THIS 2443 01:31:58,892 --> 01:32:00,727 FINDING THAT XIST IS AN 2444 01:32:00,727 --> 01:32:01,795 ENDOGENOUS SOURCE OF RNAs THAT 2445 01:32:01,795 --> 01:32:05,365 ARE CAPABLE OF ACTIVATING TLR7. 2446 01:32:05,365 --> 01:32:07,467 AS I MENTIONED, I THINK THIS IS, 2447 01:32:07,467 --> 01:32:09,536 YOU KNOW AS FAR AS WE KNOW THE 2448 01:32:09,536 --> 01:32:12,072 ONLY EXAMPLE OF A SEX SPECIFIC 2449 01:32:12,072 --> 01:32:14,441 DA AMP THAT'S BEEN IDENTIFIED TO 2450 01:32:14,441 --> 01:32:15,909 THIS IS SOMETHING THAT CAN 2451 01:32:15,909 --> 01:32:18,979 CERTAINLY CONTRIBUTE TO FEMALE 2452 01:32:18,979 --> 01:32:21,148 ADVANTAGE IN HOST DEFENSE 2453 01:32:21,148 --> 01:32:22,649 THROUGH SIGNALING THROUGH TLR 7 2454 01:32:22,649 --> 01:32:26,219 BUT IN LUPUS WHICH IS A DISEASE 2455 01:32:26,219 --> 01:32:28,488 CHARACTERIZED BY IMPAIRED 2456 01:32:28,488 --> 01:32:32,459 CLEARANCE OF APOPTOTIC DEBRIS AS 2457 01:32:32,459 --> 01:32:34,027 WELL AS AUTOANTIBODIES TARGETING 2458 01:32:34,027 --> 01:32:36,296 BINDING PROTEINS AND THE MODEL 2459 01:32:36,296 --> 01:32:39,099 IS THAT XIST WILL STIMULATE TLR 2460 01:32:39,099 --> 01:32:40,967 7 AND IMMUNE CELLS DOWN STREAM 2461 01:32:40,967 --> 01:32:42,836 OF THAT CRITICAL SENSOR, IN A 2462 01:32:42,836 --> 01:32:45,706 WAY THAT CAN CONTRIBUTE TO THE 2463 01:32:45,706 --> 01:32:50,110 PATHOGENIC IMMUNE RESPONSES THAT 2464 01:32:50,110 --> 01:32:52,979 ARE CHARACTERISTIC OF THIS 2465 01:32:52,979 --> 01:32:56,817 DISEASE EMPLOY --DISEASE. 2466 01:32:56,817 --> 01:32:59,519 I WILL POINT OUT SINCE I'M THIRD 2467 01:32:59,519 --> 01:33:01,154 WE'VE HEARD ABOUT 3 DIFFERENT 2468 01:33:01,154 --> 01:33:02,889 MECHANISMS OR FINDING INCLUDING 2469 01:33:02,889 --> 01:33:05,726 XIST ROLE IN GETTING 2470 01:33:05,726 --> 01:33:07,027 X-CHROMOSOME AND ACTIVATION, THE 2471 01:33:07,027 --> 01:33:07,728 INTERACTION WITH ANTIGEN 2472 01:33:07,728 --> 01:33:10,063 PROTEINS AND HERE THE IDENTITY 2473 01:33:10,063 --> 01:33:11,598 AS A TLR7 LIGAND, I THINK IT'S 2474 01:33:11,598 --> 01:33:14,000 EASY TO SEE HOW THESE FIT 2475 01:33:14,000 --> 01:33:15,135 TOGETHER AND CONTRIBUTE IN 2476 01:33:15,135 --> 01:33:18,171 MULTIPLE WAYS TO DWTMENT OF 2477 01:33:18,171 --> 01:33:19,906 AUTOIMMUNITY AND SLE AS WELL AS 2478 01:33:19,906 --> 01:33:22,743 OTHER FEMALE BIASED DISEASES. 2479 01:33:22,743 --> 01:33:28,648 THIS IS OUR GROUP, THIS PROJECT 2480 01:33:28,648 --> 01:33:31,518 WAS INITIALLY CONCEIVED OF BY 2481 01:33:31,518 --> 01:33:33,120 ERICA [INDISCERNIBLE], AND SHE 2482 01:33:33,120 --> 01:33:36,056 INVITED ME TO COLLABORATE ON 2483 01:33:36,056 --> 01:33:39,392 WHEN IT WAS IN ITS EARLY STAGES 2484 01:33:39,392 --> 01:33:40,427 AND JONATHAN CRAWFORD WORKED ON 2485 01:33:40,427 --> 01:33:43,196 THIS AS PART OF HIS Ph.D. ON 2486 01:33:43,196 --> 01:33:44,064 IMMUNOLOGY IN THE DIVISION, 2487 01:33:44,064 --> 01:33:45,699 WE'VE HAD A NUMBER OF 2488 01:33:45,699 --> 01:33:46,733 COLLABORATORS INCLUDING THE 2489 01:33:46,733 --> 01:33:48,135 LUPUS CENTER AND APPRECIATED 2490 01:33:48,135 --> 01:33:50,337 FUNDING FROM THE GREEN 2491 01:33:50,337 --> 01:33:52,239 FOUNDATION, NIDCR AND NIAMS. 2492 01:33:52,239 --> 01:34:02,783 SO THANK YOU AND I WILL LEAVE IT 2493 01:34:16,129 --> 01:34:16,296 THERE. 2494 01:34:16,296 --> 01:34:22,402 NOKAY, SO I WILL OPEN THE FLOOR 2495 01:34:22,402 --> 01:34:23,570 TO QUESTIONS AND I WANT TO 2496 01:34:23,570 --> 01:34:25,305 REMIND YOU IF YOU HAVE QUESTIONS 2497 01:34:25,305 --> 01:34:27,941 YOU WOULD LIKE ASKED DURING THIS 2498 01:34:27,941 --> 01:34:29,109 PORTION OF THE SESSION, FEEL 2499 01:34:29,109 --> 01:34:31,211 FREE TO PUT THEM INTO THE Q&A 2500 01:34:31,211 --> 01:34:33,647 AND WE WILL BE MONITORING THAT, 2501 01:34:33,647 --> 01:34:36,416 BUT FIRST, I AM GOING TO HAND 2502 01:34:36,416 --> 01:34:38,618 THE MICROPHONE OVER TO 2503 01:34:38,618 --> 01:34:41,555 DR. MANCINI TO GET US STARTED. 2504 01:34:41,555 --> 01:34:43,523 >> HI, THANK YOU ALL FOR THE 2505 01:34:43,523 --> 01:34:44,724 WONDERFUL TALKS SO WE HAVE A 2506 01:34:44,724 --> 01:34:46,126 LITTLE BIT OF A PLANTED QUESTION 2507 01:34:46,126 --> 01:34:47,494 WHICH I THINK WILL BE 2508 01:34:47,494 --> 01:34:49,329 INTERESTING AND GIVE YOU ALL AN 2509 01:34:49,329 --> 01:34:50,530 OPPORTUNITY TO TALK ABOUT THE 2510 01:34:50,530 --> 01:34:52,732 FUTURE, SO THE QUESTION IS HOW 2511 01:34:52,732 --> 01:34:54,034 DO YOU SEE XIST RESEARCH 2512 01:34:54,034 --> 01:34:57,137 EVOLVING OVER THE NEXT 3-5 2513 01:34:57,137 --> 01:34:57,337 YEARS? 2514 01:34:57,337 --> 01:34:59,372 SO CAN I ASK EACH OF THE 2515 01:34:59,372 --> 01:35:00,540 PANELISTS TO GIVE US THEIR POINT 2516 01:35:00,540 --> 01:35:01,374 OF VIEW ON THAT. 2517 01:35:01,374 --> 01:35:04,945 >> YOU WANT ME TO GO FIRST? 2518 01:35:04,945 --> 01:35:05,512 >> SURE. 2519 01:35:05,512 --> 01:35:05,812 >> OKAY. 2520 01:35:05,812 --> 01:35:10,150 YEAH, SO I LIKE THIS QUESTION 2521 01:35:10,150 --> 01:35:15,989 AND I SEE IT REALLY--WE'RE 2522 01:35:15,989 --> 01:35:17,490 STARTING TO HIT THE LOG PHASE OF 2523 01:35:17,490 --> 01:35:19,159 GROWTH FOR RESEARCH AND 2524 01:35:19,159 --> 01:35:20,994 INVOLVING XIST AND I THINK IT 2525 01:35:20,994 --> 01:35:22,829 WILL CONTINUE TO SKY ROCKET OVER 2526 01:35:22,829 --> 01:35:23,763 THE NEXT YEAR BECAUSE YOU CAN 2527 01:35:23,763 --> 01:35:25,999 THINK OF IT FROM THE PERSPECTIVE 2528 01:35:25,999 --> 01:35:31,171 OF AUTOIMMUNE DISEASE, SO TODAY 2529 01:35:31,171 --> 01:35:34,174 WE TALKED ABOUT SOME AUTOIMMUNE 2530 01:35:34,174 --> 01:35:37,277 DISEASES SO I HIGHLIGHTED LUPUS, 2531 01:35:37,277 --> 01:35:39,379 BUT THERE'S 25 AUTOIMMUNE DECS, 2532 01:35:39,379 --> 01:35:40,947 IS XIST GOING TO FUNCTION THE 2533 01:35:40,947 --> 01:35:42,716 SAME WAY IN ACROSS ALL 25 OF 2534 01:35:42,716 --> 01:35:44,584 THESE, ALL OF THESE ARE VERY, 2535 01:35:44,584 --> 01:35:46,386 VERY DISTINCT SO SO WE WILL SEE 2536 01:35:46,386 --> 01:35:49,890 A LOT OF DIVERSITY WITH THESE 2537 01:35:49,890 --> 01:35:53,727 MECHANISMS AND IT'S GOING TO 2538 01:35:53,727 --> 01:35:54,694 TAKE CREATIVE SCIENTISTS THIS 2539 01:35:54,694 --> 01:35:57,664 BRING TOGETHER, YOU KNOW REALLY 2540 01:35:57,664 --> 01:35:58,198 DIVERSE BACKGROUNDS AND 2541 01:35:58,198 --> 01:35:59,432 SCIENTIFIC TRAINING AND,A 2542 01:35:59,432 --> 01:36:00,533 PROACHING TO PROBLEM SOLVING 2543 01:36:00,533 --> 01:36:04,037 THAT ARE REALLY GOING TO BE KEY 2544 01:36:04,037 --> 01:36:05,872 TO FIGURING OUT HOW THE PUZZLE 2545 01:36:05,872 --> 01:36:12,712 PIECES ALL FIT ON A DISEASE BY 2546 01:36:12,712 --> 01:36:14,948 DISEASE BASIS. 2547 01:36:14,948 --> 01:36:15,282 >> THANKS. 2548 01:36:15,282 --> 01:36:20,754 DR. DOU, WOULD YOU LIKE TO ADD 2549 01:36:20,754 --> 01:36:21,554 ON? 2550 01:36:21,554 --> 01:36:22,822 >> YEAH, HIMARIE, SHE'S MY 2551 01:36:22,822 --> 01:36:25,025 PROGRAM OFFICER, SO YEAH, NO, I 2552 01:36:25,025 --> 01:36:27,460 AGREE, I THINK THIS IS A GREAT 2553 01:36:27,460 --> 01:36:29,329 CHANCE, THE COMMUNITY IS 2554 01:36:29,329 --> 01:36:33,433 GROWING, BUT I'M ALSO EXCITED 2555 01:36:33,433 --> 01:36:35,869 ABOUT THE IMPLICATIONS FOR THE 2556 01:36:35,869 --> 01:36:37,337 COMMUNITY UNITING BIOCHEMISTRY 2557 01:36:37,337 --> 01:36:42,976 AND EITHER HEALTH SCIENCES AND 2558 01:36:42,976 --> 01:36:43,710 BIOLOGY, BECAUSE [INDISCERNIBLE] 2559 01:36:43,710 --> 01:36:45,845 IS CORRECT IN SAYING THERE ARE 2560 01:36:45,845 --> 01:36:48,315 25 OTHER AUTOIMMUNE FEMALE 2561 01:36:48,315 --> 01:36:51,151 BIASED AUTOIMMUNE DECS BUT HOW 2562 01:36:51,151 --> 01:36:53,553 MANY LINK RNAs ARE ASSOCIATE 2563 01:36:53,553 --> 01:36:54,621 WIDE AUTOIMMUNE DISEASE THAT WE 2564 01:36:54,621 --> 01:36:56,022 DON'T KNOW THE FUNCTIONS OF YET 2565 01:36:56,022 --> 01:36:57,857 AS WE JUST SEE HIGH ASSOCIATIONS 2566 01:36:57,857 --> 01:36:59,426 IN THE DATA SETS SO THIS OPENS 2567 01:36:59,426 --> 01:37:01,628 THE AVENUE OF ALSO LIKE LOOKING 2568 01:37:01,628 --> 01:37:03,163 AT OTHER LINK RNAs AND HOW 2569 01:37:03,163 --> 01:37:06,466 THEY POTENTIALLY MIGHT HAVE A 2570 01:37:06,466 --> 01:37:08,668 FUNCTION IN AUTOIMMUNITY MAYBE 2571 01:37:08,668 --> 01:37:10,337 AS MOTEAR SCAFFOLDS, NOT JUST AS 2572 01:37:10,337 --> 01:37:11,604 BIOMARKERS WE DON'T KNOW THE 2573 01:37:11,604 --> 01:37:12,605 FUNCTION OF, BUT YEAH, I THINK 2574 01:37:12,605 --> 01:37:18,345 THIS IS A VERY EXCITING FIELD TO 2575 01:37:18,345 --> 01:37:26,219 BE IN AND I ALSO THINK THIS IS 2576 01:37:26,219 --> 01:37:29,956 THE PERFECT OPPORTUNITY TO GO 2577 01:37:29,956 --> 01:37:33,626 AND EVALUATE THE DATA SETS ON GO 2578 01:37:33,626 --> 01:37:36,396 BUT AND THERE ARE SO MANY 2579 01:37:36,396 --> 01:37:37,163 PATIENT STUDIES BUT WHAT HAS 2580 01:37:37,163 --> 01:37:40,333 BEEN DONE IN THE PAST IS THAT 2581 01:37:40,333 --> 01:37:41,301 THE X-CHROMESOME HAS BEEN 2582 01:37:41,301 --> 01:37:43,136 FILTERED OUT IN DISEASES THAT WE 2583 01:37:43,136 --> 01:37:45,705 KNOW HAVE A VERY STRONG SEX 2584 01:37:45,705 --> 01:37:47,340 COMPONENT WHETHER IT'S MALE OR 2585 01:37:47,340 --> 01:37:48,708 FEMALE, THERE'S SEX CHROMOSOMES 2586 01:37:48,708 --> 01:37:50,410 TEND TO BE FILTERED OUT SO WE 2587 01:37:50,410 --> 01:37:51,344 DON'T REALLY KNOW VERY MUCH 2588 01:37:51,344 --> 01:37:53,646 ABOUT THAT SO WE THINK THIS 2589 01:37:53,646 --> 01:37:54,914 PRESENTS A HUGE OPPORTUNITY TO 2590 01:37:54,914 --> 01:37:56,850 GO BACK AND COMPUTATIONALLY 2591 01:37:56,850 --> 01:38:03,990 EVALUATE THE DATA WE ALREADY 2592 01:38:03,990 --> 01:38:06,092 HAVE. 2593 01:38:06,092 --> 01:38:09,796 >> THANK YOU. 2594 01:38:09,796 --> 01:38:10,130 DR. ANTIOCHOS? 2595 01:38:10,130 --> 01:38:11,331 >> YEAH, SURE, I WILL ECHO THE 2596 01:38:11,331 --> 01:38:13,433 SENT I WANTS THAT YEAH, THERE 2597 01:38:13,433 --> 01:38:15,435 ARE ALL THESE FEMALE BIASED 2598 01:38:15,435 --> 01:38:17,937 DISEASES THAT WE DEAL WITH IN 2599 01:38:17,937 --> 01:38:19,039 RHEUMATOLOGY THAT SHARE CLINICAL 2600 01:38:19,039 --> 01:38:20,774 FEATURES, MAYBE ARE NOT 2601 01:38:20,774 --> 01:38:21,841 IDENTICAL IN THEIR PATHOGENESIS 2602 01:38:21,841 --> 01:38:23,109 BUT I THINK THERE'S AN 2603 01:38:23,109 --> 01:38:25,211 OPPORTUNITY TO TRY TO IDENTIFY 2604 01:38:25,211 --> 01:38:27,047 SUBSETS OF PATIENTS ACROSS THESE 2605 01:38:27,047 --> 01:38:28,448 DISEASES, WHERE EXIST IS PLAYING 2606 01:38:28,448 --> 01:38:32,952 AN IMPORTANT ROLE AND SO 2607 01:38:32,952 --> 01:38:33,853 ANALYZING THESE VARIOUS FACAS 2608 01:38:33,853 --> 01:38:38,058 NATIONAL LIBRARY OF MEDICINE NA, 2609 01:38:38,058 --> 01:38:42,662 X-INACTIVATION AND XIST PATTERNS 2610 01:38:42,662 --> 01:38:43,730 AUTOANTIBODIES XIST RNPs, XIST 2611 01:38:43,730 --> 01:38:45,365 EXPRESSION LEVELS, THESE THINGS 2612 01:38:45,365 --> 01:38:50,103 THAT BE APPLIED TO THE DISEASES, 2613 01:38:50,103 --> 01:38:54,374 LUPUS, ET CETERA TO IAT IDENTIY 2614 01:38:54,374 --> 01:38:56,009 PATIENTS THAT HAVE THE MECHANISM 2615 01:38:56,009 --> 01:38:56,810 RESPONSIBLE FOR DRIVING THE 2616 01:38:56,810 --> 01:38:58,411 DISEASE AND OF COURSE NEXT STEP 2617 01:38:58,411 --> 01:39:00,180 WOULD BE FIGURING OUT THERAPIES 2618 01:39:00,180 --> 01:39:01,481 THAT WILL BE MOST EFFECTIVE FOR 2619 01:39:01,481 --> 01:39:02,816 PATIENTS WITH DECS AND THAT'S 2620 01:39:02,816 --> 01:39:04,717 WHERE IT'S EXCITING TO SEE THAT 2621 01:39:04,717 --> 01:39:05,885 THERE ARE TLR 7 INHIBITORS THAT 2622 01:39:05,885 --> 01:39:08,788 ARE IN WILL EARLY STAGES OF 2623 01:39:08,788 --> 01:39:10,056 DEVELOPMENT SO THE QUESTION OF 2624 01:39:10,056 --> 01:39:12,492 WHETHER ANY OF THESE MARKERS WE 2625 01:39:12,492 --> 01:39:13,893 DISCUSSED TODAY COULD IDENTIFY 2626 01:39:13,893 --> 01:39:15,295 PATIENTS WHO WILL BE SUITABLE 2627 01:39:15,295 --> 01:39:17,397 FOR THAT OR OTHER THERAPIES THAT 2628 01:39:17,397 --> 01:39:19,532 INTERRUPT THE SIGNALING THAT MAY 2629 01:39:19,532 --> 01:39:22,702 BE RESPONSIBLE FOR DISEASE 2630 01:39:22,702 --> 01:39:23,103 PATHOLOGY. 2631 01:39:23,103 --> 01:39:24,804 I GUESS I WILL ALSO POINT OUT AT 2632 01:39:24,804 --> 01:39:26,539 THE SAME TIME THERE ARE THESE 2633 01:39:26,539 --> 01:39:27,941 EXCITING FIND XTION THERE'S A 2634 01:39:27,941 --> 01:39:29,342 LOT OF BASIC WORK LEFT TO 2635 01:39:29,342 --> 01:39:34,581 UNDERSTAND AND EXACTLY HOW ALL 2636 01:39:34,581 --> 01:39:36,449 OF THE VARIOUS THINGS IT CAN DO 2637 01:39:36,449 --> 01:39:37,417 BEYOND THE STAGES OF DEVELOPMENT 2638 01:39:37,417 --> 01:39:38,852 AND AT THE SAME TIME THERE'S 2639 01:39:38,852 --> 01:39:39,886 THIS OPPORTUNITY TO KIND OF MOVE 2640 01:39:39,886 --> 01:39:41,187 IN A MORE TRANSLATIONAL 2641 01:39:41,187 --> 01:39:42,388 DIRECTION, I THINK THAT THERE'S 2642 01:39:42,388 --> 01:39:44,891 STILL A NEED TO UNDERSTAND THE 2643 01:39:44,891 --> 01:39:49,996 NUT ANDS BOLTS OF WHAT XIST IS 2644 01:39:49,996 --> 01:39:52,832 DOG IN THESE QUEPMENTAL 2645 01:39:52,832 --> 01:39:54,267 DEPARTMENTS DURING THIS 2646 01:39:54,267 --> 01:39:55,201 DEVELOPMENTAL PHASE. 2647 01:39:55,201 --> 01:39:57,937 >> OKAY, I THINK GOING ON TO THE 2648 01:39:57,937 --> 01:40:00,507 NEXT QUESTION, I THINK IT MAY BE 2649 01:40:00,507 --> 01:40:01,774 A LITTLE REDUNDANT BECAUSE SOME 2650 01:40:01,774 --> 01:40:04,077 OF YOU ADDRESSED IT, PARTIALLY 2651 01:40:04,077 --> 01:40:05,145 IS WHAT HAPPENS FIRST WITH 2652 01:40:05,145 --> 01:40:06,312 ADVANCES OF SCIENCE, SO I GUESS 2653 01:40:06,312 --> 01:40:08,848 ANOTHER QUESTION I HAVE FOR YOU 2654 01:40:08,848 --> 01:40:11,384 IS WHAT ARE THE RESEARCH GAPS 2655 01:40:11,384 --> 01:40:14,053 THAT YOU THINK REALLY NEED TO BE 2656 01:40:14,053 --> 01:40:17,690 FILLED, YOU KNOW TO 2657 01:40:17,690 --> 01:40:18,391 ACTUALLY--EXCUSE ME, ACCELERATE 2658 01:40:18,391 --> 01:40:23,029 THE PROGRESS THAT YOU JUST 2659 01:40:23,029 --> 01:40:23,296 MENTIONED. 2660 01:40:23,296 --> 01:40:25,798 >> SO, I GUESS I WILL TART WITH 2661 01:40:25,798 --> 01:40:30,470 THAT, I THINK THERE'S A COUPLE 2662 01:40:30,470 --> 01:40:33,339 OF THINGS, FIRST, JUST AMOUNT OF 2663 01:40:33,339 --> 01:40:35,208 MONITOR THAT'S IS DEDICATED TO 2664 01:40:35,208 --> 01:40:35,708 RESEARCH THAT CONCERNS 2665 01:40:35,708 --> 01:40:38,278 AUTOIMMUNE DISEASE IS NOT THE 2666 01:40:38,278 --> 01:40:39,812 SAME AS CANCER FOR EXAMPLE, AND 2667 01:40:39,812 --> 01:40:42,515 THERE'S A LOT OF PATIENTS THAT 2668 01:40:42,515 --> 01:40:43,316 HAVE AUTOIMMUNE DECS. 2669 01:40:43,316 --> 01:40:45,718 I THINK IT'S ABOUT 5% OF THE 2670 01:40:45,718 --> 01:40:48,521 WORLD'S POPULATION HAS AN 2671 01:40:48,521 --> 01:40:50,123 AUTOIMMUNE DISORDER, AND SO, I 2672 01:40:50,123 --> 01:40:53,760 THINK--I THINK WE NEED A LOT 2673 01:40:53,760 --> 01:40:55,728 MORE FUNDING AND SORT OF 2674 01:40:55,728 --> 01:41:00,767 THIS--THE OTHER ASPECT OF THIS, 2675 01:41:00,767 --> 01:41:02,969 IS MY LAB DOES BASIC SCIENCE 2676 01:41:02,969 --> 01:41:05,471 RESEARCH INTO FUNDAMENTAL MECH 2677 01:41:05,471 --> 01:41:06,539 NIMS, AND I REALLY STRONGLY 2678 01:41:06,539 --> 01:41:08,808 BELIEVE THAT WE CAN LEARN SO 2679 01:41:08,808 --> 01:41:11,678 MUCH ABOUT UNDERSTANDING HOW THE 2680 01:41:11,678 --> 01:41:12,712 POLICIES TAKE PLACE IN THE 2681 01:41:12,712 --> 01:41:15,148 HEALTHY STATE, RIGHT AND THEN 2682 01:41:15,148 --> 01:41:16,282 HOW--USE THAT INFORMATION THEN 2683 01:41:16,282 --> 01:41:18,885 TO UNDERSTAND HOW THE PROCESSES 2684 01:41:18,885 --> 01:41:20,820 GO WRONG IN DIFFERENT DEC 2685 01:41:20,820 --> 01:41:21,888 CONTEXTS, RIGHT? 2686 01:41:21,888 --> 01:41:25,091 BUT HAVING THAT MECHANISTIC 2687 01:41:25,091 --> 01:41:26,125 UNDERSTANDING IS ABSOLUTELY 2688 01:41:26,125 --> 01:41:28,928 CRITICAL TO THIS, AND SO, I 2689 01:41:28,928 --> 01:41:29,529 THINK--I THINK IT'S REALLY 2690 01:41:29,529 --> 01:41:32,031 IMPORTANT TO HAVE A GOOD BALANCE 2691 01:41:32,031 --> 01:41:32,966 OF THE BASIC SCIENCE RESEARCH 2692 01:41:32,966 --> 01:41:35,935 ALONG WITH THE TRANSLATIONAL 2693 01:41:35,935 --> 01:41:43,009 COMPONENT FOR INVESTIGATING 2694 01:41:43,009 --> 01:41:45,311 THIS. 2695 01:41:45,311 --> 01:41:46,112 >> DRS. DOU AND ANTIOCHOS, DO 2696 01:41:46,112 --> 01:41:50,883 YOU HAVE ANYTHING TO ADD? 2697 01:41:50,883 --> 01:41:52,952 >> I KNOW MONTSERRAT IS PUT IT 2698 01:41:52,952 --> 01:41:53,786 REALLY ELOQUENTLY, AND GOING OFF 2699 01:41:53,786 --> 01:41:55,121 THE SECOND THING SHE SAID, 2700 01:41:55,121 --> 01:41:57,156 COLLABORATION AND COMMUNE KAIG 2701 01:41:57,156 --> 01:41:58,558 WILL BE KEY BECAUSE WE SEE 2702 01:41:58,558 --> 01:42:04,063 THINGS FROM A VERY BASIC SCIENCE 2703 01:42:04,063 --> 01:42:05,365 PERSPECTIVE BUT BRINGING IN 2704 01:42:05,365 --> 01:42:06,065 CLINICIANS IS IMPORTANT. 2705 01:42:06,065 --> 01:42:07,433 AND I THINK AS BASIC SCIENTISTS 2706 01:42:07,433 --> 01:42:08,868 WE HAVE A SPECIALTY BECAUSE IT'S 2707 01:42:08,868 --> 01:42:11,037 REALLY HARD TO EACH KEEP UP WITH 2708 01:42:11,037 --> 01:42:13,406 LIKE 1 SPECIALTY, GENOMICS OR IF 2709 01:42:13,406 --> 01:42:14,907 YOU LIKE T-CELL OR B-CELL OR 2710 01:42:14,907 --> 01:42:18,778 SOMETHING BUT I THINK THIS IS A 2711 01:42:18,778 --> 01:42:19,612 REALLY--NEED IS ALMOST THESE 2712 01:42:19,612 --> 01:42:22,715 HUBS THAT WE CAN BRING MULTIPLE 2713 01:42:22,715 --> 01:42:23,549 SPECIALTIES TOGETHER, MULTIPLE 2714 01:42:23,549 --> 01:42:25,318 SCIENTISTS TOGETHER, WE CAN 2715 01:42:25,318 --> 01:42:26,786 BRING BIOCHEMISTS IN, WE CAN 2716 01:42:26,786 --> 01:42:29,088 BRING PEOPLE IN WHO STUDY THE 2717 01:42:29,088 --> 01:42:30,490 STRUCTURE OF THE BIOPHYSICIST 2718 01:42:30,490 --> 01:42:32,825 PEOPLE PEOPLE WHO CAN REALLY 2719 01:42:32,825 --> 01:42:34,227 SOLVE THE STRUCTURE, FIGURE OUT 2720 01:42:34,227 --> 01:42:37,530 THE COMPONENTS OF EXIST AND IF 2721 01:42:37,530 --> 01:42:39,165 THERE ARE VARIATIONS IN 2722 01:42:39,165 --> 01:42:42,435 STRUCTURE THAT CAN IMPACT 2723 01:42:42,435 --> 01:42:43,236 FUNCTION AS WELL. 2724 01:42:43,236 --> 01:42:45,104 WE SEE THAT IN PATIENTS AS WELL 2725 01:42:45,104 --> 01:42:46,306 AND GENOMICS AND PEOPLE CAN 2726 01:42:46,306 --> 01:42:48,941 GENERATE THESE DATA SETS AND 2727 01:42:48,941 --> 01:42:49,976 ALSO LIKE PATTIALLY CONNECT THEM 2728 01:42:49,976 --> 01:42:51,544 AS WELL IN THE ORGAN AND 2729 01:42:51,544 --> 01:42:53,346 CLINICIANS ARE SO IMPORTANT 2730 01:42:53,346 --> 01:42:55,748 BECAUSE THEY CAN SEE THE ENTIRE 2731 01:42:55,748 --> 01:42:57,283 PATIENT, THE ENTIRE ORGANISM 2732 01:42:57,283 --> 01:42:58,584 WHERE SOMETIMES, YOU KNOW FOR 2733 01:42:58,584 --> 01:43:00,119 ME, I HAD THIS, I WAS LIKE, 2734 01:43:00,119 --> 01:43:02,789 OKAY, WE WILL LOOK AT THE WHOLE 2735 01:43:02,789 --> 01:43:04,357 SPLEEN BUT THEN WE WOULD LOVE TO 2736 01:43:04,357 --> 01:43:05,858 ASSESS THE KIDNEY AS WELL, WE 2737 01:43:05,858 --> 01:43:07,727 WOULD LOVE TO ASSESS LUNGS ALL 2738 01:43:07,727 --> 01:43:11,464 THESE ORGANS, SO I THINK THIS 2739 01:43:11,464 --> 01:43:13,499 LIKE WHOLE BODY ALMOST LIKE 2740 01:43:13,499 --> 01:43:14,801 WHOLE SCIENTIFIC COMMUNITY, NOT 2741 01:43:14,801 --> 01:43:16,202 JUST RESTRICTED TO BIOLOGY, BUT 2742 01:43:16,202 --> 01:43:18,438 EXPANDING OUT TO PHYSICS, 2743 01:43:18,438 --> 01:43:20,940 CHEMISTRY AND MATH, COMPUTER 2744 01:43:20,940 --> 01:43:22,208 SCIENCES, I THINK THAT WILL BE 2745 01:43:22,208 --> 01:43:28,047 REALLY KEY IN HELPING US 2746 01:43:28,047 --> 01:43:28,281 ADVANCE. 2747 01:43:28,281 --> 01:43:32,585 ANYTHING ELSE BEFORE I MOVE TO 2748 01:43:32,585 --> 01:43:33,319 THE NEXT QUESTION? 2749 01:43:33,319 --> 01:43:34,487 >> OKAY, I'M GOING TO PULL OUT A 2750 01:43:34,487 --> 01:43:35,855 QUESTION FROM THE CHAT. 2751 01:43:35,855 --> 01:43:37,290 WE HAVE LOTS AND LOTS OF 2752 01:43:37,290 --> 01:43:39,859 QUESTIONS IN THE CHAT AND THE Q, 2753 01:43:39,859 --> 01:43:41,327 ANDA AND WE'RE GOING TO TRY TO 2754 01:43:41,327 --> 01:43:43,796 PULL A FEW OF THEM SO TO GET YOU 2755 01:43:43,796 --> 01:43:44,864 STARTED, AND I GUESS WE WILL 2756 01:43:44,864 --> 01:43:49,035 STICK WITH THE SAME ORDER IN 2757 01:43:49,035 --> 01:43:51,137 TERMS OF RESPONSES SO WE TALKED 2758 01:43:51,137 --> 01:43:52,672 A LOT TODAY ABOUT LUPUS AND A 2759 01:43:52,672 --> 01:43:53,940 COUPLE FOLLOW UP QUESTIONS ON 2760 01:43:53,940 --> 01:43:56,342 THAT AND THEN A QUESTION ABOUT 2761 01:43:56,342 --> 01:43:57,944 THE MICE. 2762 01:43:57,944 --> 01:43:59,712 SO IN LUPUS, IS IT THOUGHT THAT 2763 01:43:59,712 --> 01:44:03,850 THERE'S A DEFECT IN OW THE 2764 01:44:03,850 --> 01:44:06,352 X-CHROMESOME IS BEING 2765 01:44:06,352 --> 01:44:07,086 ENACTIVATED INVOLVING XIST, IS 2766 01:44:07,086 --> 01:44:09,122 THERE A TRIGGER ASK WHAT MIGHT 2767 01:44:09,122 --> 01:44:10,656 WE KNOW ABOUT THE TRIGGER? 2768 01:44:10,656 --> 01:44:13,993 AND THEN YOU TALKED A LOT, 2769 01:44:13,993 --> 01:44:15,995 CERTAINLY DR. ANG UERA, TALKED 2770 01:44:15,995 --> 01:44:16,596 ABOUT THE B-CELLS WHAT'S 2771 01:44:16,596 --> 01:44:18,664 HAPPENING IN OTHER CELLS OF THE 2772 01:44:18,664 --> 01:44:19,832 BODY, SPECIFIC TO LUPUS AND 2773 01:44:19,832 --> 01:44:21,701 THIRD PART OF THAT QUESTION, DO 2774 01:44:21,701 --> 01:44:24,404 THE MICE GET ANYTHING ELSE? 2775 01:44:24,404 --> 01:44:25,838 WE KNOW IN OTHER AUTOIMMUNE DECS 2776 01:44:25,838 --> 01:44:29,275 THERE ARE A LOT OF CO OCCURRING 2777 01:44:29,275 --> 01:44:30,676 AUTOIMMUNE DISEASES, DO THE MICE 2778 01:44:30,676 --> 01:44:33,446 ONLY HAVE LUPUS, DO THEY GET ANY 2779 01:44:33,446 --> 01:44:36,816 OTHER AUTOIMMUNITY? 2780 01:44:36,816 --> 01:44:37,650 >> YEAH, GOOD QUESTIONS. 2781 01:44:37,650 --> 01:44:39,919 YEAH, SO THE FIRST QUESTION, SO 2782 01:44:39,919 --> 01:44:42,355 WHAT ARE OUR WORK HAS FOUND IS 2783 01:44:42,355 --> 01:44:51,230 THAT IN LUPUS PATIENTS THERE ARE 2784 01:44:51,230 --> 01:44:52,498 PROBLEMS WITH X-INACTIVATION IN 2785 01:44:52,498 --> 01:44:53,699 BOTH B-CELLS AND T-CELLS. 2786 01:44:53,699 --> 01:44:57,136 SO WHAT WE SEE IS THAT IF YOU 2787 01:44:57,136 --> 01:44:58,538 TAKE A PERIPHERAL BLOOD SAMPLES 2788 01:44:58,538 --> 01:45:01,107 FROM A PATIENT AND YOU TAKE--YOU 2789 01:45:01,107 --> 01:45:03,609 ISOLATE T-CELLS AND YOU ISOLATE 2790 01:45:03,609 --> 01:45:05,578 B-CELLS AND YOU INVITRO ACTIVATE 2791 01:45:05,578 --> 01:45:07,513 THESE CELLS, EXIST RNA DOES NOT 2792 01:45:07,513 --> 01:45:09,949 GO BACK TO THE INACTIVE 2793 01:45:09,949 --> 01:45:11,884 X-CHROMESOME AND FORM THIS 2794 01:45:11,884 --> 01:45:13,186 FLUFFY CLOUD, LIKE IT SHOULD, 2795 01:45:13,186 --> 01:45:17,290 AND INSTEAD WHAT WE SEE IS THAT 2796 01:45:17,290 --> 01:45:18,224 THERE'S PINPOINTS OF XIST 2797 01:45:18,224 --> 01:45:20,026 CLUSTERS THAT ARE ALL OVER THE 2798 01:45:20,026 --> 01:45:22,261 NUCLEUS, SO INSTEAD OF A FLUFFY 2799 01:45:22,261 --> 01:45:26,933 CLOUD, THERE'S PINPOINTS ALL 2800 01:45:26,933 --> 01:45:28,601 OVER THE PLACE AND THEN THE 2801 01:45:28,601 --> 01:45:32,772 SECOND PART OF THE QUESTION IS 2802 01:45:32,772 --> 01:45:33,506 ENACTIVATED X-CHROMESOME 2803 01:45:33,506 --> 01:45:34,674 DIFFERENT IN B-CELLS AND OTHER 2804 01:45:34,674 --> 01:45:36,309 PARTS OF THE BODY. 2805 01:45:36,309 --> 01:45:38,544 SO YES, IN IMMUNE SES IT TURNS 2806 01:45:38,544 --> 01:45:39,579 OUT THAT X-ACTIVATION IS 2807 01:45:39,579 --> 01:45:41,113 MAINTAIN INDEED A VERY DIFFERENT 2808 01:45:41,113 --> 01:45:45,551 WAY AND THERE'S A DIVERSITY OF 2809 01:45:45,551 --> 01:45:49,121 WAYS THAT THE INACTIVE X IS 2810 01:45:49,121 --> 01:45:49,422 MAINTAINED. 2811 01:45:49,422 --> 01:45:50,790 SO FOR EXAMPLE, IN B-CELLS AND 2812 01:45:50,790 --> 01:45:52,325 T-CELLS IN THE RESTING ESTATE, 2813 01:45:52,325 --> 01:45:55,194 THESE ARE CELLS THAT ARE 2814 01:45:55,194 --> 01:45:58,598 QUIESCENT, THEY DO NOT HAVE XIST 2815 01:45:58,598 --> 01:46:00,600 ERROR NA LOCALIZE AT THE ACTIVE 2816 01:46:00,600 --> 01:46:04,637 X, THEY DO FOCUS ON THE HAVE 2817 01:46:04,637 --> 01:46:05,238 MODISKS, CYTOLOGICALLY ENRICH. 2818 01:46:05,238 --> 01:46:06,772 WHEN THESE CELLS ARE INVITRO 2819 01:46:06,772 --> 01:46:09,909 ACTIVATED IN A DISH, XIST RNA 2820 01:46:09,909 --> 01:46:14,080 COMES BACK TO THE XCHROME SOM AS 2821 01:46:14,080 --> 01:46:15,114 DO THESE EPIGENETIC MODISHS TO 2822 01:46:15,114 --> 01:46:17,116 THE POINT WHERE WE CAN SEE IT 2823 01:46:17,116 --> 01:46:17,617 USING MICROSCOPY. 2824 01:46:17,617 --> 01:46:21,454 SO IF YOU LOOK AT A NUTRIFILL 2825 01:46:21,454 --> 01:46:23,422 FOR EXAMPLE, NUTRIFILLS EXPRESS 2826 01:46:23,422 --> 01:46:26,092 FROM FEMALES, MOUSE AND HUMAN 2827 01:46:26,092 --> 01:46:27,627 THEY EXPRESS RNETWORKA AND YOU 2828 01:46:27,627 --> 01:46:28,928 DO RNA FISH FOR EXIST, THEY ARE 2829 01:46:28,928 --> 01:46:31,964 NONAPOPTOTIC THE ON THE INACTIVE 2830 01:46:31,964 --> 01:46:33,366 CHROMESOME AND NUTRIFILLS, SAME 2831 01:46:33,366 --> 01:46:35,434 THING WITH PLASMA SIGNIFYATOID 2832 01:46:35,434 --> 01:46:36,502 DENDRITIC CELLS, SO THIS IS 2833 01:46:36,502 --> 01:46:38,871 EXPRESSED BUT NOT LOCALIZED ON 2834 01:46:38,871 --> 01:46:39,705 THE INACTIVE X-CHROMESOME, SO 2835 01:46:39,705 --> 01:46:47,780 WHY ARE THESE CELLS DOING IT THE 2836 01:46:47,780 --> 01:46:48,281 LIKE THIS. 2837 01:46:48,281 --> 01:46:52,952 WE DON'T KNOW BUT THERE'S A 2838 01:46:52,952 --> 01:46:55,555 DIVERSITY OF FILTRATION THAT 2839 01:46:55,555 --> 01:46:58,424 EXIST FOR XIST AND INACTIVATION, 2840 01:46:58,424 --> 01:46:59,625 AND IT HIGHLIGHTS HOW MUCH WE 2841 01:46:59,625 --> 01:47:01,460 DON'T UNDERSTAND IN THIS PROCESS 2842 01:47:01,460 --> 01:47:02,995 IN IMMUNE CELLS WHICH MAKE ITS 2843 01:47:02,995 --> 01:47:04,297 REALLY EXCITING FOR SCIENTISTS 2844 01:47:04,297 --> 01:47:06,465 WHO ARE INTERESTED IN MECHANISM, 2845 01:47:06,465 --> 01:47:09,101 TO FIGURE OUT HOW DOES IT WORK, 2846 01:47:09,101 --> 01:47:11,337 WHY IS IT WORKING LIKE THIS? 2847 01:47:11,337 --> 01:47:12,972 THEN THE THIRD PART OF THE 2848 01:47:12,972 --> 01:47:14,941 QUESTION, REMIND ME AGAIN? 2849 01:47:14,941 --> 01:47:17,510 >> IT'S A QUESTION REALLY FOR 2850 01:47:17,510 --> 01:47:21,414 YOU AND MAYBE DR. DOU, AND THEN 2851 01:47:21,414 --> 01:47:27,853 WE'LL ASK DR. ANTIOCHOS, BECAUSE 2852 01:47:27,853 --> 01:47:29,822 HE'S MORE INTO HUMANS THAN 2853 01:47:29,822 --> 01:47:30,189 MOUSE. 2854 01:47:30,189 --> 01:47:31,757 NYEAH, GREAT QUESTION. 2855 01:47:31,757 --> 01:47:34,226 SO IN OUR XIST KNOCKOUT MICE BE, 2856 01:47:34,226 --> 01:47:35,328 WE LOOKEDDA THE AUTOANTIBODY 2857 01:47:35,328 --> 01:47:36,629 PROFILES AND WE WERE REALLY 2858 01:47:36,629 --> 01:47:37,763 SURPRISED BECAUSE WE DID NOT 2859 01:47:37,763 --> 01:47:40,733 EXIST TO SEE THAT THERE WAS 2860 01:47:40,733 --> 01:47:43,903 GOING TO BE ELEVATED 2861 01:47:43,903 --> 01:47:45,671 AUTOANTIBODIES DECIDES DSDNA AND 2862 01:47:45,671 --> 01:47:46,505 ANTISMITH. 2863 01:47:46,505 --> 01:47:49,442 SO THE MDA 51S WERE LIKE WHOA, 2864 01:47:49,442 --> 01:47:50,376 HOLD ON, WHAT'S HAPPENING? 2865 01:47:50,376 --> 01:47:51,677 SO BECAUSE OF THAT WE'RE NOW 2866 01:47:51,677 --> 01:47:54,347 LOOKING AT OTHER TISSUES IN THE 2867 01:47:54,347 --> 01:47:55,982 ANIMALS TO SEE IF THERE IS 2868 01:47:55,982 --> 01:47:58,017 EVIDENT OF PATHOLOGY THAT WOULD 2869 01:47:58,017 --> 01:47:59,885 BE SIMILAR TO OTHER AUTOIMMUNE 2870 01:47:59,885 --> 01:48:00,386 PATIENTS. 2871 01:48:00,386 --> 01:48:04,690 SO IN THE ORIGINAL LIKE COHORT, 2872 01:48:04,690 --> 01:48:06,759 BECAUSE AUTORANDOM RIGHT AND THE 2873 01:48:06,759 --> 01:48:08,394 PENETRANTS IS LIKE 15-18% OF 2874 01:48:08,394 --> 01:48:10,262 ANIMALS BEYOND THE AIMS OF 12 2875 01:48:10,262 --> 01:48:13,733 MONTHS WE ONLY LOOKEDDA THE 2876 01:48:13,733 --> 01:48:15,101 KIDNEYS IN THOSE ORIGINAL 3 2877 01:48:15,101 --> 01:48:18,704 MICE, AND SO WE JUST HAVE TO GET 2878 01:48:18,704 --> 01:48:22,475 LUCKY AND BE PATIENT AND THIS IS 2879 01:48:22,475 --> 01:48:24,677 WHY MY MD-Ph.D. STUDENT 2880 01:48:24,677 --> 01:48:26,212 CLAUDIA IS SO INEDIBLE -LY 2881 01:48:26,212 --> 01:48:27,747 AMAZING BECAUSE SHE SHOWING GRIT 2882 01:48:27,747 --> 01:48:29,382 AND PERSISTENCE TO FOLLOW THE 2883 01:48:29,382 --> 01:48:31,751 COHORT OF ANIMALS OVER TIME AND 2884 01:48:31,751 --> 01:48:33,619 MAKE SURE NONE OF THEM DIE ON 2885 01:48:33,619 --> 01:48:35,454 US, RIGHT, LIKE WE'RE GOING TO 2886 01:48:35,454 --> 01:48:37,123 BE CHECKING THEM EVERY COUPLE OF 2887 01:48:37,123 --> 01:48:37,356 WEEKS. 2888 01:48:37,356 --> 01:48:40,826 SO THAT WE CAN GET THEM AND THEN 2889 01:48:40,826 --> 01:48:41,861 DO THE EXTENSIVE PATHOLOGY TO 2890 01:48:41,861 --> 01:48:47,199 SEE WHAT ELSE MAY MIGHT BE GOOD 2891 01:48:47,199 --> 01:48:47,700 MODELS FOR. 2892 01:48:47,700 --> 01:48:49,335 >> YEAH, SO FOR US, WE ACTUALLY 2893 01:48:49,335 --> 01:48:51,303 TOOK THE MICE, I THINK IF YOU 2894 01:48:51,303 --> 01:48:54,073 RECALL, I SAID 16 WEEKS WE 2895 01:48:54,073 --> 01:48:55,374 WOULDN'T LOSE ANY FEMALES, WHAT 2896 01:48:55,374 --> 01:48:57,043 I DIDN'T SAY IS IF YOU LOOK AT 2897 01:48:57,043 --> 01:48:59,345 THE SAME CHART, THE MALES THAT 2898 01:48:59,345 --> 01:49:00,880 ARE WILD-TYPE DON'T DROP OFF 2899 01:49:00,880 --> 01:49:02,948 UNTIL AROUND 23 WEEKS SO FOR 2900 01:49:02,948 --> 01:49:05,484 THEM IT WAS KIND OF EARLY SO I 2901 01:49:05,484 --> 01:49:07,720 THINK WITH THE FEMALES WITH THE 2902 01:49:07,720 --> 01:49:12,491 SERUM, WE USE PJs SORT OF 2903 01:49:12,491 --> 01:49:13,626 LUPUS AUTOANTIGEN ARRAY BUT 2904 01:49:13,626 --> 01:49:16,696 THERE WERE SOME OVERLAPPED WITH 2905 01:49:16,696 --> 01:49:19,699 I THINK MYOCYTEIS AND MAYBE SOME 2906 01:49:19,699 --> 01:49:21,967 SCLERODERMA BUT AGAIN SOME OF 2907 01:49:21,967 --> 01:49:23,602 THE AUTOANTIBODIES TEND TO BE 2908 01:49:23,602 --> 01:49:25,705 SHARED ACROSS DISEASES AS WELL, 2909 01:49:25,705 --> 01:49:29,608 SO WE--I'M NOT A CLINICIAN, I'M 2910 01:49:29,608 --> 01:49:31,510 NOT A RHEUMATOLOGIST, WE HAVE 2911 01:49:31,510 --> 01:49:32,445 GREAT COLLABORATORS SO WE JUST 2912 01:49:32,445 --> 01:49:34,413 ASH ASSESSESSED FOR YOU KNOW 2913 01:49:34,413 --> 01:49:36,015 SIGNS OF LUPUS BUT I DON'T THINK 2914 01:49:36,015 --> 01:49:37,817 WE CAN RULE OUT THAT AND MAYBE 2915 01:49:37,817 --> 01:49:38,984 WE HAVE CHARACTERISTICS FROM 2916 01:49:38,984 --> 01:49:40,820 OTHER STEEZS AS WELL BECAUSE 2917 01:49:40,820 --> 01:49:42,621 IMEAN, SOME OF THESE SYMPTOMS IN 2918 01:49:42,621 --> 01:49:45,391 PATIENTS AS WELL, ARE HIGHLY 2919 01:49:45,391 --> 01:49:49,962 OVERLAPPING AND VERY ETICSER O 2920 01:49:49,962 --> 01:49:51,831 GENIUS AND AS FOR AS FEMALES 2921 01:49:51,831 --> 01:49:54,366 THERE WAS A RANGE OF SEVERITY OF 2922 01:49:54,366 --> 01:49:56,235 WHAT THEY WERE GETTING WITH THE 2923 01:49:56,235 --> 01:49:58,571 FEMALES AND WITH THE GROUPS IN 2924 01:49:58,571 --> 01:50:00,372 THE SAMPLE COHORT THAT WE WERE 2925 01:50:00,372 --> 01:50:02,341 TESTING ON AS WELL. 2926 01:50:02,341 --> 01:50:05,978 SO, I THINK IT'S A VERY 2927 01:50:05,978 --> 01:50:07,980 INTERESTING QUESTION AND 2928 01:50:07,980 --> 01:50:08,748 DEFINITELY WORTH EXPLORING. 2929 01:50:08,748 --> 01:50:11,083 >> OKAY, I WILL GIVE YOU A CHAND 2930 01:50:11,083 --> 01:50:15,554 TO ANSWER AS WELL BRENDAN. 2931 01:50:15,554 --> 01:50:16,155 >> YOU'RE MUTED. 2932 01:50:16,155 --> 01:50:17,056 >> SORRY WITH A QUESTION OF 2933 01:50:17,056 --> 01:50:20,226 WHETHER THERE ARE ANY SPECIFIC 2934 01:50:20,226 --> 01:50:21,527 FINDINGS, YOU KNOW WITHIN 2935 01:50:21,527 --> 01:50:23,028 SUBSETS OF HUMANS WHO SHOW 2936 01:50:23,028 --> 01:50:24,330 DIFFERING LEVELS OF EXISTING 2937 01:50:24,330 --> 01:50:26,165 EXPRESSION, WE HAVEN'T HAD 2938 01:50:26,165 --> 01:50:27,333 ACCESS TO MEASURE EXIST IN A 2939 01:50:27,333 --> 01:50:28,267 LARGE ENOUGH GROUP OF PATIENTS 2940 01:50:28,267 --> 01:50:31,170 TO REALLY KNOW IF THERE'S A 2941 01:50:31,170 --> 01:50:32,538 SPECIFIC PHENOTYPE, THAT'S ON 2942 01:50:32,538 --> 01:50:33,973 THE VERY LONG TO DO LIST, I 2943 01:50:33,973 --> 01:50:36,475 THINK OF THINGS THAT WOULD BE 2944 01:50:36,475 --> 01:50:39,979 USEFUL TO DO TO DETERMINE YOU 2945 01:50:39,979 --> 01:50:41,046 KNOW WHAT EXIST EXPRESSION 2946 01:50:41,046 --> 01:50:42,815 LEVELS LOOK LIKE IN LARGER 2947 01:50:42,815 --> 01:50:44,784 COHORTS OF PATIENTS, 2948 01:50:44,784 --> 01:50:46,085 LOCKITUDEINAL SAMPLES, IS THIS 2949 01:50:46,085 --> 01:50:47,052 SOMETHING THAT CHANGES OVERTIME 2950 01:50:47,052 --> 01:50:52,224 OR IS IT STATIC, IN THOSE VERY 2951 01:50:52,224 --> 01:50:54,493 VALUABLE PRECLINICAL COHORTS, IS 2952 01:50:54,493 --> 01:50:55,427 XIST SOMETHING THAT'S THERE 2953 01:50:55,427 --> 01:50:57,930 BEFORE HAND OR COMES AFTER 2954 01:50:57,930 --> 01:50:58,998 DISEASE DEVELOPED AND THERE'S A 2955 01:50:58,998 --> 01:51:01,634 LOT OF QUESTIONS THAT WOULD BE, 2956 01:51:01,634 --> 01:51:03,135 YOU KNOW INTERESTING TO RUN DOWN 2957 01:51:03,135 --> 01:51:04,103 WHICH ARE SIMILAR TO THE 2958 01:51:04,103 --> 01:51:05,304 QUESTIONS THAT HAVE BEEN PHRASED 2959 01:51:05,304 --> 01:51:08,240 WITH RESPECT TO THE INTERFERON 2960 01:51:08,240 --> 01:51:10,409 SIGNATURE ITSELF. 2961 01:51:10,409 --> 01:51:13,012 SO, MAYBE IF WE COME ACROSS SOME 2962 01:51:13,012 --> 01:51:16,382 OF THOSE FUNDS THAT DR. ANG 2963 01:51:16,382 --> 01:51:17,650 UERA WAS MENTIONING TO DO ALL 2964 01:51:17,650 --> 01:51:18,851 THIS WORK, THAT'S SOME OF THE 2965 01:51:18,851 --> 01:51:20,386 SORTS OF THINGS WE CAN COULD 2966 01:51:20,386 --> 01:51:23,422 ANSWER IN LARGER STUDIES. 2967 01:51:23,422 --> 01:51:26,158 >> AND I'M GOING TO PULL ANOTHER 2968 01:51:26,158 --> 01:51:29,929 QUESTION OUT FROM THE Q&A AS 2969 01:51:29,929 --> 01:51:33,199 WELL, AND IT'S REALLY SPEAKING 2970 01:51:33,199 --> 01:51:36,936 TO THIS DISCIPLINARY MORPHISM OF 2971 01:51:36,936 --> 01:51:37,203 RESPONSES. 2972 01:51:37,203 --> 01:51:41,674 AND SO, WE KNOW THAT WHILE THERE 2973 01:51:41,674 --> 01:51:44,410 ARE SOME MALE PATIENT WHO IS 2974 01:51:44,410 --> 01:51:46,045 HAVE AN ADDITIONAL X-CHROMOSOME 2975 01:51:46,045 --> 01:51:47,780 WHO GET LUPUS, WE KNOW THERE ARE 2976 01:51:47,780 --> 01:51:51,016 MALE PATIENTS WHO DON'T HAVE AN 2977 01:51:51,016 --> 01:51:52,051 ADDITIONAL MALE X-CHROMOSOME WHO 2978 01:51:52,051 --> 01:51:55,554 GET LUPUS WHAT MIGHT BE GOING ON 2979 01:51:55,554 --> 01:51:57,957 IN THE B-CELLS THERE? 2980 01:51:57,957 --> 01:52:01,026 ARE THERE OTHER X-LINKED IMMUNE 2981 01:52:01,026 --> 01:52:02,461 RELATED GENES BEING SEEN 2982 01:52:02,461 --> 01:52:02,795 UPREGULATED. 2983 01:52:02,795 --> 01:52:05,564 DO YOU THINK THOSE ARE 2984 01:52:05,564 --> 01:52:06,765 TRANSLOCATIONS OF GENERATED 2985 01:52:06,765 --> 01:52:08,701 THETIC MATERIALS, DO YOU HAVE 2986 01:52:08,701 --> 01:52:15,908 ANY THOUGHTS ABOUT HOW THAT 2987 01:52:15,908 --> 01:52:17,710 COULD BE STUDIED? 2988 01:52:17,710 --> 01:52:19,211 >> YEAH, SO WITH MALE PATIENTS 2989 01:52:19,211 --> 01:52:24,984 LIKE SAY ABOUT 15% OF LUPUS 2990 01:52:24,984 --> 01:52:26,118 PATIENTS ARE MALE IT'S REALLY 2991 01:52:26,118 --> 01:52:27,887 HARD TO RECRUIT THEM IN OUR 2992 01:52:27,887 --> 01:52:30,856 STUDIES, LIKE FEMALE PATIENTS, 2993 01:52:30,856 --> 01:52:33,492 ARE THE PREDOMINANT 1S, RIGHT 2994 01:52:33,492 --> 01:52:39,832 AND SO, WITH RESPECT TO LUPUS, 2995 01:52:39,832 --> 01:52:43,569 MALE AND FEMALES, HAVE PRETTY 2996 01:52:43,569 --> 01:52:46,305 SIMILAR DISEASE ACTIVITY, SO, WE 2997 01:52:46,305 --> 01:52:48,841 CAN'T REALLY SAY THAT LIKE, IT'S 2998 01:52:48,841 --> 01:52:51,810 DIFFERENT TO SAY FOR EXAMPLE, 2999 01:52:51,810 --> 01:52:54,113 SCLERODERMA WHERE THERE ARE MALE 3000 01:52:54,113 --> 01:52:55,381 PATIENTS PRESENT WITH MUCH MORE 3001 01:52:55,381 --> 01:52:56,348 DISEEEVER DISEASE AND THEN YOU 3002 01:52:56,348 --> 01:52:57,950 GD SAY, IS THERE SOMETHING 3003 01:52:57,950 --> 01:53:01,387 PROTECTIVE ON THE Y OR IN LUPUS 3004 01:53:01,387 --> 01:53:06,325 THAT IN THE CONTEXT OF 3005 01:53:06,325 --> 01:53:07,660 SCLERODERMA AGGRAVATES DISEASE 3006 01:53:07,660 --> 01:53:08,093 MORE, MAYBE? 3007 01:53:08,093 --> 01:53:10,162 PERHAPS WHAT THAT IS, WE'RE NOT 3008 01:53:10,162 --> 01:53:13,265 SURE, IS IT--HOW IS IT 3009 01:53:13,265 --> 01:53:15,134 MANIFESTING THIS, RIGHT IN IS 3010 01:53:15,134 --> 01:53:16,435 THROUGH PRODECLARATION OF 3011 01:53:16,435 --> 01:53:16,702 CYTOKINES? 3012 01:53:16,702 --> 01:53:18,504 IS IT THROUGH MEMBERS OF IMUBE 3013 01:53:18,504 --> 01:53:21,173 CELL POPULATIONS LIKE PROTECTED 3014 01:53:21,173 --> 01:53:25,210 1S, ADAPTIVE VERSUS INNATE, WE 3015 01:53:25,210 --> 01:53:26,412 REAL REALLY DON'T KNOW AND THEN 3016 01:53:26,412 --> 01:53:28,814 TO KIND OF GET BACK AT THE 3017 01:53:28,814 --> 01:53:33,118 QUESTION WITH LUPUS PATIENTS IN 3018 01:53:33,118 --> 01:53:34,620 MALES, REMEMBER THE SLIDE THAT 3019 01:53:34,620 --> 01:53:36,588 SOME--I THINK MAYBE ALL OF US 3020 01:53:36,588 --> 01:53:39,124 SHOWED THAT DOSAGE OF 3021 01:53:39,124 --> 01:53:40,492 X-CHROMESOMES IS LINKED TO 3022 01:53:40,492 --> 01:53:42,361 INCREASED RISK FOR DEVELOPING 3023 01:53:42,361 --> 01:53:43,862 THESE DISEASES SUCH AS LUPUS, 3024 01:53:43,862 --> 01:53:45,631 AND SO AN INDIVIDUAL MIGHT HAVE 3025 01:53:45,631 --> 01:53:48,500 TO COPIES OF AN X-CHROMESOME BUT 3026 01:53:48,500 --> 01:53:49,568 NEVER KNOW THAT, RIGHT? 3027 01:53:49,568 --> 01:53:52,771 SO AN INDIVIDUAL MIGHT BE X-Y 3028 01:53:52,771 --> 01:53:55,074 BUT MIGHT BE EXTINGUISHING 3029 01:53:55,074 --> 01:53:57,109 XY AND HAVE LUPUS LIKE DEC BUT 3030 01:53:57,109 --> 01:54:00,346 MAY NOT HAVE BEEN EVERY KERIO 3031 01:54:00,346 --> 01:54:04,083 TYPED TO PRESENT WITH THAT SO WE 3032 01:54:04,083 --> 01:54:07,086 HAVEN'T SEEN ANY--LIKE WE HAVE 3033 01:54:07,086 --> 01:54:08,587 RECRUITED ANY MALES IN OUR STUDY 3034 01:54:08,587 --> 01:54:13,025 WE WOULD WANT TO CHECK FOR 3035 01:54:13,025 --> 01:54:14,326 ABERRATIONS WITH X-INACTIVATION 3036 01:54:14,326 --> 01:54:15,561 MAINTENANCE BECAUSE IF THEY ARE, 3037 01:54:15,561 --> 01:54:18,263 AND XY THEY WOULD PREDICT THEY 3038 01:54:18,263 --> 01:54:19,398 HAVE MISLOCALLIZED EXIST, THEY 3039 01:54:19,398 --> 01:54:21,533 WOULD HAVE CHANGES IN EXCELLENT 3040 01:54:21,533 --> 01:54:22,735 GENE EXPRESSION, AND THEN AGAIN 3041 01:54:22,735 --> 01:54:23,936 IN THAT CONTEXT, IS THERE 3042 01:54:23,936 --> 01:54:25,437 SOMETHING PROTECTIVE ON THE 3043 01:54:25,437 --> 01:54:27,940 YRK-CHROMESOME IN THOSE 3044 01:54:27,940 --> 01:54:28,974 INDIVIDUALS, WE JUST DON'T KNOW, 3045 01:54:28,974 --> 01:54:32,911 WE DON'T KNOW YET. 3046 01:54:32,911 --> 01:54:34,880 >> GOING OFF LIKE WHY MALES, 3047 01:54:34,880 --> 01:54:36,648 SOME MALES MAY BE XY MAY 3048 01:54:36,648 --> 01:54:39,118 DEVELOP, I THINK THERE'S A 3049 01:54:39,118 --> 01:54:39,885 STRONG GENETIC CORRELATION 3050 01:54:39,885 --> 01:54:42,087 BECAUSE NOT ALL FEMALES WILL 3051 01:54:42,087 --> 01:54:43,022 DEVELOP AUTOIMMUNITY EITHER AND 3052 01:54:43,022 --> 01:54:47,826 WE CAN SEE AS I MENTIONED, WE 3053 01:54:47,826 --> 01:54:48,861 HAD AN AUTORESISTANT STREAM OF 3054 01:54:48,861 --> 01:54:52,431 BLACK 6 AND THEN WE HAD THE 3055 01:54:52,431 --> 01:54:54,600 AUTOIMMUNE PERMISSIVE AND WE 3056 01:54:54,600 --> 01:54:56,435 GOT VERY DIFFERENT IMMUNOLOGICAL 3057 01:54:56,435 --> 01:54:58,971 RESULTS AND THEY'RE THERE, SO 3058 01:54:58,971 --> 01:55:00,706 STRONGLY IN 6, THEY'RE NOT 3059 01:55:00,706 --> 01:55:02,107 PROGRESSING BUT IN THE DISEASES 3060 01:55:02,107 --> 01:55:05,210 BUT IN THE SDL, YOU SEE THAT THE 3061 01:55:05,210 --> 01:55:06,779 WILD-TYPE MALES ARE PROGRESSING 3062 01:55:06,779 --> 01:55:08,113 SO IT'S A CONTRIBUTION OF 3063 01:55:08,113 --> 01:55:11,250 FACTORS, I DON'T THINK-I DON'T 3064 01:55:11,250 --> 01:55:13,986 THINK THAT XIST IS THE ONLY 1 3065 01:55:13,986 --> 01:55:16,088 THAT IS INVOLVED, I THINK IT'S A 3066 01:55:16,088 --> 01:55:17,356 VERY STRONG COMPONENT AS WE'VE 3067 01:55:17,356 --> 01:55:19,425 SHOWN IN OUR TALKS TODAY BUT 3068 01:55:19,425 --> 01:55:23,195 ALSO GOING OFF THE SET, WAABOUT 3069 01:55:23,195 --> 01:55:24,263 THE OTHER LINK RNAs THAT ARE 3070 01:55:24,263 --> 01:55:26,031 OUT THERE THAT ARE HIGHLY 3071 01:55:26,031 --> 01:55:27,066 ASSOCIATED, MAYBE THEY HAVE SOME 3072 01:55:27,066 --> 01:55:30,235 KIND OF ROLE THERE BECAUSE I 3073 01:55:30,235 --> 01:55:31,770 THINK I SAW IN THE CHAT GROUP, 3074 01:55:31,770 --> 01:55:33,272 THERE WAS A QUESTION ABOUT 3075 01:55:33,272 --> 01:55:37,109 WHETHER WE SAW DIFFERENCES IN 3076 01:55:37,109 --> 01:55:38,877 THE REACTIVITY IN THE 3077 01:55:38,877 --> 01:55:44,016 MONOARRAYS, AND LIKE MONTSERRAT, 3078 01:55:44,016 --> 01:55:45,451 SAID, WE DIDN'T HAVE ENOUGH 3079 01:55:45,451 --> 01:55:46,885 MALES IN THE SERUM, SO I WAS 3080 01:55:46,885 --> 01:55:48,554 SAYING DO YOU HAVE ANY SERUM, SO 3081 01:55:48,554 --> 01:55:50,656 IF WE INCREASE THE SAMPLE SIZE, 3082 01:55:50,656 --> 01:55:52,424 I DO RECALL SEEING SOME OF THE 3083 01:55:52,424 --> 01:55:56,662 MALES HAVING GREATER THAN A BASE 3084 01:55:56,662 --> 01:55:57,463 LINE REACTIVITY, SEROREACTIVITY 3085 01:55:57,463 --> 01:56:01,400 TO THE SOME OF THE PROTEINS ON 3086 01:56:01,400 --> 01:56:03,001 THE XIST RNP, AND WHAT'S 3087 01:56:03,001 --> 01:56:04,970 INTERESTING ABOUT THE XIST RNP 3088 01:56:04,970 --> 01:56:07,406 ARE THESE PROTEINS ARE IN OVER 3089 01:56:07,406 --> 01:56:09,108 ABUNDANCE COMPARED TO XIST AND 3090 01:56:09,108 --> 01:56:10,309 THEY HAD BIOLOGICAL PROCESSES, 3091 01:56:10,309 --> 01:56:11,543 THEY ARE THERE FOR A REASON, 3092 01:56:11,543 --> 01:56:12,277 THEY'RE EXPRESSED FOR A REASON 3093 01:56:12,277 --> 01:56:14,913 AND PART OF IT IS TO BIND WITH 3094 01:56:14,913 --> 01:56:16,582 XIST, BUT NOT THE ONLY THING SO 3095 01:56:16,582 --> 01:56:19,318 THESE PROTEINS ALSO MIGHT BE IN 3096 01:56:19,318 --> 01:56:23,689 OTHER COMPLEXES OR HAVE OTHER 3097 01:56:23,689 --> 01:56:25,090 MECHANISMs AS WELL THAT 3098 01:56:25,090 --> 01:56:26,391 THEY'RE INVOLVED IN SEPARATE 3099 01:56:26,391 --> 01:56:28,227 FROM XIST SO IT COULD BE THAT 3100 01:56:28,227 --> 01:56:30,529 THIS SEROACTIVITY THAT WE'RE 3101 01:56:30,529 --> 01:56:31,930 IDENTIFYING COULD BE FROM, YOU 3102 01:56:31,930 --> 01:56:35,734 KNOW, THEY MIGHT BE IN ANOTHER 3103 01:56:35,734 --> 01:56:36,702 LINK RNA-RNP COMPLEX OR INVOLVED 3104 01:56:36,702 --> 01:56:38,003 IN A DIFFERENT WAY AS WELL. 3105 01:56:38,003 --> 01:56:40,305 SO I THINK GENETICS AND HORMONES 3106 01:56:40,305 --> 01:56:47,112 AND ALL OF THESE THINGS PLAY 3107 01:56:47,112 --> 01:56:52,251 VERY SIGNIFICANT ROLES. 3108 01:56:52,251 --> 01:56:55,487 NAND DR. ANT IOCH OS, I WILL LET 3109 01:56:55,487 --> 01:56:56,989 YOU HAVE THE LAST WORD AND THEN 3110 01:56:56,989 --> 01:56:59,258 I'M TOLD WE NEED TO WRAP IT UP. 3111 01:56:59,258 --> 01:57:02,528 >> OH, WELL, OKAY, I WILL ECHO 3112 01:57:02,528 --> 01:57:03,595 FACT THAT THEY'RE HETEROGENEOUS 3113 01:57:03,595 --> 01:57:05,797 ORY GENIUS AND IN LUPUS IN 3114 01:57:05,797 --> 01:57:06,665 PARTICULAR, THERE'S SUCH 3115 01:57:06,665 --> 01:57:08,567 VARIABILITY IN THE PATTERNS OF 3116 01:57:08,567 --> 01:57:10,135 INVOLVE AM, SEROLONLIC FEATURES, 3117 01:57:10,135 --> 01:57:11,837 ET CETERA AND SO, THE STUDY OF, 3118 01:57:11,837 --> 01:57:14,940 YOU KNOW MEN WITH THAT DISEASE, 3119 01:57:14,940 --> 01:57:15,641 YES, IMETTING SIGNIFICANT 3120 01:57:15,641 --> 01:57:17,276 NUMBERS ARE A PROBLEM, WE'VE 3121 01:57:17,276 --> 01:57:18,544 BEEN INTERESTED IN MEASURING 3122 01:57:18,544 --> 01:57:20,179 EXISTING LEVELS IN MEN AS WELL 3123 01:57:20,179 --> 01:57:21,113 BUT THERE JUST AREN'T MANY OF 3124 01:57:21,113 --> 01:57:25,584 THEM OUT THERE IN THESE COHORTS. 3125 01:57:25,584 --> 01:57:27,019 IN TERMS OF APPLYING FILTERS 3126 01:57:27,019 --> 01:57:28,987 THAT CAN MAKE IT EASIER TO 3127 01:57:28,987 --> 01:57:31,857 INTERPRET ALL THIS, JUST TO ECHO 3128 01:57:31,857 --> 01:57:33,158 WHAT DR. DOU JUST MENTIONED, 3129 01:57:33,158 --> 01:57:34,893 THERE ARE LOTS OF PATHWAYS THAT 3130 01:57:34,893 --> 01:57:35,961 CONTRIBUTE TO THESE DISEASES, 3131 01:57:35,961 --> 01:57:37,362 YOU KNOW IT'S UNLIKELY OF 3132 01:57:37,362 --> 01:57:39,765 COURSE, THAT EXIST IS THE MAIN 3133 01:57:39,765 --> 01:57:41,733 DRIVER IN MOST PATIENTS WITH 3134 01:57:41,733 --> 01:57:45,804 THESE CONDITIONS BUT AT THE SAME 3135 01:57:45,804 --> 01:57:47,239 TIME, YOU KNOW, THE FACT THAT 3136 01:57:47,239 --> 01:57:49,975 ANYONE VIEWING THIS TODAY WHO IS 3137 01:57:49,975 --> 01:57:51,043 TOTALLY UNFAMILIAR WITH XIST, 3138 01:57:51,043 --> 01:57:53,145 WOULD SAY WOW IT'S PRETTY 3139 01:57:53,145 --> 01:57:55,447 AMAZING THIS THIS 1 RNA CAN BE 3140 01:57:55,447 --> 01:57:56,815 IMPLICATED IN SO MANY AS 3141 01:57:56,815 --> 01:57:57,816 CONTRIBUTING TO THESE DISEASES, 3142 01:57:57,816 --> 01:58:01,153 SO I GUESS THAT I WILL EMPHASIZE 3143 01:58:01,153 --> 01:58:02,588 THE IMPORTANCE PERHAPS OF TRYING 3144 01:58:02,588 --> 01:58:03,755 TO,A CHIEF CORHOTTERS OF 3145 01:58:03,755 --> 01:58:06,291 PATIENTS WHO ARE REALLY--COHORTS 3146 01:58:06,291 --> 01:58:08,860 OF PATIENTS WHO ARE REALLY 3147 01:58:08,860 --> 01:58:10,462 GENIUS TO INTERROGATE A PATHWAY 3148 01:58:10,462 --> 01:58:12,664 LIKE THIS 1 IN A SIGNIFICANTLY 3149 01:58:12,664 --> 01:58:14,299 SIZED POPULATION WHERE PATIENTS 3150 01:58:14,299 --> 01:58:16,935 REALLY HAVE DISEASE PATHOLOGY 3151 01:58:16,935 --> 01:58:19,304 ATTRIBUTABLE TO 1 PATHWAY, TO 3152 01:58:19,304 --> 01:58:20,606 TRY TO COUNTERACT THAT 3153 01:58:20,606 --> 01:58:22,674 INCREDIBLE NOISE THAT THERE IS 3154 01:58:22,674 --> 01:58:24,509 IN RHEUMATIC DISEASES OF THIS 3155 01:58:24,509 --> 01:58:25,510 VARIABILITY AND THE CLINICAL 3156 01:58:25,510 --> 01:58:28,780 PATTERNS OF THE DISEASE. 3157 01:58:28,780 --> 01:58:29,982 >> YEAH, AND MAYBE, MAYBE I WILL 3158 01:58:29,982 --> 01:58:32,184 HAVE THE LAST WORD MYSELF, AND 3159 01:58:32,184 --> 01:58:35,554 SAY PERHAPS GOING UP STREAM OF 3160 01:58:35,554 --> 01:58:36,488 DISEASE AND PERHAPS PREE DEC 3161 01:58:36,488 --> 01:58:37,789 ALSO MIGHT BE A NICE PLACE TO 3162 01:58:37,789 --> 01:58:39,191 LOOK AND JUST SEE BECAUSE IF 3163 01:58:39,191 --> 01:58:40,692 IT'S A HUGE DRIVER, YOU WOULD 3164 01:58:40,692 --> 01:58:44,229 EXPECT TO SEE BEFORE THE OTHER 3165 01:58:44,229 --> 01:58:46,632 AUTOANTIBODY PERHAPS BECOME 3166 01:58:46,632 --> 01:58:47,032 MANIFEST, RIGHT? 3167 01:58:47,032 --> 01:58:48,634 >> OKAY, SO I WILL WRAP US UP 3168 01:58:48,634 --> 01:58:51,603 HERE, I WANT TO SAY A HUGE THANK 3169 01:58:51,603 --> 01:58:53,171 YOU TO OUR 3 SPEAKERS, THAT WAS 3170 01:58:53,171 --> 01:58:54,706 JUST A WONDERFUL SESSION, I REAL 3171 01:58:54,706 --> 01:58:56,108 LE ENJOYED ALL OF YOUR TALKS AND 3172 01:58:56,108 --> 01:58:59,044 A HUGE THANK YOU ALSO TO 3173 01:58:59,044 --> 01:59:00,679 DRS. MANCINI AND PERG-I SON FOR 3174 01:59:00,679 --> 01:59:01,947 MODERATING THE DISCUSSION AND 3175 01:59:01,947 --> 01:59:04,650 HELPING US WITH THE ORGANIZATION 3176 01:59:04,650 --> 01:59:05,584 OF THIS SYMPOSIUM. 3177 01:59:05,584 --> 01:59:07,819 IT'S NICE TO KIND OF LISTEN TO 3178 01:59:07,819 --> 01:59:11,657 THE SCIENCE SPEAK FOR ITSELF. 3179 01:59:11,657 --> 01:59:13,558 SO PLUGS FROM THE OFFICE OF 3180 01:59:13,558 --> 01:59:14,259 AUTOIMMUNE DISEASE RESEARCH, IF 3181 01:59:14,259 --> 01:59:15,527 YOU WOULD LIKE TO HEAR MORE 3182 01:59:15,527 --> 01:59:16,395 ABOUT OUR OFFICE AND THE WORK 3183 01:59:16,395 --> 01:59:19,264 THAT WE ARE DOING, PLEASE JOIN 3184 01:59:19,264 --> 01:59:21,500 OUR NEXT UPDATE SESSION, WE HAVE 3185 01:59:21,500 --> 01:59:22,801 THESE QUARTER LEE, THE NEXT 1 3186 01:59:22,801 --> 01:59:24,636 WILL BE ON FRIDAY MAY THIRD, IF 3187 01:59:24,636 --> 01:59:25,971 YOU SCAN THE QR CODE, IT WILL 3188 01:59:25,971 --> 01:59:27,306 TAKE YOU TO THE EVENT PAGE AND 3189 01:59:27,306 --> 01:59:30,609 YOU CAN SIGN UP FOR THE LINK. 3190 01:59:30,609 --> 01:59:31,877 IT'S VIRTUAL AS YULE NOTICE A 3191 01:59:31,877 --> 01:59:33,478 LOT OF OUR THINGS ARE ONLINE 3192 01:59:33,478 --> 01:59:35,180 ONLY, JUDGE UOF THE TO INCREASE 3193 01:59:35,180 --> 01:59:37,416 ACCESSIBILITY FOR OUR LISTENERS. 3194 01:59:37,416 --> 01:59:40,419 WE ALSO WANT TO GIVE A PLUG TO 3195 01:59:40,419 --> 01:59:45,023 THE EIGHTH ANNUAL VIVIAN 3196 01:59:45,023 --> 01:59:45,857 PENN SYMPOSIUM ON MAY 15th, IT 3197 01:59:45,857 --> 01:59:50,095 IS 1 OF THE NIH'S MECHANISMS BY 3198 01:59:50,095 --> 01:59:51,830 WHICH NIH SPONSORED WOMEN'S 3199 01:59:51,830 --> 01:59:53,332 HEALTH WEEK, WHICH FOR THOSE WHO 3200 01:59:53,332 --> 01:59:54,499 DON'T KNOW ALWAYS HAPPENS THE 3201 01:59:54,499 --> 01:59:56,168 WEEK AFTER MOTHER'S DAY SO MAY 3202 01:59:56,168 --> 01:59:58,136 15th, PUT IT IN YOUR CALENDAR, 3203 01:59:58,136 --> 02:00:01,473 WE HAVE A FABULOUS LINE UP OF 3204 02:00:01,473 --> 02:00:05,577 SPEAKERS RUNNING THE SPECTRUM OF 3205 02:00:05,577 --> 02:00:07,179 SCIENCE, CLINICAL, CARE, PATIENT 3206 02:00:07,179 --> 02:00:09,948 ADVOCACY, A REAL MIX, I WILL 3207 02:00:09,948 --> 02:00:11,350 SAY, REGISTRATION FOR THIS IS 3208 02:00:11,350 --> 02:00:17,723 LIMITED TO THE FIRST 1000 PEOPLE 3209 02:00:17,723 --> 02:00:19,391 SO YOU DON'T MISS A CHANCE, THE 3210 02:00:19,391 --> 02:00:21,026 QRR CODE WILL TAKE YOU TO THE 3211 02:00:21,026 --> 02:00:22,327 REGISTRATION SITE AND IT WILL BE 3212 02:00:22,327 --> 02:00:23,428 WEBCAST AS WELL AND THEN 3213 02:00:23,428 --> 02:00:24,496 FINALLY, IF YOU WOULD LIKE TO 3214 02:00:24,496 --> 02:00:26,198 STAY CONNECT WIDE US IN 3215 02:00:26,198 --> 02:00:27,499 PARTICULARLY HERE ABOUT FUNDING 3216 02:00:27,499 --> 02:00:29,601 OPPORTUNITIES ON THEN SIGN UP 3217 02:00:29,601 --> 02:00:30,569 OUR E-MAILS THIS QR CODE WILL 3218 02:00:30,569 --> 02:00:33,004 TAKE YOU TO THE E-MAIL SIGN UP 3219 02:00:33,004 --> 02:00:34,272 AND JUST TO HIGHLIGHT FOR YOU, 3220 02:00:34,272 --> 02:00:37,175 YOU NEED TO CLICK TO ASK TO SIGN 3221 02:00:37,175 --> 02:00:38,910 UP FOR SUBSCRIPTION TO THE 3222 02:00:38,910 --> 02:00:40,345 OFFICE OF AUTOIMMUNE DISEASE 3223 02:00:40,345 --> 02:00:42,547 RESEARCH, WE DO SEND OUT REGULAR 3224 02:00:42,547 --> 02:00:43,515 COMMUNICATIONS WHEN EVENT 3225 02:00:43,515 --> 02:00:44,783 REGISTRATIONS OPEN UP AND WHEN 3226 02:00:44,783 --> 02:00:47,052 WE HAVE NEW FUNDING 3227 02:00:47,052 --> 02:00:48,320 OPPORTUNITIES, OTHER EVENTS AND 3228 02:00:48,320 --> 02:00:49,888 LOTS AND LOTS TO HEAR ABOUT IN 3229 02:00:49,888 --> 02:00:51,189 THE WORLD OF AUTOIMMUNE DISEASE, 3230 02:00:51,189 --> 02:00:53,392 SO WITH THAT, I AM GOING TO WRAP 3231 02:00:53,392 --> 02:00:53,625 UP. 3232 02:00:53,625 --> 02:00:55,260 I WANT TO THANK YOU ALL FOR 3233 02:00:55,260 --> 02:00:56,928 COMING, WE HAD A FABULOUS TIME 3234 02:00:56,928 --> 02:00:58,997 AND I WANT TO THANK AGAIN, ALL 3235 02:00:58,997 --> 02:01:01,767 OF OUR SPEAKERS AND THE 3236 02:01:01,767 --> 02:01:05,971 MODERATORS FOR RUNNING A GREAT 3237 02:01:05,971 --> 02:01:16,114 SESSION.