1 00:00:05,080 --> 00:00:07,880 >>THIS IS MICHAEL GOTTESMAN, 2 00:00:07,880 --> 00:00:09,960 NIH'S DEPUTY DIRECTOR FOR 3 00:00:09,960 --> 00:00:11,120 INTRAMURAL RESEARCH. 4 00:00:11,120 --> 00:00:14,280 I'M DELIGHTED TO INTRODUCE 5 00:00:14,280 --> 00:00:15,560 TODAY'S NIH LECTURER, NIKI 6 00:00:15,560 --> 00:00:19,080 MOUTSOPOULOS, WHO IS SENIOR 7 00:00:19,080 --> 00:00:20,280 INVESTIGATOR AND CHIEF OF THE 8 00:00:20,280 --> 00:00:22,280 ORAL IMMUNITY AND INFECTION 9 00:00:22,280 --> 00:00:24,800 SECTION, NATIONAL INSTITUTE OF 10 00:00:24,800 --> 00:00:26,280 DENTAL AND CRANIOFACIAL 11 00:00:26,280 --> 00:00:27,920 RESEARCH. 12 00:00:27,920 --> 00:00:35,680 SHE RECEIVED HER DDS FROM 13 00:00:35,680 --> 00:00:39,680 ARISTOTLE UNIVERSITY OFS THEY 14 00:00:39,680 --> 00:00:46,720 IN GREECE, IN 2003 CERTIFICATE 15 00:00:46,720 --> 00:00:48,040 IN PERIODONTICS, UNIVERSITY OF 16 00:00:48,040 --> 00:00:49,680 MARYLAND, Ph.D. FROM 17 00:00:49,680 --> 00:00:51,480 DEPARTMENT OF DIAGNOSTIC 18 00:00:51,480 --> 00:00:52,720 SCIENCES IN PATHOLOGY AT THE 19 00:00:52,720 --> 00:00:54,600 BALTIMORE COLLEGE OF DENTAL 20 00:00:54,600 --> 00:00:56,840 SURGERY AS WELL, BUT SHE WORKED 21 00:00:56,840 --> 00:01:01,280 AT THE NIH IN THE LABORATORY OF 22 00:01:01,280 --> 00:01:03,480 SHARON WALL, ALSO IN NIDCR, 23 00:01:03,480 --> 00:01:06,080 RESEARCH FELLOW FOLLOWING THAT 24 00:01:06,080 --> 00:01:08,960 IN NIDCR, AND THEN CLINICAL 25 00:01:08,960 --> 00:01:11,280 FELLOW WORKING IN NIDCR WITH THE 26 00:01:11,280 --> 00:01:12,720 MENTORSHIP OF STEVE HOLLAND, WHO 27 00:01:12,720 --> 00:01:18,280 IS OF COURSE THE SCIENTIFIC 28 00:01:18,280 --> 00:01:19,720 DIRECTOR IN NIAID. 29 00:01:19,720 --> 00:01:23,240 ABOUT A DOZEN YEARS AGO BECAME 30 00:01:23,240 --> 00:01:26,560 ASSISTANT CLINICAL INVESTIGATOR, 31 00:01:26,560 --> 00:01:30,560 ALSO AT NIDCR, AND THEN RECENTLY 32 00:01:30,560 --> 00:01:31,560 BECAME TENURED SENIOR 33 00:01:31,560 --> 00:01:34,200 INVESTIGATOR, AFTER HER PERIOD 34 00:01:34,200 --> 00:01:37,480 AS A TENURE-TRACK INVESTIGATOR. 35 00:01:37,480 --> 00:01:39,560 SHE'S ALSO -- HAS A DEAN'S 36 00:01:39,560 --> 00:01:40,280 FACULTY APPOINTMENT UNIVERSITY 37 00:01:40,280 --> 00:01:43,280 OF MARYLAND SCHOOL OF DENTISTRY, 38 00:01:43,280 --> 00:01:47,080 WELL RECOGNIZED IN HER FIELD, 39 00:01:47,080 --> 00:01:48,640 THE FIELD OF ORAL IMMUNITY, BY 40 00:01:48,640 --> 00:01:52,800 QUITE A NUMBER OF INVITATIONS TO 41 00:01:52,800 --> 00:01:54,720 SPEAK AND PARTICIPATION AND 42 00:01:54,720 --> 00:01:58,560 SERVICE COMMITTEES AT THE NIH 43 00:01:58,560 --> 00:02:01,800 AND ELSEWHERE. 44 00:02:01,800 --> 00:02:03,000 DR. MOUTSOPOULOS' RESEARCH IS 45 00:02:03,000 --> 00:02:04,800 FOCUSED ON ORAL BARRIER IMMUNE 46 00:02:04,800 --> 00:02:06,400 SYSTEM, GOAL TO UNDERSTAND 47 00:02:06,400 --> 00:02:09,720 MOLECULAR AND CELLULAR BASIS OF 48 00:02:09,720 --> 00:02:13,040 ORAL IMMUNITY IN HEALTH AND ALSO 49 00:02:13,040 --> 00:02:14,720 IN THE RATHER COMMON DISEASE 50 00:02:14,720 --> 00:02:15,600 PERIODONTITIS WHICH MANY OF YOU 51 00:02:15,600 --> 00:02:19,440 ARE BOTH SUFFERING FROM AND 52 00:02:19,440 --> 00:02:20,080 FAMILIAR WITH. 53 00:02:20,080 --> 00:02:21,920 IT'S COMMON IN HUMANS AND LEADS 54 00:02:21,920 --> 00:02:24,280 EVENTUALLY TO THE DESTRUCTION OF 55 00:02:24,280 --> 00:02:25,840 TOOTH-SUPPORTING STRUCTURES WITH 56 00:02:25,840 --> 00:02:28,080 LOSS OF TEETH. 57 00:02:28,080 --> 00:02:28,920 BUT THE INFLAMMATION ASSOCIATED 58 00:02:28,920 --> 00:02:33,520 WITH IT IS ALSO A PROBLEM 59 00:02:33,520 --> 00:02:35,160 RESULTING IN SYSTEMIC 60 00:02:35,160 --> 00:02:36,040 INFLAMMATORY CONDITIONS, 61 00:02:36,040 --> 00:02:38,120 UNDERSCORING POSSIBILITY OF 62 00:02:38,120 --> 00:02:39,200 COMMON MECHANISMS OF 63 00:02:39,200 --> 00:02:41,360 SUSCEPTIBILITY TO DISEASE 64 00:02:41,360 --> 00:02:42,280 TRIGGERING ASSOCIATED WITH 65 00:02:42,280 --> 00:02:42,960 INFLAMMATION. 66 00:02:42,960 --> 00:02:44,880 SO UNDERSTANDING THESE 67 00:02:44,880 --> 00:02:47,920 MECHANISMS OF INFLAMMATION THAT 68 00:02:47,920 --> 00:02:51,880 COME FROM THE PERIODONTITIS HAS 69 00:02:51,880 --> 00:02:54,400 LED TO A ROBUST RESEARCH 70 00:02:54,400 --> 00:02:54,640 PROGRAM. 71 00:02:54,640 --> 00:02:57,640 WITHOUT FURTHER ADO LET ME 72 00:02:57,640 --> 00:02:58,240 INTRODUCE DR. MOUTSOPOULOS'S 73 00:02:58,240 --> 00:03:00,680 TALK, MUCOSAL IMMUNITY AT THE 74 00:03:00,680 --> 00:03:02,760 ORAL BARRIER FROM BEDSIDE TO 75 00:03:02,760 --> 00:03:03,280 BENCH. 76 00:03:03,280 --> 00:03:04,520 NIKI, YOU'RE ON. 77 00:03:04,520 --> 00:03:06,600 >> THANK YOU, DR. GOTTESMAN. 78 00:03:06,600 --> 00:03:08,560 IT'S REALLY AN HONOR TO BE PART 79 00:03:08,560 --> 00:03:12,480 OF THE NIH DIRECTOR SEMINAR 80 00:03:12,480 --> 00:03:12,880 SERIES. 81 00:03:12,880 --> 00:03:16,280 A FANTASTIC OPPORTUNITY FOR ME 82 00:03:16,280 --> 00:03:17,200 TO DESCRIBE THE RESEARCH PROGRAM 83 00:03:17,200 --> 00:03:19,400 I BUILT OVER THE YEARS AT NIDCR. 84 00:03:19,400 --> 00:03:22,640 HOWEVER, BEFORE I GO INTO THE 85 00:03:22,640 --> 00:03:24,120 SCIENTIFIC PART OF MY TALK, I 86 00:03:24,120 --> 00:03:27,600 WANTED TO MAKE SOME 87 00:03:27,600 --> 00:03:28,160 INTRODUCTIONS. 88 00:03:28,160 --> 00:03:30,000 ON THIS SLIDE YOU'LL SEE ALL THE 89 00:03:30,000 --> 00:03:31,560 MEMBERS THAT HAVE BEEN PART OF 90 00:03:31,560 --> 00:03:33,400 THE ORAL IMMUNITY AND 91 00:03:33,400 --> 00:03:34,400 INFLAMMATION SECTION THROUGHOUT 92 00:03:34,400 --> 00:03:38,120 THE YEARS, IN THE PAST REALLY 93 00:03:38,120 --> 00:03:38,360 DECADE. 94 00:03:38,360 --> 00:03:39,960 THIS IS A DIVERSE GROUP OF 95 00:03:39,960 --> 00:03:40,920 INDIVIDUALS, FROM MANY PARTS OF 96 00:03:40,920 --> 00:03:42,960 THE WORLD THAT HAVE COME TO THE 97 00:03:42,960 --> 00:03:45,160 NIH FOR THEIR TRAINING. 98 00:03:45,160 --> 00:03:47,840 THEY BROUGHT TOGETHER A LOT OF 99 00:03:47,840 --> 00:03:49,600 TALENT, AND THEY HAVE ALL, EACH 100 00:03:49,600 --> 00:03:52,840 ONE OF THEM, BEEN TREMENDOUSLY 101 00:03:52,840 --> 00:03:54,680 DEVOTED TO SCIENTIFIC INQUIRY. 102 00:03:54,680 --> 00:03:57,320 THEY HAVE BEEN VERY COLLEGIAL 103 00:03:57,320 --> 00:04:01,600 BUNCH, TREMENDOUS TEAM MEMBERS, 104 00:04:01,600 --> 00:04:03,920 AND HAVE ENRICHED MY LIFE 105 00:04:03,920 --> 00:04:05,120 PROFESSIONAL AND PERSONALLY. 106 00:04:05,120 --> 00:04:09,520 I WANTED TO ACKNOWLEDGE THEIR 107 00:04:09,520 --> 00:04:10,520 CONTRIBUTION AND THANK EACH ONE 108 00:04:10,520 --> 00:04:12,480 FOR EVERYTHING THAT THEY HAVE 109 00:04:12,480 --> 00:04:13,120 DONE SO FAR. 110 00:04:13,120 --> 00:04:14,720 AND SO WITHOUT FURTHER ADO I 111 00:04:14,720 --> 00:04:16,520 WILL GO INTO THE SCIENTIFIC PART 112 00:04:16,520 --> 00:04:17,440 OF THIS. 113 00:04:17,440 --> 00:04:19,120 WHAT DO WE STUDY? 114 00:04:19,120 --> 00:04:21,440 WE'RE BROADLY INTERESTED IN 115 00:04:21,440 --> 00:04:23,680 BARRIER IMMUNITY. 116 00:04:23,680 --> 00:04:26,600 BARRIERS ARE PARTS OF THE HOST 117 00:04:26,600 --> 00:04:28,520 EXPOSED TO ENVIRONMENT. 118 00:04:28,520 --> 00:04:35,320 SKIN, MOUTH, LUNGS, 119 00:04:35,320 --> 00:04:36,600 GASTROINTESTINAL TRACT THAT COME 120 00:04:36,600 --> 00:04:37,720 IN CONTACT WITH THE OUTSIDE 121 00:04:37,720 --> 00:04:37,920 WORLD. 122 00:04:37,920 --> 00:04:38,600 WE'RE INTERESTED IN 123 00:04:38,600 --> 00:04:41,120 UNDERSTANDING HOW THE LOCAL 124 00:04:41,120 --> 00:04:42,680 IMMUNE SYSTEM CAN REGULATE 125 00:04:42,680 --> 00:04:44,400 RESPONSES WITH THE OUTSIDE. 126 00:04:44,400 --> 00:04:46,800 MANY OF THE FUNDAMENTAL 127 00:04:46,800 --> 00:04:48,960 QUESTIONS FOR BARRIER IMMUNITY 128 00:04:48,960 --> 00:04:50,720 ARE REALLY SHARED AMONG ALL OF 129 00:04:50,720 --> 00:04:52,480 THE STRUCTURES. 130 00:04:52,480 --> 00:04:55,520 SOME OF THEM INCLUDE HOW DO 131 00:04:55,520 --> 00:04:57,160 TISSUES MAINTAIN INTEGRITY AND 132 00:04:57,160 --> 00:04:59,520 FUNCTION DESPITE BEING 133 00:04:59,520 --> 00:05:01,080 CONSTANTLY BOMBARDED WITH 134 00:05:01,080 --> 00:05:02,040 ENVIRONMENTAL EXPOSURES. 135 00:05:02,040 --> 00:05:04,480 HOW DOES THE LOCAL IMMUNE SYSTEM 136 00:05:04,480 --> 00:05:06,000 PROTECT US FROM PATHOGENS THAT 137 00:05:06,000 --> 00:05:08,160 WE COME IN CONTACT WITH? 138 00:05:08,160 --> 00:05:10,000 AND HOW ARE WE PROTECTED FROM 139 00:05:10,000 --> 00:05:12,000 THESE PATHOGENS BUT AT THE SAME 140 00:05:12,000 --> 00:05:16,920 TIME WE CAN TOLERATE EVERYTHING 141 00:05:16,920 --> 00:05:17,480 THAT'S INNOCUOUS, COMMENSAL 142 00:05:17,480 --> 00:05:19,960 MICROBIOME, FOOD, HOW DO WE NOT 143 00:05:19,960 --> 00:05:20,400 OVERINFLAME? 144 00:05:20,400 --> 00:05:21,680 HOWEVER, WHEN WE START THINKING 145 00:05:21,680 --> 00:05:23,560 OF HOW TO ANSWER THESE 146 00:05:23,560 --> 00:05:25,120 QUESTIONS, IN AS MANY IN THE 147 00:05:25,120 --> 00:05:26,960 FIELD OF BARRIER IMMUNITY HAVE 148 00:05:26,960 --> 00:05:30,160 DONE SO, WE START TO REALIZE 149 00:05:30,160 --> 00:05:31,800 THAT THE ANSWERS BECOME VERY 150 00:05:31,800 --> 00:05:34,360 TISSUE SPECIFIC, AND THAT IT'S 151 00:05:34,360 --> 00:05:35,520 VERY IMPORTANT TO UNDERSTAND 152 00:05:35,520 --> 00:05:37,160 EACH ENVIRONMENT SEPARATELY TO 153 00:05:37,160 --> 00:05:38,720 UNDERSTAND HOW IMMUNITY IS 154 00:05:38,720 --> 00:05:39,040 REGULATED. 155 00:05:39,040 --> 00:05:42,200 EACH ONE OF THESE TISSUES HAS A 156 00:05:42,200 --> 00:05:44,720 VERY UNIQUE FUNCTIONALITY, HAS 157 00:05:44,720 --> 00:05:45,480 UNIQUE ENVIRONMENTAL EXPOSURES, 158 00:05:45,480 --> 00:05:47,480 THE SKIN COMES IN CONTACT WITH 159 00:05:47,480 --> 00:05:48,760 THE OUTSIDE AND SUNLIGHT, MOUTH 160 00:05:48,760 --> 00:05:51,120 COMES IN CONTACT WITH FOOD. 161 00:05:51,120 --> 00:05:53,040 SO UNDERSTANDING THE EXPOSURES 162 00:05:53,040 --> 00:05:56,520 IS VERY IMPORTANT, ULTIMATELY 163 00:05:56,520 --> 00:05:58,320 FOR THOSE THAT ARE CLINICIANS 164 00:05:58,320 --> 00:06:00,680 EACH TISSUE SIGHT IS 165 00:06:00,680 --> 00:06:01,240 SUSCEPTIBILITY TO DIFFERENT 166 00:06:01,240 --> 00:06:04,200 TYPES OF DISEASE SUSCEPTIBILITY. 167 00:06:04,200 --> 00:06:05,920 NOW, THE AREA YOU'VE HEARD FROM 168 00:06:05,920 --> 00:06:06,760 DR. GOTTESMAN WE'RE INTERESTED 169 00:06:06,760 --> 00:06:09,840 IN BOTH BECOMES MANY OF OUR 170 00:06:09,840 --> 00:06:13,000 CLINICAL BACKGROUNDS, THE ORAL 171 00:06:13,000 --> 00:06:13,440 MUCOSA. 172 00:06:13,440 --> 00:06:15,920 AND I WITH A LOT OF BIAS WILL 173 00:06:15,920 --> 00:06:19,680 SAY ALTHOUGH THIS AREA THAT BE 174 00:06:19,680 --> 00:06:20,760 RELATIVELY UNDERSTUDIED PAIRED 175 00:06:20,760 --> 00:06:22,720 TO OTHER BARRIER TISSUES, IT'S 176 00:06:22,720 --> 00:06:24,040 AN EQUALLY IMPORTANT ONE. 177 00:06:24,040 --> 00:06:27,840 MOUTH COMES IN CONTACT WITH A 178 00:06:27,840 --> 00:06:29,280 LOT OF ENVIRONMENTAL EXPOSURES, 179 00:06:29,280 --> 00:06:32,040 AND ACTUALLY IS THE PLACE OF THE 180 00:06:32,040 --> 00:06:34,960 HUMAN AND MAMMALIAN BODY WHERE A 181 00:06:34,960 --> 00:06:37,800 LOT OF THESE OUTSIDE ELEMENTS 182 00:06:37,800 --> 00:06:39,520 ARE ENCOUNTERED FOR THE FIRST 183 00:06:39,520 --> 00:06:40,720 TIME FROM OUR BODY. 184 00:06:40,720 --> 00:06:42,720 WE BREATHE THROUGH OUR NOSE AND 185 00:06:42,720 --> 00:06:44,480 THROUGH OUR MOUTH TO SOME DEGREE 186 00:06:44,480 --> 00:06:53,920 SO A LOT OF AIR PARTICLES AND AL 187 00:06:53,920 --> 00:06:54,960 ALLERGENS COME THROUGH THE 188 00:06:54,960 --> 00:07:01,760 MOUTH, AND WE EAT THROUGH MOUTH, 189 00:07:01,760 --> 00:07:02,320 PATHOGENS FROM MICROBIOTA, 190 00:07:02,320 --> 00:07:06,760 BEFORE THEY ENTER THE 191 00:07:06,760 --> 00:07:08,120 RESPIRATORY SYSTEM BUT ALSO 192 00:07:08,120 --> 00:07:10,040 GASTROINTESTINAL TRACT. 193 00:07:10,040 --> 00:07:12,760 HOW FIRST EXPOSURES REGULATE OUR 194 00:07:12,760 --> 00:07:13,880 IMMUNE RESPONSIVENESS LOCALLY 195 00:07:13,880 --> 00:07:15,000 AND SYSTEMICALLY WE DON'T 196 00:07:15,000 --> 00:07:16,720 UNDERSTAND VERY WELL. 197 00:07:16,720 --> 00:07:19,240 SO, OUR LAB HAS BEEN VERY 198 00:07:19,240 --> 00:07:20,280 INTERESTED TO UNDERSTAND HOW 199 00:07:20,280 --> 00:07:23,920 HEALTH IS REGULATED IN THE ORAL 200 00:07:23,920 --> 00:07:26,800 MUCOSA, HOW THIS ENVIRONMENT AND 201 00:07:26,800 --> 00:07:29,360 HOST BALANCE IS MAINTAINED, BUT 202 00:07:29,360 --> 00:07:31,360 ALSO HOW DOES THE IMBALANCE 203 00:07:31,360 --> 00:07:35,120 BETWEEN EXPOSURES AND HOST LEAD 204 00:07:35,120 --> 00:07:36,760 TO DISEASE. 205 00:07:36,760 --> 00:07:39,480 WE'VE PARTNERED WITH NIH 206 00:07:39,480 --> 00:07:41,120 HOSPITALS INTERESTED IN ORAL 207 00:07:41,120 --> 00:07:42,560 MUCOSA MANIFESTATIONS AND 208 00:07:42,560 --> 00:07:43,920 DISEASES BUT I WON'T TALK ABOUT 209 00:07:43,920 --> 00:07:44,880 MANY OF THESE TODAY. 210 00:07:44,880 --> 00:07:47,160 I WILL FOCUS ON THE DISEASE THAT 211 00:07:47,160 --> 00:07:49,000 WE HAVE PARTICULARLY BEEN 212 00:07:49,000 --> 00:07:55,720 INTERESTED IN IN OUR GROUP, 213 00:07:55,720 --> 00:08:00,680 WHICH IS PERIODONTITIS DISEASE. 214 00:08:00,680 --> 00:08:01,800 IT'S A PREVALENT GENERAL HUMAN 215 00:08:01,800 --> 00:08:04,400 DISEASE, ONE OF THE MOST 216 00:08:04,400 --> 00:08:05,160 PREVALENT INFLAMMATORY DISEASES 217 00:08:05,160 --> 00:08:06,120 IN FACT IN HUMANS. 218 00:08:06,120 --> 00:08:09,320 YOU'LL SEE HERE FROM AN OLD CDC 219 00:08:09,320 --> 00:08:12,080 SLIDE THAT THE PREVALENCE OF 220 00:08:12,080 --> 00:08:13,160 PERIODONTITIS DISEASE IN GENERAL 221 00:08:13,160 --> 00:08:14,920 POPULATION IN SEVERE FORMS IS 222 00:08:14,920 --> 00:08:16,520 ABOUT 8% OF THE GENERAL 223 00:08:16,520 --> 00:08:21,480 POPULATION, THAT IS VERY HIGH. 224 00:08:21,480 --> 00:08:23,440 WHAT HAPPENS IS PERIODONTITIS 225 00:08:23,440 --> 00:08:29,240 DISEASE, WE FIND MANY HAVE 226 00:08:29,240 --> 00:08:31,040 DOCUMENTED THIS, DYSBIOTIC 227 00:08:31,040 --> 00:08:31,960 MICROBIAL COMMUNITY PRESENT ON 228 00:08:31,960 --> 00:08:35,640 THE ROOT SURFACE OF TEETH. 229 00:08:35,640 --> 00:08:40,080 THIS MICROBIOME IS THOUGHT TO 230 00:08:40,080 --> 00:08:41,520 TRIGGER INFLAMMATORY RESPONSES 231 00:08:41,520 --> 00:08:43,080 WITHIN MUCOSAL TISSUES 232 00:08:43,080 --> 00:08:46,960 PARTICULARLY DESTRUCTIVE IN 233 00:08:46,960 --> 00:08:47,840 SUSCEPTIBLE INDIVIDUALS, LEADING 234 00:08:47,840 --> 00:08:51,320 TO DESTRUCTION BOTH OF THE SOFT 235 00:08:51,320 --> 00:08:52,160 TISSUES MUCOSA SURROUNDING 236 00:08:52,160 --> 00:08:54,920 DENTITION AS WELL AS SUPPORTING 237 00:08:54,920 --> 00:08:56,760 BONE, LEADING TO FUNCTIONAL 238 00:08:56,760 --> 00:08:58,720 ISSUES, LEADING TO A LOT OF 239 00:08:58,720 --> 00:09:02,120 HEALTH COSTS, ALSO TO TOOTH LOSS 240 00:09:02,120 --> 00:09:05,120 IN SEVERE CASES. 241 00:09:05,120 --> 00:09:07,680 NOW, WHAT ARE OUR QUESTIONS AS 242 00:09:07,680 --> 00:09:10,200 WE TRY TO UNDERSTAND 243 00:09:10,200 --> 00:09:11,400 PERIODONTITIS DISEASE 244 00:09:11,400 --> 00:09:12,600 SUSCEPTIBILITY AND PATHOGENESIS? 245 00:09:12,600 --> 00:09:15,680 AS FOR MANY OTHER COMPLEX 246 00:09:15,680 --> 00:09:17,520 INFLAMMATORY DISEASES WHERE BOTH 247 00:09:17,520 --> 00:09:20,360 HOST AND EXPOSURE TO IMMUNE 248 00:09:20,360 --> 00:09:22,040 ENVIRONMENTAL EXPOSURES ARE 249 00:09:22,040 --> 00:09:24,560 IMPORTANT, IN PERIODONTITIS IT'S 250 00:09:24,560 --> 00:09:27,360 BEEN DIFFICULT TO DISSECT OUT 251 00:09:27,360 --> 00:09:32,120 THE COMPLEX GENETICS OF 252 00:09:32,120 --> 00:09:32,520 SUSCEPTIBILITY. 253 00:09:32,520 --> 00:09:35,280 WHILE WE KNOW THAT PERIODONTITIS 254 00:09:35,280 --> 00:09:39,080 DOES SEGREGATE WITHIN FAMILIES, 255 00:09:39,080 --> 00:09:40,360 ESPECIALLY ITS MORE AGGRESSIVE 256 00:09:40,360 --> 00:09:41,800 FORMS IN YOUNGER INDIVIDUALS, 257 00:09:41,800 --> 00:09:45,320 WE'LL SEE IN HIGHLY PREVALENT IN 258 00:09:45,320 --> 00:09:47,280 TWINS, IN FAMILIES, IT'S BEEN 259 00:09:47,280 --> 00:09:49,600 VERY HARD TO DISSECT OUT 260 00:09:49,600 --> 00:09:51,080 SPECIFIC GENES AND PATHWAYS THAT 261 00:09:51,080 --> 00:09:57,120 PREDISPOSE TO US THIS CONDITION. 262 00:09:57,120 --> 00:10:00,200 SECONDLY, WE DON'T COMPLETELY 263 00:10:00,200 --> 00:10:00,800 UNDERSTAND PATHOPHYSIOLOGY AND 264 00:10:00,800 --> 00:10:02,400 BECAUSE OF THAT DON'T HAVE 265 00:10:02,400 --> 00:10:03,360 TARGETED THERAPY OF 266 00:10:03,360 --> 00:10:05,240 INTERVENTION. 267 00:10:05,240 --> 00:10:09,080 SO WHAT WE TYPICALLY DO 268 00:10:09,080 --> 00:10:11,320 CLINICALLY WILL REMOVE DYSBIOTIC 269 00:10:11,320 --> 00:10:12,200 MICROBIOME BY DENTAL CLEANINGS, 270 00:10:12,200 --> 00:10:16,040 AS MANY OF YOU HAVE EXPERIENCED, 271 00:10:16,040 --> 00:10:17,680 ALSO BY COMBINED CLEANING AND 272 00:10:17,680 --> 00:10:19,000 SURGICAL APPROACHES WHICH WILL 273 00:10:19,000 --> 00:10:20,520 REMOVE ALSO SOME DISEASED 274 00:10:20,520 --> 00:10:21,520 TISSUE. 275 00:10:21,520 --> 00:10:23,560 HOWEVER, THESE ARE NOT TARGETED 276 00:10:23,560 --> 00:10:25,560 APPROACHES TO SPECIFIC 277 00:10:25,560 --> 00:10:27,520 MICROBIOTA OR SPECIFIC 278 00:10:27,520 --> 00:10:29,560 INFLAMMATORY RESPONSES. 279 00:10:29,560 --> 00:10:30,920 THESE ARE MANY TIMES PROCEDURES 280 00:10:30,920 --> 00:10:32,960 THAT WILL HAVE TO BE 281 00:10:32,960 --> 00:10:35,520 CONTINUOUSLY REPEATED, IT 282 00:10:35,520 --> 00:10:37,240 BECOMES A LIFE-LONG TREATMENT 283 00:10:37,240 --> 00:10:39,960 RATHER THAN INTERVENTION THAT 284 00:10:39,960 --> 00:10:41,120 TARGETS DISEASE ALSO ON AND WILL 285 00:10:41,120 --> 00:10:42,800 STOP IT. 286 00:10:42,800 --> 00:10:44,640 WE WANT TO UNDERSTAND 287 00:10:44,640 --> 00:10:45,320 PATHOPHYSIOLOGIC MECHANISMS TO 288 00:10:45,320 --> 00:10:47,520 START TO EDUCATE OURSELVES AND 289 00:10:47,520 --> 00:10:51,000 THINK OF TARGETED THERAPY. 290 00:10:51,000 --> 00:10:52,760 NOW, PERIODONTITIS HAS BEEN 291 00:10:52,760 --> 00:10:54,640 ASSOCIATED CLINICALLY WITH 292 00:10:54,640 --> 00:10:57,720 NUMBER OF DISTAL AND SYSTEMIC 293 00:10:57,720 --> 00:10:59,160 OTHER DISEASES, AND IT'S STILL 294 00:10:59,160 --> 00:11:01,600 HARD TO DISSECT OUT WHETHER 295 00:11:01,600 --> 00:11:06,040 THERE'S A CAUSATIVE LINK BETWEEN 296 00:11:06,040 --> 00:11:08,120 PERIODONTITIS OR PERIODONTAL 297 00:11:08,120 --> 00:11:09,680 MICROBIOTA AND ILLNESS OR SHARED 298 00:11:09,680 --> 00:11:10,880 SUSCEPTIBILITY, ALSO QUESTIONS 299 00:11:10,880 --> 00:11:12,520 THAT BECOME RELEVANT NOT ONLY TO 300 00:11:12,520 --> 00:11:17,320 THE ORAL FIELD BUT ALSO TO THE 301 00:11:17,320 --> 00:11:19,000 GENERAL MEDICAL AUDIENCE. 302 00:11:19,000 --> 00:11:20,320 AND FINALLY, FOR THOSE OF US 303 00:11:20,320 --> 00:11:24,040 THAT ARE INTERESTED IN BASIC 304 00:11:24,040 --> 00:11:28,200 BIOLOGY, WE THINK THAT 305 00:11:28,200 --> 00:11:28,920 PERIODONTITIS DISEASE ALSO 306 00:11:28,920 --> 00:11:31,960 PRESENTS IDEAL MODEL TO START TO 307 00:11:31,960 --> 00:11:36,800 LOOK AT CONCEPTS THAT RELATE TO 308 00:11:36,800 --> 00:11:37,600 HOST-MICROBE INTERACTION AT 309 00:11:37,600 --> 00:11:38,560 MUCOSAL SITES AT THE SETTING OF 310 00:11:38,560 --> 00:11:39,960 HEALTH AND SETTING OF DISEASE. 311 00:11:39,960 --> 00:11:42,240 AND SO WHILE THESE ARE QUESTIONS 312 00:11:42,240 --> 00:11:45,400 THAT ARE BROAD AND VERY MUCH 313 00:11:45,400 --> 00:11:46,120 SHARED WITHIN THE WHOLE 314 00:11:46,120 --> 00:11:47,720 COMMUNITY, INTERESTING IN THIS 315 00:11:47,720 --> 00:11:50,320 DISEASE, WHAT WE TRY TO DO 316 00:11:50,320 --> 00:11:51,120 DIFFERENTLY WITH MY PROGRAM, 317 00:11:51,120 --> 00:11:53,400 BECAUSE OF THE NIH ENVIRONMENT, 318 00:11:53,400 --> 00:11:56,920 TAILOR THE WAY WE WILL LOOK AT 319 00:11:56,920 --> 00:11:57,960 THESE QUESTIONS AND TRY TO TAKE 320 00:11:57,960 --> 00:12:00,400 ADVANTAGE OF THE UNIQUE SETTING 321 00:12:00,400 --> 00:12:01,680 OF THE INTRAMURAL PROGRAM. 322 00:12:01,680 --> 00:12:05,080 AND AS YOU ALL KNOW, THE NIH 323 00:12:05,080 --> 00:12:06,800 CLINICAL CENTER AS MANY OF US DO 324 00:12:06,800 --> 00:12:10,840 CONSIDER THE CROWN JEWEL OF THE 325 00:12:10,840 --> 00:12:12,400 NIH, IT IS THE BIGGEST RESEARCH 326 00:12:12,400 --> 00:12:14,960 HOSPITAL IN THE WORLD AND VERY 327 00:12:14,960 --> 00:12:17,160 MUCH SPECIALIZES ON RARE AND 328 00:12:17,160 --> 00:12:17,840 GENETIC DISEASES. 329 00:12:17,840 --> 00:12:20,680 AND SO BY BRINGING AT THE NIH A 330 00:12:20,680 --> 00:12:22,320 LOT OF THESE COHORT OF RARE 331 00:12:22,320 --> 00:12:24,080 DISEASES WE HAVE THE OPPORTUNITY 332 00:12:24,080 --> 00:12:26,280 TO TREAT PATIENTS THAT DON'T 333 00:12:26,280 --> 00:12:28,920 HAVE ACCESS TO TREATMENT OUTSIDE 334 00:12:28,920 --> 00:12:30,840 BECAUSE OF THE RARITY OF DISEASE 335 00:12:30,840 --> 00:12:33,480 SOMETIMES BUT ALSO WE CAN STUDY 336 00:12:33,480 --> 00:12:36,720 THEM HOW SPECIFIC GENES AND 337 00:12:36,720 --> 00:12:39,480 RELATED PATHWAYS LINK TO 338 00:12:39,480 --> 00:12:41,320 PARTICULAR DISEASE 339 00:12:41,320 --> 00:12:41,760 SUSCEPTIBILITY. 340 00:12:41,760 --> 00:12:42,760 THROUGH THESE CLINICAL 341 00:12:42,760 --> 00:12:45,360 PHENOTYPING STUDIES WE CAN START 342 00:12:45,360 --> 00:12:48,640 TO LINK GENOTYPES TO CLINICAL 343 00:12:48,640 --> 00:12:50,320 PHENOTYPES. 344 00:12:50,320 --> 00:12:54,320 AND MANY OF US DO MANY OF THESE 345 00:12:54,320 --> 00:12:55,240 STUDIES UNDER THE LENS OF 346 00:12:55,240 --> 00:12:57,080 DISEASE WE CARE ABOUT. 347 00:12:57,080 --> 00:12:58,360 IN OUR CASE IT'S PERIODONTITIS 348 00:12:58,360 --> 00:12:58,600 DISEASE. 349 00:12:58,600 --> 00:12:59,520 THROUGH THE YEARS WE'VE BEEN 350 00:12:59,520 --> 00:13:02,720 SEEING A LOT OF PATIENTS WITH 351 00:13:02,720 --> 00:13:03,720 GENETIC DESTRUCTIONS IN THE 352 00:13:03,720 --> 00:13:06,000 IMMUNE SYSTEM THAT ARE LINKED TO 353 00:13:06,000 --> 00:13:06,840 PERIODONTITIS DISEASE. 354 00:13:06,840 --> 00:13:09,320 AND THAT HAS STARTED TO GIVE US 355 00:13:09,320 --> 00:13:14,400 A LITTLE BIT OF MAP OF TIMES OF 356 00:13:14,400 --> 00:13:15,200 IMMUNE CELLS AND IMMUNE PATHWAYS 357 00:13:15,200 --> 00:13:16,840 THAT MAY RELATE. 358 00:13:16,840 --> 00:13:19,000 WE EXTEND THESE STUDIES BEYOND 359 00:13:19,000 --> 00:13:21,880 CLINICAL PHENOTYPING TO STUDY 360 00:13:21,880 --> 00:13:26,200 ORAL TISSUES, ORAL CELLS, TRY TO 361 00:13:26,200 --> 00:13:27,880 UNDERSTAND IMMUNE RESPONSIVENESS 362 00:13:27,880 --> 00:13:28,720 OF ORAL CAVITY, FURTHER EXTEND 363 00:13:28,720 --> 00:13:30,720 TO ANIMAL MODELS WHEN WE HAVE 364 00:13:30,720 --> 00:13:32,040 ANIMAL MODELS THAT WILL 365 00:13:32,040 --> 00:13:33,000 PHENOCOPY HUMAN DISEASE AND TRY 366 00:13:33,000 --> 00:13:37,600 TO DO THIS WITH THE IDEA OF 367 00:13:37,600 --> 00:13:39,240 TURNING THIS FULL CIRCLE BACK 368 00:13:39,240 --> 00:13:42,000 INTO HUMAN INTERVENTION WHEN WE 369 00:13:42,000 --> 00:13:47,480 CAN, TO TARGET THESE RARE SEVERE 370 00:13:47,480 --> 00:13:48,680 DISEASES WHEN POSSIBLE. 371 00:13:48,680 --> 00:13:50,320 AND SO THROUGH THE YEARS IT 372 00:13:50,320 --> 00:13:54,000 BECAME OBVIOUS TO US THAT THERE 373 00:13:54,000 --> 00:13:55,680 IS A SPECIFIC IMMUNE PATHWAY 374 00:13:55,680 --> 00:13:59,520 THAT BECAME OF IMPORTANCE FOR 375 00:13:59,520 --> 00:14:01,080 PERIODONTITIS STABILITY AND 376 00:14:01,080 --> 00:14:05,520 IMMUNOPATHOLOGY, AND THAT IS THE 377 00:14:05,520 --> 00:14:09,120 Th17-NEUTROPHIL AXIS THAT I 378 00:14:09,120 --> 00:14:12,560 WILL INTRODUCE SUPER OFFICIALLY. 379 00:14:12,560 --> 00:14:15,520 Th17 CELLS ARE CD4 POSITIVE, 380 00:14:15,520 --> 00:14:18,240 CELLS THAT TYPICALLY FOUND AT 381 00:14:18,240 --> 00:14:20,440 BARRIER SITES, UNDERNEATH THE 382 00:14:20,440 --> 00:14:21,960 MUCOSA OR THE SKIN, AND THEY ARE 383 00:14:21,960 --> 00:14:23,160 THOUGHT TO BE THERE BECAUSE THEY 384 00:14:23,160 --> 00:14:29,080 PLAY A ROLE IN BARRIER IMMUNITY, 385 00:14:29,080 --> 00:14:31,560 THROUGH THE CYTOKINE THEY 386 00:14:31,560 --> 00:14:32,120 STIMULATE CONNECTION BETWEEN 387 00:14:32,120 --> 00:14:34,960 EPITHELIAL CELLS IN ORDER TO 388 00:14:34,960 --> 00:14:38,520 HAVE BARRIER INTEGRITY, THEY 389 00:14:38,520 --> 00:14:40,560 STIMULATE EPITHELIAL CELLS TO 390 00:14:40,560 --> 00:14:45,040 SECRETE ANTIMICROBIAL PEPTIDES 391 00:14:45,040 --> 00:14:46,560 SO THEY MEDIATE EPITHELIAL THIS 392 00:14:46,560 --> 00:14:52,120 WAY BUT HAVE PRIMARY ROLE IN 393 00:14:52,120 --> 00:14:53,240 RECRUITING INNATE CELLS 394 00:14:53,240 --> 00:14:54,200 NEUTROPHILS, AND THAT'S 395 00:14:54,200 --> 00:14:56,920 CONNECTION THAT WE HAVE VERY 396 00:14:56,920 --> 00:14:58,520 MUCH ZEROED IN ON THROUGH THE 397 00:14:58,520 --> 00:14:58,800 YEARS. 398 00:14:58,800 --> 00:15:01,160 AGAIN, FOR THE PURPOSES OF THIS 399 00:15:01,160 --> 00:15:04,920 TALK, A VERY SHORT INTRODUCTION 400 00:15:04,920 --> 00:15:08,600 ON NEUTROPHIL IMMUNE RESPONSES. 401 00:15:08,600 --> 00:15:09,720 NEUTROPHILS ARE THE MOST 402 00:15:09,720 --> 00:15:12,120 ABUNDANT IMMUNE CELLS IN THE 403 00:15:12,120 --> 00:15:14,640 BODY, INNATE CELLS THAT COME 404 00:15:14,640 --> 00:15:15,960 RAPIDLY INTO A TISSUE WHEN 405 00:15:15,960 --> 00:15:19,800 THERE'S INJURY, WHEN THERE'S 406 00:15:19,800 --> 00:15:24,160 INFECTION, AND HAVE PRIMARILY OR 407 00:15:24,160 --> 00:15:24,720 MAJORLY ANTIMICROBIAL 408 00:15:24,720 --> 00:15:25,600 CAPACITIES. 409 00:15:25,600 --> 00:15:29,400 THEY WILL TRY TO TARGET 410 00:15:29,400 --> 00:15:31,840 MICROBIAL INFECTIONS EITHER BY 411 00:15:31,840 --> 00:15:33,440 PHAGOCYTOSING MICROBES, BY 412 00:15:33,440 --> 00:15:35,120 SECRETING GRANULES WITH ENZYMES 413 00:15:35,120 --> 00:15:37,080 THAT WILL BE DESTRUCTIVE TO 414 00:15:37,080 --> 00:15:38,800 MICROBES, BUT ALSO BY RELEASING 415 00:15:38,800 --> 00:15:44,200 THEIR DNA CONTENT INTO THE FORM 416 00:15:44,200 --> 00:15:50,320 OF NETS TO CAPTURE LARGER 417 00:15:50,320 --> 00:15:51,320 MICROBIOTA. 418 00:15:51,320 --> 00:15:54,040 WHEN THEY ARE OVERACTIVATED 419 00:15:54,040 --> 00:15:55,040 BECOME PATHOGENIC. 420 00:15:55,040 --> 00:15:56,240 THE PARADIGM SET FOR NEUTROPHIL 421 00:15:56,240 --> 00:15:58,720 RESPONSE WHEN YOU DON'T HAVE 422 00:15:58,720 --> 00:15:59,760 NEUTROPHILS OR HAVE DEFICIENT 423 00:15:59,760 --> 00:16:01,000 NEUTROPHILS YOU END UP WITH 424 00:16:01,000 --> 00:16:01,440 INFECTION. 425 00:16:01,440 --> 00:16:02,720 WHEN HAVE YOU TOO MANY 426 00:16:02,720 --> 00:16:04,920 NEUTROPHIL YOU END UP WITH 427 00:16:04,920 --> 00:16:05,240 INFLAMMATION. 428 00:16:05,240 --> 00:16:08,720 I WILL SAY THAT THROUGH THE 429 00:16:08,720 --> 00:16:09,920 YEARS WE'VE CHALLENGED THE 430 00:16:09,920 --> 00:16:11,080 PARADIGM, NOT THAT IT DOESN'T 431 00:16:11,080 --> 00:16:14,920 HOLD TRUE, BUT TO REALIZE 432 00:16:14,920 --> 00:16:16,640 SOMETIMES NEUTROPHIL WILL ALSO 433 00:16:16,640 --> 00:16:17,600 LEADS TO INFLAMMATION. 434 00:16:17,600 --> 00:16:18,920 SO THROUGH THE YEARS WE'VE DONE 435 00:16:18,920 --> 00:16:22,120 A LOT OF WORK BOTH ON BASIC 436 00:16:22,120 --> 00:16:25,120 Th17 BIOLOGY AT THE ORAL 437 00:16:25,120 --> 00:16:29,400 CAVITY, BUT ALSO TO UNDERSTAND 438 00:16:29,400 --> 00:16:30,520 GENETIC SUSCEPTIBILITY TO 439 00:16:30,520 --> 00:16:32,200 PERIODONTITIS THROUGH STUDY OF 440 00:16:32,200 --> 00:16:35,320 NEUTROPHIL DEFECT. 441 00:16:35,320 --> 00:16:37,600 IN THE SETTING OF BASIC STUDIES 442 00:16:37,600 --> 00:16:40,920 IN OUR LAB WE VERY MUCH FOCUSED 443 00:16:40,920 --> 00:16:43,720 ON THE BIOLOGY OF Th17 CELLS 444 00:16:43,720 --> 00:16:45,720 AND THEIR REGULATION IN HEALTH 445 00:16:45,720 --> 00:16:47,680 AND DISEASE, AND A LOT OF THESE 446 00:16:47,680 --> 00:16:50,320 FUNDAMENTAL STUDIES WERE DONE 447 00:16:50,320 --> 00:16:54,880 FROM MY FIRST TWO POSTDOCAL 448 00:16:54,880 --> 00:16:58,240 FELLOWS IN THE LAB, BOTH NOW 449 00:16:58,240 --> 00:16:59,160 INDEPENDENT INVESTIGATORS, 450 00:16:59,160 --> 00:17:00,880 UNIVERSITY OF CHILE. 451 00:17:00,880 --> 00:17:01,920 WE'VE COMPETE COMPLETED A LARGE 452 00:17:01,920 --> 00:17:07,520 EFFORT IN THE LAB SPEARHEADED BY 453 00:17:07,520 --> 00:17:13,320 ANOTHER TALENTED POSTDOCTORAL 454 00:17:13,320 --> 00:17:15,400 FELLOW DRAKE WILLIAMS WHO 455 00:17:15,400 --> 00:17:16,520 COMPILED SINGLE CELL ANALYSIS, 456 00:17:16,520 --> 00:17:18,480 FUNDAMENTAL STUDIES THAT HAVE 457 00:17:18,480 --> 00:17:21,880 GIVEN US UNDERSTANDING OF TISSUE 458 00:17:21,880 --> 00:17:23,160 PHYSIOLOGY, WITHIN THE ORAL 459 00:17:23,160 --> 00:17:25,680 MUCOSA, BUT I WILL NOT BE ABLE 460 00:17:25,680 --> 00:17:27,880 TO COVER ANY OF THESE TODAY. 461 00:17:27,880 --> 00:17:29,400 I THOUGHT THAT FOR THIS, FOR THE 462 00:17:29,400 --> 00:17:31,360 PURPOSE OF THIS TALK, IT MADE 463 00:17:31,360 --> 00:17:34,440 MORE SENSE TO FOCUS ON MORE 464 00:17:34,440 --> 00:17:36,000 CLINICAL TRANSLATIONAL STUDIES 465 00:17:36,000 --> 00:17:36,840 IN GENETIC FORMS OF 466 00:17:36,840 --> 00:17:38,160 PERIODONTITIS, AND I THOUGHT 467 00:17:38,160 --> 00:17:39,360 THAT WAS APPROPRIATE BECAUSE IN 468 00:17:39,360 --> 00:17:43,520 SOME WAYS THIS TYPE OF SEMINAR 469 00:17:43,520 --> 00:17:44,600 IS CELEBRATION OF THE INTRAMURAL 470 00:17:44,600 --> 00:17:46,680 PROGRAM SO I WANTED TO HIGHLIGHT 471 00:17:46,680 --> 00:17:50,160 THE TYPES OF STUDIES THAT REALLY 472 00:17:50,160 --> 00:17:52,360 CAN ONLY UNIQUELY ALMOST BE DONE 473 00:17:52,360 --> 00:17:53,560 WITHIN THE INTRAMURAL 474 00:17:53,560 --> 00:17:55,640 ENVIRONMENT, AND BECAUSE OF 475 00:17:55,640 --> 00:17:56,520 COLLABORATIONS WITH MANY GROUPS 476 00:17:56,520 --> 00:17:59,680 IN ORDER TO MAKE THIS POSSIBLE. 477 00:17:59,680 --> 00:18:04,560 SO, WHAT OUR CLINICAL STUDIES 478 00:18:04,560 --> 00:18:06,520 WITHIN GENETIC COHORTS HAVE 479 00:18:06,520 --> 00:18:09,920 SHOWN US IS THAT NOT HAVING 480 00:18:09,920 --> 00:18:12,840 NEUTROPHILS OR SETTINGS OF 481 00:18:12,840 --> 00:18:14,120 NEUTROPENIA LINKED TO 482 00:18:14,120 --> 00:18:14,560 PERIODONTITIS DISEASE 483 00:18:14,560 --> 00:18:16,920 SUSCEPTIBILITY, BUT ALSO THAT 484 00:18:16,920 --> 00:18:20,760 THE OVERABUNDANCE OF NEUTROPHILS 485 00:18:20,760 --> 00:18:22,960 ALSO IS LINKED TO PERIODONTITIS 486 00:18:22,960 --> 00:18:25,680 IMMUNOPATHOLOGY, TELLING US THIS 487 00:18:25,680 --> 00:18:26,640 BALANCE OF NEUTROPHILS BECOMES 488 00:18:26,640 --> 00:18:28,920 IMPORTANT FOR THIS SITE. 489 00:18:28,920 --> 00:18:31,080 SO, TODAY I WILL IN A LITTLE BIT 490 00:18:31,080 --> 00:18:34,040 MORE DETAIL PRESENT WORK WE'VE 491 00:18:34,040 --> 00:18:38,040 DONE ON LESS SPECIFIC MONOGENIC 492 00:18:38,040 --> 00:18:39,720 NEUTROPENIA, THIS IS WORK THAT I 493 00:18:39,720 --> 00:18:43,440 STARTED EARLY ON AS AN ASSISTANT 494 00:18:43,440 --> 00:18:45,280 CLINICAL INVESTIGATOR WORKING 495 00:18:45,280 --> 00:18:50,120 WITH DR. HOLLAND IN NIAID, IN 496 00:18:50,120 --> 00:18:50,960 COLLABORATION WITH GEORGE GALLES 497 00:18:50,960 --> 00:18:51,800 AT THE UNIVERSITY OF MARYLAND 498 00:18:51,800 --> 00:18:53,600 TWO SUPPORTED US THROUGH STUDIES 499 00:18:53,600 --> 00:18:55,720 OF AND CLINICAL MODELS OF THIS 500 00:18:55,720 --> 00:18:56,120 DISEASE. 501 00:18:56,120 --> 00:18:59,600 I WILL ALSO PRESENT ON THE FLIP 502 00:18:59,600 --> 00:19:04,440 SLIDE MONOGENIC DISORDER THAT IS 503 00:19:04,440 --> 00:19:07,040 LINKED TO NEUTROPHIL 504 00:19:07,040 --> 00:19:07,840 HYPERACTIVATION, 505 00:19:07,840 --> 00:19:08,480 IMMUNODEFICIENCY, COLLABORATIVE 506 00:19:08,480 --> 00:19:11,200 WORK, COMBINED PROJECT OF OUR 507 00:19:11,200 --> 00:19:12,720 GROUP, AND OUR INSTITUTE, AND 508 00:19:12,720 --> 00:19:14,360 LED BY A TALENTED FELLOW THAT 509 00:19:14,360 --> 00:19:20,160 WAS CO-MENTORED BY THE TWO LABS. 510 00:19:20,160 --> 00:19:24,320 I'LL START WITH NEUTROPHIL 511 00:19:24,320 --> 00:19:25,080 IMMUNODEFICIENCIES, IN GENERAL 512 00:19:25,080 --> 00:19:29,080 THEY HAVE BEEN LINKED TO 513 00:19:29,080 --> 00:19:29,920 PERIODONTITIS, AND HERE LIKE 514 00:19:29,920 --> 00:19:31,400 YEARS AGO PUT THIS CARTOON 515 00:19:31,400 --> 00:19:32,640 TOGETHER TO LOOK AT NEUTROPHIL 516 00:19:32,640 --> 00:19:37,520 DEVELOPMENT IN THE BONE MARROW, 517 00:19:37,520 --> 00:19:39,400 NEUTROPHIL EGRESS, TRAFFICKING 518 00:19:39,400 --> 00:19:41,720 THROUGH THE BLOODSTREAM, AND 519 00:19:41,720 --> 00:19:43,560 ATTACHMENT TO GO INTO TISSUES. 520 00:19:43,560 --> 00:19:48,000 AND AS WE'VE MAPPED THIS PATHWAY 521 00:19:48,000 --> 00:19:49,120 OF NEUTROPHILS OUT WE REALIZE 522 00:19:49,120 --> 00:19:52,120 DEFECTS IN MANY PARTS OF THIS 523 00:19:52,120 --> 00:19:53,760 PATHWAY ARE ASSOCIATED WITH 524 00:19:53,760 --> 00:19:55,040 SEVERE PERIODONTITIS IN HUMANS. 525 00:19:55,040 --> 00:19:58,520 IF YOU DON'T HAVE GOOD 526 00:19:58,520 --> 00:19:59,520 APPROPRIATE NEUTROPHIL 527 00:19:59,520 --> 00:20:02,720 DEVELOPMENT YOU HAVE TREMENDOUS 528 00:20:02,720 --> 00:20:03,080 PERIODONTITIS. 529 00:20:03,080 --> 00:20:04,560 IF NEUTROPHILS GET STUCK IN BONE 530 00:20:04,560 --> 00:20:06,120 MARROW, CANNOT TRAFFIC OR ENTER 531 00:20:06,120 --> 00:20:12,320 TISSUES, ALL OF THESE ARE LINKED 532 00:20:12,320 --> 00:20:13,640 WITH PERIODONTAL PATHOLOGY. 533 00:20:13,640 --> 00:20:17,720 WE ZEROED IN VERY MUCH ON 534 00:20:17,720 --> 00:20:18,800 LEUKOCYTE ADHESION DEFICIENCY, 535 00:20:18,800 --> 00:20:23,520 WE HAD A COHORT AT THE NIH, AND 536 00:20:23,520 --> 00:20:32,080 IT IS CAUSED -- IS A PROTOTYPIC 537 00:20:32,080 --> 00:20:35,320 MENDELIAN DEFACT IN THE CD18 538 00:20:35,320 --> 00:20:41,760 GENE, THE COMMON CHAIN FOR BETA2 539 00:20:41,760 --> 00:20:43,880 INTEGRIN USED TO FORM TIGHT 540 00:20:43,880 --> 00:20:47,000 ADHESION ON EPITHELIAL CELL 541 00:20:47,000 --> 00:20:54,680 WALL, TRANSMIGRATE INTO TISSUES. 542 00:20:54,680 --> 00:20:57,200 IF YOU HAVE DISRUPTION OF CD18 543 00:20:57,200 --> 00:20:58,560 THEY CAN NOT GO INTO THE TISSUE. 544 00:20:58,560 --> 00:21:00,440 THIS IS A MODEL DISEASE TO 545 00:21:00,440 --> 00:21:03,560 UNDERSTAND WHAT HAPPENS IN THE 546 00:21:03,560 --> 00:21:05,080 SETTING OF TISSUE NEUTROPENIA. 547 00:21:05,080 --> 00:21:07,800 CLINICALLY WHAT HAPPENS TO THE 548 00:21:07,800 --> 00:21:10,520 PATIENT, THEY HAVE RECURRENT 549 00:21:10,520 --> 00:21:12,840 INFECTION, NON-HEALING WOUNDS 550 00:21:12,840 --> 00:21:13,720 AND SPONTANEOUS LESIONS IN THE 551 00:21:13,720 --> 00:21:15,320 SKIN THAT WILL NOT HEAL, MANY 552 00:21:15,320 --> 00:21:15,680 TIMES. 553 00:21:15,680 --> 00:21:18,160 THEY HAVE A DOMINANT ORAL 554 00:21:18,160 --> 00:21:19,840 PHENOTYPE, THEY WILL PRESENT 555 00:21:19,840 --> 00:21:21,480 WITH SEVERE PERIODONTITIS AT A 556 00:21:21,480 --> 00:21:24,080 VERY YOUNG AGE, AND RECURRENT 557 00:21:24,080 --> 00:21:25,920 ORAL ULCERS THAT WILL IMPEDE 558 00:21:25,920 --> 00:21:27,240 THEM FROM EATING. 559 00:21:27,240 --> 00:21:29,960 NOW, I TOOK A LEAP HERE AND 560 00:21:29,960 --> 00:21:32,200 DECIDED TO SHOW A CLINICAL 561 00:21:32,200 --> 00:21:33,720 DENTAL RADIOGRAPH, I'LL WALK YOU 562 00:21:33,720 --> 00:21:36,600 THROUGH IT FOR THOSE NOT 563 00:21:36,600 --> 00:21:37,080 DENTISTS ON THE CALL. 564 00:21:37,080 --> 00:21:38,040 THIS IS A 13-YEAR-OLD FEMALE 565 00:21:38,040 --> 00:21:40,040 THAT HAD BEEN SEEN AT THE NIH 566 00:21:40,040 --> 00:21:42,720 PRETTY MUCH THROUGHOUT HER LIFE. 567 00:21:42,720 --> 00:21:46,040 WHAT I'VE DONE HERE, PANORAMIC 568 00:21:46,040 --> 00:21:48,320 X-RAY, I DREW YELLOW LINE WHERE 569 00:21:48,320 --> 00:21:50,320 I DEPICT WHERE BONE LEVELS 570 00:21:50,320 --> 00:21:52,000 THEORETICALLY WOULD BE IN A 571 00:21:52,000 --> 00:21:53,960 PATIENT OF THIS AGE. 572 00:21:53,960 --> 00:21:55,760 AND THE WHITE LINE IS WHERE THE 573 00:21:55,760 --> 00:21:57,200 BONE IS IN THIS PATIENT. 574 00:21:57,200 --> 00:22:00,240 SO ALL OF THIS DARK SPACE IS HOW 575 00:22:00,240 --> 00:22:02,160 MUCH BONE HAS BEEN LOST AROUND 576 00:22:02,160 --> 00:22:03,040 THE DENTITION. 577 00:22:03,040 --> 00:22:03,880 NOW, IT'S IMPORTANT TO 578 00:22:03,880 --> 00:22:06,880 APPRECIATE THAT THIS IS ONLY A 579 00:22:06,880 --> 00:22:07,640 13-YEAR-OLD. 580 00:22:07,640 --> 00:22:08,920 PERMANENT DENTITION HAS ONLY 581 00:22:08,920 --> 00:22:11,320 BEEN HERE FOR A FEW YEARS, IN 582 00:22:11,320 --> 00:22:12,760 THE PATIENT'S MOUTH. 583 00:22:12,760 --> 00:22:15,520 THIS PATIENT HAD BEEN ON BROAD 584 00:22:15,520 --> 00:22:18,400 SPECTRUM ANTIBIOTICS ALL THEIR 585 00:22:18,400 --> 00:22:21,080 LIFE, RECEIVED DENTAL CARE. 586 00:22:21,080 --> 00:22:24,360 HOWEVER, THIS TYPE OF DISEASE IS 587 00:22:24,360 --> 00:22:25,320 RECALCITRANT, LARGELY 588 00:22:25,320 --> 00:22:26,640 RECALCITRANT TO STANDARD OF CARE 589 00:22:26,640 --> 00:22:26,960 TREATMENT. 590 00:22:26,960 --> 00:22:29,280 WE HAVE SOMETHING VERY SEVERE 591 00:22:29,280 --> 00:22:30,720 THAT WE CAN'T TREAT WITH MEANS 592 00:22:30,720 --> 00:22:31,360 WE KNOW. 593 00:22:31,360 --> 00:22:33,120 THESE PATIENTS END UP LOSING 594 00:22:33,120 --> 00:22:34,520 THEIR TEETH EARLY IN LIFE 595 00:22:34,520 --> 00:22:35,920 BECAUSE THEY ARE NOT SUPPORTED 596 00:22:35,920 --> 00:22:37,160 BY BONE. 597 00:22:37,160 --> 00:22:38,640 THEY BECOME VERY MOBILE. 598 00:22:38,640 --> 00:22:39,760 AND WE EITHER EXTRACT THEM 599 00:22:39,760 --> 00:22:42,280 BECAUSE THEY ARE UNCOMFORTABLE 600 00:22:42,280 --> 00:22:43,440 OR THEY EXFOLIATE. 601 00:22:43,440 --> 00:22:45,320 SO, WHEN WE EXTRACT TEETH FROM 602 00:22:45,320 --> 00:22:46,480 THESE PATIENTS, WE SEE THAT ALL 603 00:22:46,480 --> 00:22:50,560 OF THE BONE HAS BEEN REPLACED BY 604 00:22:50,560 --> 00:22:52,280 INFLAMMATORY SOFT TISSUE, 605 00:22:52,280 --> 00:22:53,720 THERE'S TONS OF INFLAMMATION. 606 00:22:53,720 --> 00:22:59,600 WHEN WE LOOK AT INFLAMMATORY 607 00:22:59,600 --> 00:23:01,720 INFILL STRAIGHT WE SEE A SEA OF 608 00:23:01,720 --> 00:23:03,000 CELLS AND CHARACTERIZE THEM AS 609 00:23:03,000 --> 00:23:04,200 Th17 CELLS. 610 00:23:04,200 --> 00:23:05,920 IF WE LOOK AT CYTOKINE 611 00:23:05,920 --> 00:23:07,040 EXPRESSION IN THESE REGIONS WE 612 00:23:07,040 --> 00:23:15,240 SEE CYTOKINES RELATED TO 613 00:23:15,240 --> 00:23:15,760 DIFFERENTIATION NEUTROPHIL 614 00:23:15,760 --> 00:23:20,080 RECRUITMENT, ONE OF THE MAIN 615 00:23:20,080 --> 00:23:21,120 PATHWAYS Th17 REGULATES. 616 00:23:21,120 --> 00:23:23,560 THIS AXIS IS SUPER UPREGULATED 617 00:23:23,560 --> 00:23:26,320 IN THESE PATIENTS BUT DON'T KNOW 618 00:23:26,320 --> 00:23:28,360 WHETHER THESE TYPES CELLS OF 619 00:23:28,360 --> 00:23:29,120 CELLS, OR DIDN'T KNOW, WHETHER 620 00:23:29,120 --> 00:23:31,680 THEY PLAY A ROLE IN DISEASE 621 00:23:31,680 --> 00:23:32,120 PATHOGENESIS. 622 00:23:32,120 --> 00:23:34,080 THE WAY WE WERE THINKING ABOUT 623 00:23:34,080 --> 00:23:35,440 THIS, AT LEAST HYPOTHETICALLY, 624 00:23:35,440 --> 00:23:42,320 IS THAT AS I MENTIONED IL-17 AND 625 00:23:42,320 --> 00:23:45,600 Th17 ARE IMPORTANT FOR 626 00:23:45,600 --> 00:23:46,880 NEUTROPHIL CHEMO ATTRACTION. 627 00:23:46,880 --> 00:23:48,520 IF NEUTROPHILS HAVE IMPAIRMENT 628 00:23:48,520 --> 00:23:50,160 AND CANNOT MAKE IT BACK INTO THE 629 00:23:50,160 --> 00:23:55,200 TISSUE WE SUSPECT THEY AXIS 630 00:23:55,200 --> 00:23:57,720 AMPLIFIES TO COMPENSATE AND MAKE 631 00:23:57,720 --> 00:24:01,600 NEUTROPHILS COME BACK IN AND 632 00:24:01,600 --> 00:24:04,560 SUSPECT THIS AMPLIFICATION LEADS 633 00:24:04,560 --> 00:24:05,880 TO DISRUPTIVE IMMUNOPATHOLOGY. 634 00:24:05,880 --> 00:24:07,160 HOWEVER, IN THE BEGINNING THIS 635 00:24:07,160 --> 00:24:08,600 WAS MORE OF A HYPOTHESIS. 636 00:24:08,600 --> 00:24:10,560 WE REALLY DIDN'T KNOW WHETHER 637 00:24:10,560 --> 00:24:13,320 Th17 CELLS AND THEIR RELATED 638 00:24:13,320 --> 00:24:14,560 CYTOKINES DRIVE IMMUNOPATHOLOGY. 639 00:24:14,560 --> 00:24:18,000 SO, THAT WAS THE TIME THAT WE 640 00:24:18,000 --> 00:24:20,520 REACHED OUT TO GEORGE, WHO HAD 641 00:24:20,520 --> 00:24:25,520 BEEN -- WAS AN EXPERT IN THE 642 00:24:25,520 --> 00:24:27,440 FIELD, ALREADY WORKING ON THE 643 00:24:27,440 --> 00:24:28,520 LFA KNOCKOUT MOUSE, THE MODEL 644 00:24:28,520 --> 00:24:29,160 FOR DISEASE. 645 00:24:29,160 --> 00:24:30,720 WHAT GEORGE HAD SEEN PRIOR TO 646 00:24:30,720 --> 00:24:33,040 WORKING WITH US ALREADY THESE 647 00:24:33,040 --> 00:24:33,800 MICE HAVE SPONTANEOUS 648 00:24:33,800 --> 00:24:35,440 PERIODONTITIS DISEASE AND THEIR 649 00:24:35,440 --> 00:24:38,400 TISSUES HAVE A LOT OF 650 00:24:38,400 --> 00:24:39,120 UPREGULATION OF IL-17-RELATED 651 00:24:39,120 --> 00:24:40,520 RESPONSES, SO WHEN WE GOT 652 00:24:40,520 --> 00:24:44,520 TOGETHER WE FELT THIS WAS A 653 00:24:44,520 --> 00:24:45,720 TREMENDOUS FORTUNE FOR US TO 654 00:24:45,720 --> 00:24:53,000 ALREADY HAVE A MODEL WHERE WE 655 00:24:53,000 --> 00:24:57,320 COULD DO PRE-CLINICAL TRIALS, 656 00:24:57,320 --> 00:24:57,880 INHIBIT DIFFERENTIAL OR 657 00:24:57,880 --> 00:25:00,200 FUNCTION, SEE IF THEY ARE 658 00:25:00,200 --> 00:25:00,600 IMMUNOPATHOGENNIC. 659 00:25:00,600 --> 00:25:03,400 SO WHAT YOU'LL SEE HERE IS BONE 660 00:25:03,400 --> 00:25:05,560 LOSS MEASUREMENT, AMOUNT OF 661 00:25:05,560 --> 00:25:07,440 DESTRUCTION THAT THE LFA 662 00:25:07,440 --> 00:25:09,000 KNOCKOUT MICE HAVE, 663 00:25:09,000 --> 00:25:10,600 SIGNIFICANTLY HIGHER FROM 664 00:25:10,600 --> 00:25:10,840 CONTROL. 665 00:25:10,840 --> 00:25:13,520 HOWEVER, WHEN -- OOPS, SORRY. 666 00:25:13,520 --> 00:25:15,720 WHEN GEORGE'S GROUP TREATED 667 00:25:15,720 --> 00:25:18,720 THESE MICE, EITHER WITH IL-17 OR 668 00:25:18,720 --> 00:25:21,440 23, THEY COULD INHIBIT DISEASE 669 00:25:21,440 --> 00:25:25,720 PROGRESSION ALMOST COMPLETELY, 670 00:25:25,720 --> 00:25:27,880 WHILE WHEN HE USED ANTIBODIES 671 00:25:27,880 --> 00:25:30,080 COULD NOT INHIBIT DISEASE 672 00:25:30,080 --> 00:25:30,720 PROCESS. 673 00:25:30,720 --> 00:25:33,120 SO THIS MADE US KIND OF ALMOST 674 00:25:33,120 --> 00:25:36,640 COME FULL CIRCLE WITH THIS 675 00:25:36,640 --> 00:25:38,280 PROCESS, STARTING FROM CLINICAL 676 00:25:38,280 --> 00:25:40,600 OBSERVATIONS TO STUDIES IN HUMAN 677 00:25:40,600 --> 00:25:42,720 TISSUES TO CLINICAL STUDIES IN 678 00:25:42,720 --> 00:25:43,120 MOUSE MODELS. 679 00:25:43,120 --> 00:25:46,040 AND STARTING TO THINK ABOUT 680 00:25:46,040 --> 00:25:46,480 HUMAN INTERVENTION. 681 00:25:46,480 --> 00:25:49,680 AND WE STARTED TO THINK ABOUT 682 00:25:49,680 --> 00:25:51,920 HUMAN INTERVENTION ALSO BECAUSE 683 00:25:51,920 --> 00:25:55,560 THERE WAS ALREADY AGE AVAILABLE 684 00:25:55,560 --> 00:26:00,360 AND FDA APPROVE THAT WERE 685 00:26:00,360 --> 00:26:01,760 TARGETED RELEVANT PATHWAYS. 686 00:26:01,760 --> 00:26:03,280 WITH THE P 40 ANTIBODY THAT 687 00:26:03,280 --> 00:26:07,680 INHIBITS PART OF THE IL-23 688 00:26:07,680 --> 00:26:09,400 CYTOKINE, AND THUS INHIBITS 689 00:26:09,400 --> 00:26:12,040 Th17 DIFFERENTIATION, WAS 690 00:26:12,040 --> 00:26:13,240 ALREADY FDA APPROVED FOR 691 00:26:13,240 --> 00:26:19,920 PSORIASIS AND PSORIATIC 692 00:26:19,920 --> 00:26:21,440 ARTHRITIS, LATER FOR CROHNS, HAD 693 00:26:21,440 --> 00:26:23,120 A PRETTY GOOD SAFETY PROFILE, AT 694 00:26:23,120 --> 00:26:24,720 LEAST FOR DISEASE THAT IT WAS 695 00:26:24,720 --> 00:26:25,280 USED BEFORE. 696 00:26:25,280 --> 00:26:27,720 AND IT WAS SOMETHING THAT WE 697 00:26:27,720 --> 00:26:30,400 COULD START CONSIDERING FOR LAD. 698 00:26:30,400 --> 00:26:32,600 THESE STUDIES AGAIN WERE DONE IN 699 00:26:32,600 --> 00:26:34,360 A VERY CLOSE PARTNERSHIP WITH 700 00:26:34,360 --> 00:26:40,040 DR. HOLLAND AND HIS GROUP, AND 701 00:26:40,040 --> 00:26:41,280 BETTY MACIANO WAS INSTRUMENTAL 702 00:26:41,280 --> 00:26:44,520 PUTTING TOGETHER A CLINICAL 703 00:26:44,520 --> 00:26:46,720 PROTOCOL FOR LAD, USE IN LAD. 704 00:26:46,720 --> 00:26:48,360 PRIOR TO PUTTING TOGETHER A 705 00:26:48,360 --> 00:26:49,680 PROTOCOL WE FIRST HAD ONE 706 00:26:49,680 --> 00:26:55,480 PATIENT THAT CAME TO US WHERE 707 00:26:55,480 --> 00:26:57,840 USING THIS AGENT AS A ONE-CASE 708 00:26:57,840 --> 00:26:59,040 PROOF OF CONCEPT BECAME 709 00:26:59,040 --> 00:27:01,560 IMPORTANT BECAUSE OF CLINICAL 710 00:27:01,560 --> 00:27:02,760 NEED. 711 00:27:02,760 --> 00:27:06,160 THIS WAS A 19-YEAR-OLD MALE 712 00:27:06,160 --> 00:27:09,640 FROM -- ACTUALLY FROM ITALY, 713 00:27:09,640 --> 00:27:16,640 REFERRED TO US BY DR. ANGELO, 714 00:27:16,640 --> 00:27:18,760 ORAL DISEASE, 100% OF SITES HAD 715 00:27:18,760 --> 00:27:19,840 SEVERE INFLAMMATORY MARKERS BUT 716 00:27:19,840 --> 00:27:22,400 THE PATIENT ALSO HAD A 717 00:27:22,400 --> 00:27:24,320 TREMENDOUS SACRAL WOUND BECAUSE 718 00:27:24,320 --> 00:27:26,040 OF AN ACCIDENT THAT HAD BEEN 719 00:27:26,040 --> 00:27:30,440 NON-HEALING FOR OVER TWO YEARS, 720 00:27:30,440 --> 00:27:32,640 DESPITE SURGICAL APPROACHES, 721 00:27:32,640 --> 00:27:33,520 DESPITE ANTIBIOTICS, AND 722 00:27:33,520 --> 00:27:33,840 STEROIDS. 723 00:27:33,840 --> 00:27:35,720 AND WHEN WE LOOKED AT THE ISSUES 724 00:27:35,720 --> 00:27:39,160 OF THESE AND OTHER PATIENTS THAT 725 00:27:39,160 --> 00:27:43,000 HAD LESIONS WE RELATESSED THE 726 00:27:43,000 --> 00:27:43,680 IL-17 HYPER RESPONSIVENESS IS 727 00:27:43,680 --> 00:27:45,160 NOT JUST A FEATURE OF ORAL 728 00:27:45,160 --> 00:27:47,640 CAVITY BUT OF OTHER 729 00:27:47,640 --> 00:27:49,440 IMMUNOPATHOLOGICAL REGIONS IN 730 00:27:49,440 --> 00:27:49,760 LAD. 731 00:27:49,760 --> 00:27:52,720 SO THIS ALSO JUSTIFIED US TO 732 00:27:52,720 --> 00:27:54,680 THINK OF SYSTEMIC TREATMENT WITH 733 00:27:54,680 --> 00:27:56,520 SUCH AN AGENT. 734 00:27:56,520 --> 00:27:59,760 AND SO WHEN WE TREATED THIS 735 00:27:59,760 --> 00:28:01,320 PATIENT, WITHIN WEEKS WE STARTED 736 00:28:01,320 --> 00:28:03,320 TO SEE REDUCTION IN ORAL 737 00:28:03,320 --> 00:28:05,600 INFLAMMATION, WE ALSO SAW 738 00:28:05,600 --> 00:28:07,320 REDUCTION IN CYTOKINE RESPONSES, 739 00:28:07,320 --> 00:28:09,200 RELATED TO IL-17, WITHIN THE 740 00:28:09,200 --> 00:28:09,880 TISSUES. 741 00:28:09,880 --> 00:28:12,120 AND MAYBE MOST SIGNIFICANTLY FOR 742 00:28:12,120 --> 00:28:13,920 THIS PATIENT, WITHIN A FEW 743 00:28:13,920 --> 00:28:15,720 MONTHS HE STARTED HAVING THE 744 00:28:15,720 --> 00:28:17,720 WOUND BECOME TO HEAL, AND WITHIN 745 00:28:17,720 --> 00:28:21,000 A YEAR THIS WOUND BECAME TOTALLY 746 00:28:21,000 --> 00:28:24,600 CLOSED, WITH VERY MINIMAL 747 00:28:24,600 --> 00:28:25,800 SCARRING COMPARED TO HOW OTHER 748 00:28:25,800 --> 00:28:28,320 LAD PATIENTS OF COURSE HEAL. 749 00:28:28,320 --> 00:28:30,560 AND SO THIS WAS AN EXCITING 750 00:28:30,560 --> 00:28:31,840 CLINICAL CASE FOR US. 751 00:28:31,840 --> 00:28:34,480 IT WAS PUBLISHED AS A SINGLE 752 00:28:34,480 --> 00:28:35,800 CASE, INDEX CASE, BUT BECAME 753 00:28:35,800 --> 00:28:37,760 IMPORTANT TO US BECAUSE ALSO IT 754 00:28:37,760 --> 00:28:40,800 BECAME THE IMPETUS FOR US TO 755 00:28:40,800 --> 00:28:42,120 CONSIDER PUTTING A FORMAL 756 00:28:42,120 --> 00:28:46,600 PROTOCOL TOGETHER, TO TREAT LAD 757 00:28:46,600 --> 00:28:47,280 PATIENTS. 758 00:28:47,280 --> 00:28:49,640 WE PUT THIS PROTOCOL TOGETHER 759 00:28:49,640 --> 00:28:52,080 WITH DR. HOLLAND'S GROUP TO 760 00:28:52,080 --> 00:28:53,760 BRING IN FIVE TO TEN LAD 761 00:28:53,760 --> 00:28:55,720 PATIENTS WITH VERY RARE DISEASE, 762 00:28:55,720 --> 00:28:57,640 MOSTLY TO LOOK AT SAFETY, BUT TO 763 00:28:57,640 --> 00:29:00,360 ALSO START TO GET SOME INSIGHT 764 00:29:00,360 --> 00:29:01,720 ABOUT THE POTENTIAL OF THIS 765 00:29:01,720 --> 00:29:03,760 AGENT TO LEAD TO RESOLUTION OF 766 00:29:03,760 --> 00:29:04,360 INFLAMMATION. 767 00:29:04,360 --> 00:29:07,040 AND I WILL SAY THAT SO FAR, THE 768 00:29:07,040 --> 00:29:09,240 PROTOCOL'S BEEN UP FOR 2 1/2 OR 769 00:29:09,240 --> 00:29:10,760 3 YEARS, WE'VE RECRUITED FIVE 770 00:29:10,760 --> 00:29:12,320 PATIENTS, HOPING FOR A COUPLE 771 00:29:12,320 --> 00:29:12,560 MORE. 772 00:29:12,560 --> 00:29:18,120 AND SO WHERE ARE WE WITH LAD? 773 00:29:18,120 --> 00:29:20,480 AS I MENTIONED BEFORE, WE HAVE 774 00:29:20,480 --> 00:29:23,760 COME FULL CIRCLE, WE'RE HERE TO 775 00:29:23,760 --> 00:29:26,520 EVALUATE REALLY THE VALUE OF 776 00:29:26,520 --> 00:29:28,280 THIS SPECIFIC INTERVENTION WE'VE 777 00:29:28,280 --> 00:29:30,000 CHOSEN, WE'RE IN THE MIDST OF 778 00:29:30,000 --> 00:29:31,320 THE TRIAL. 779 00:29:31,320 --> 00:29:32,880 WE KNOW AT THE NIH THAT THIS IS 780 00:29:32,880 --> 00:29:34,280 A RARE DISEASE, WE WILL NOT BE 781 00:29:34,280 --> 00:29:36,040 ABLE TO GET TOO MANY MORE 782 00:29:36,040 --> 00:29:40,160 PATIENTS BUT WE'VE BEEN TALKING 783 00:29:40,160 --> 00:29:41,920 TO CENTERS AROUND THE WORLD TO 784 00:29:41,920 --> 00:29:44,520 SEE IF WE CAN PARTNER TO EXTEND 785 00:29:44,520 --> 00:29:46,960 CLINICAL STUDIES IN LAD WITH A 786 00:29:46,960 --> 00:29:49,240 MORE MULTI-CENTERED TYPE STUDY. 787 00:29:49,240 --> 00:29:52,520 WE'RE INTERESTED IN OTHER 788 00:29:52,520 --> 00:29:54,720 NEUTROPHIL THAT ARE SEEN IN 789 00:29:54,720 --> 00:29:58,720 OTHER CENTERS TO SEE WHETHER 790 00:29:58,720 --> 00:29:59,840 THIS Th17 HYPERCOMPENSATION 791 00:29:59,840 --> 00:30:01,720 LEADS TO PERIODONTITIS IN ALL OF 792 00:30:01,720 --> 00:30:04,000 THE TYPES OF NEUTROPHIL 793 00:30:04,000 --> 00:30:06,000 DEFICIENCY OR OR WHETHER 794 00:30:06,000 --> 00:30:06,720 ADDITIONAL BIOLOGICAL MECHANISMS 795 00:30:06,720 --> 00:30:07,160 ARE IMPORTANT. 796 00:30:07,160 --> 00:30:09,480 WE HAVE A LOT TO DO AND WE'RE -- 797 00:30:09,480 --> 00:30:13,640 THIS IS PART OF OUR FOCUS. 798 00:30:13,640 --> 00:30:14,520 WITHIN THE Th17 BIOLOGY SPHERE 799 00:30:14,520 --> 00:30:16,040 THERE'S A LOT OF QUESTIONS FOR 800 00:30:16,040 --> 00:30:17,800 US TO CONTINUE THINKING ABOUT 801 00:30:17,800 --> 00:30:23,280 WHEN IT COMES TO REGULATION OF 802 00:30:23,280 --> 00:30:24,480 Th17 PATHWAYS. 803 00:30:24,480 --> 00:30:31,240 I WILL MOVE ON FROM THE SETTING 804 00:30:31,240 --> 00:30:33,520 OF NEUTROPENIA TO ACTIVATION AND 805 00:30:33,520 --> 00:30:34,200 RECRUITMENT, AND JUST SAY THAT 806 00:30:34,200 --> 00:30:41,720 UP TO NOW WE'VE BEEN THINKING OF 807 00:30:41,720 --> 00:30:44,640 OVERABUNDANCE OF NEUTROPHIL 808 00:30:44,640 --> 00:30:48,000 SETTING OF COMMON FORMS, THOSE 809 00:30:48,000 --> 00:30:49,080 SEEN IN YOUNGER ADULTS. 810 00:30:49,080 --> 00:30:51,600 WE CAME TO STUDY UNDER THE 811 00:30:51,600 --> 00:30:55,000 PRISM, THE LENS OF ANOTHER 812 00:30:55,000 --> 00:31:06,720 GENETIC DEFECT, WHICH IS 813 00:31:06,720 --> 00:31:09,960 PLASMIOGEN DEFICIENCY, IT'S AN 814 00:31:09,960 --> 00:31:16,120 ENZYME WE SEE REDUCED ENZYMATIC 815 00:31:16,120 --> 00:31:18,640 ACTIVITY AND WIDESPREAD 816 00:31:18,640 --> 00:31:19,000 IMMUNOPATHOLOGY. 817 00:31:19,000 --> 00:31:22,440 HOW THEY PRESENT, THEY HAVE 818 00:31:22,440 --> 00:31:25,720 CONJUNCTIVE LESIONS, THEY HAVE 819 00:31:25,720 --> 00:31:28,680 GASTROINTESTINAL LESIONS, LUNG 820 00:31:28,680 --> 00:31:30,120 DISEASE, VAGINAL DISEASE, AND 821 00:31:30,120 --> 00:31:31,400 TREMENDOUS PERIODONTITIS EARLY 822 00:31:31,400 --> 00:31:34,000 IN LIFE, SIMILAR TO WHAT 823 00:31:34,000 --> 00:31:35,680 CLINICALLY WE'VE SEEN WITH LAD. 824 00:31:35,680 --> 00:31:42,120 AND SO JUST A COUPLE WORDS OF 825 00:31:42,120 --> 00:31:44,760 PLASMINOGEN AS AN ENZYME, IT'S A 826 00:31:44,760 --> 00:31:48,920 PROTEASE ACTIVATED INTO THE 827 00:31:48,920 --> 00:31:51,200 ACTIVE FORM PLASMIN, MAJOR ROLE 828 00:31:51,200 --> 00:31:57,240 IN DEGRADING FIBRIN CLOTS, THE 829 00:31:57,240 --> 00:31:59,240 KEY COMPONENT OF HEMOSTATIC 830 00:31:59,240 --> 00:32:03,800 PLUG, NECESSARY FOR HEMOSTASIS. 831 00:32:03,800 --> 00:32:05,120 HOWEVER, AFTER HEMOSTASIS IS 832 00:32:05,120 --> 00:32:07,200 ACHIEVED IT'S IMPORTANT TO 833 00:32:07,200 --> 00:32:09,400 REMOVE FIBRIN TO ALLOW FOR WOUND 834 00:32:09,400 --> 00:32:10,080 HEALING TO OCCUR. 835 00:32:10,080 --> 00:32:12,680 WHEN PLASMINOGEN IS NOT THERE, 836 00:32:12,680 --> 00:32:13,320 FIBRIN CONTINUOUSLY DEPOSITS, 837 00:32:13,320 --> 00:32:20,120 AND IN FACT WHAT IS SEEN IN 838 00:32:20,120 --> 00:32:22,200 THESE PATIENTS WITH PLASMINOGEN 839 00:32:22,200 --> 00:32:25,720 DEFICIENCY THERE ARE DEPOSITS IN 840 00:32:25,720 --> 00:32:28,120 THE LESIONS MENTIONED HERE. 841 00:32:28,120 --> 00:32:30,120 THIS DISEASE BECAME OF INTEREST 842 00:32:30,120 --> 00:32:31,640 BECAUSE OF ANOTHER ANOTHER 843 00:32:31,640 --> 00:32:36,720 COLLABORATION WITHIN OUR 844 00:32:36,720 --> 00:32:37,040 INSTITUTE. 845 00:32:37,040 --> 00:32:39,760 THOMAS BOOGA, NIDCR, HAD BEEN 846 00:32:39,760 --> 00:32:42,200 WORKING ON PLASMINOGEN AND LYSIS 847 00:32:42,200 --> 00:32:44,120 FOR DECADES AND BROUGHT THIS 848 00:32:44,120 --> 00:32:46,080 DISEASE TO MY ATTENTION. 849 00:32:46,080 --> 00:32:51,040 HE'S THE REASON WE ENGAGED IN 850 00:32:51,040 --> 00:32:51,720 THESE STUDIES. 851 00:32:51,720 --> 00:32:54,120 THOMAS HAD MADE THE PLASMINOGEN 852 00:32:54,120 --> 00:32:57,280 KNOCKOUT MOUSE DECADES AGO AND 853 00:32:57,280 --> 00:33:01,480 HAD SEEN THESE MICE PHENOCOPY 854 00:33:01,480 --> 00:33:02,320 CLOSELY HUMAN DISEASE, 855 00:33:02,320 --> 00:33:03,680 SPONTANEOUSLY HAVE A LOT OF 856 00:33:03,680 --> 00:33:12,600 PHENOTYPES SEEN IN HUMAN 857 00:33:12,600 --> 00:33:13,160 DISEASE, CONJUNCTIVITIS, 858 00:33:13,160 --> 00:33:16,320 SYSTEMIC INFLAMMATION SHOWN BY 859 00:33:16,320 --> 00:33:18,600 SPLENOMEGALY, ALSO ENLARGED 860 00:33:18,600 --> 00:33:19,720 LYMPH NODES THAT DRAIN 861 00:33:19,720 --> 00:33:21,480 GASTROINTESTINAL TRACT, AND MORE 862 00:33:21,480 --> 00:33:24,760 RECENTLY SHOWN TO HAVE 863 00:33:24,760 --> 00:33:25,440 SPONTANEOUS PERIODONTITIS 864 00:33:25,440 --> 00:33:26,120 DISEASE. 865 00:33:26,120 --> 00:33:29,080 WE THOUGHT THIS IS A GOOD PLACE, 866 00:33:29,080 --> 00:33:31,600 GOOD MODEL TO ANSWER THE 867 00:33:31,600 --> 00:33:33,240 QUESTION OR TO START TRYING TO 868 00:33:33,240 --> 00:33:35,840 ANSWER THE QUESTION OF HOW DOES 869 00:33:35,840 --> 00:33:38,120 PLASMINOGEN DEFICIENCY LEAD TO 870 00:33:38,120 --> 00:33:40,560 MUCOSAL IMMUNOPATHOLOGY, AND IN 871 00:33:40,560 --> 00:33:46,960 OUR CASE PERIODONTITIS DISEASE. 872 00:33:46,960 --> 00:33:48,200 LAKMLAI SAW A SPONTANEOUS 873 00:33:48,200 --> 00:33:50,720 PHENOTYPE, TREMENDOUS BONE LOSS. 874 00:33:50,720 --> 00:33:52,680 SHE'S DONE MICRO CT SCANS, CAN 875 00:33:52,680 --> 00:33:54,640 YOU SEE THE TEETH AND THE BONE 876 00:33:54,640 --> 00:33:56,400 LEVELS, AND IT'S EASY TO 877 00:33:56,400 --> 00:33:57,880 APPRECIATE EVEN WITH NAKED EYE 878 00:33:57,880 --> 00:34:00,280 THAT THERE'S A LOT MORE BONE 879 00:34:00,280 --> 00:34:01,960 LOSS IN THE DEFICIENT MICE 880 00:34:01,960 --> 00:34:04,080 VERSUS WILD TYPE. 881 00:34:04,080 --> 00:34:05,760 WHEN SHE QUANTIFIES SHE SEES 882 00:34:05,760 --> 00:34:07,080 THERE'S SIGNIFICANT BONE LOSS BY 883 00:34:07,080 --> 00:34:10,920 11 WEEKS OF AGE WHICH BECOMES A 884 00:34:10,920 --> 00:34:13,600 LOT MORE DRAMATIC BY 24 OR SO 885 00:34:13,600 --> 00:34:14,360 WEEKS OF AGE. 886 00:34:14,360 --> 00:34:20,720 AND SO SHE THEN LOOKS AT THE 887 00:34:20,720 --> 00:34:26,320 MUCOSAL TISSUE AND SEES 888 00:34:26,320 --> 00:34:28,320 DESTRUCTION, FIBRIN DEPOSITION 889 00:34:28,320 --> 00:34:29,800 IN THE MUCOSAL COMPARTMENT 890 00:34:29,800 --> 00:34:32,000 REPLACING COLLAGEN, DESTRUCTION 891 00:34:32,000 --> 00:34:33,320 OF EPITHELIUM, AND INFLAMMATORY 892 00:34:33,320 --> 00:34:33,600 INFILTRATE. 893 00:34:33,600 --> 00:34:36,560 AND SO BECAUSE OF THIS DOMINANT 894 00:34:36,560 --> 00:34:39,400 FIBRIN AFFILIATION WE ASKED THE 895 00:34:39,400 --> 00:34:41,320 QUESTION, WHETHER FIBRIN IS WHAT 896 00:34:41,320 --> 00:34:42,440 DRIVES IMMUNOPATHOLOGY. 897 00:34:42,440 --> 00:34:44,560 AND THE CLEAR GENETIC WAY OF 898 00:34:44,560 --> 00:34:47,120 ANSWERING THIS QUESTION IS THAT 899 00:34:47,120 --> 00:34:48,960 WE CAN CROSS PLASMINOGEN 900 00:34:48,960 --> 00:34:51,800 DEFICIENT MICE WITH MICE ALREADY 901 00:34:51,800 --> 00:34:54,920 AVAILABLE THAT DON'T HAVE FIBRIN 902 00:34:54,920 --> 00:34:57,200 OHGEN AND FIBRIN AND ASK WHETHER 903 00:34:57,200 --> 00:35:01,400 THIS WOULD RESCUE DISEASE. 904 00:35:01,400 --> 00:35:02,320 INDEED, COMPLETE RESCUE OF 905 00:35:02,320 --> 00:35:04,800 PHENOTYPE WHEN YOU SEE IT 906 00:35:04,800 --> 00:35:06,440 QUANTIFIED YOU WILL APPRECIATE 907 00:35:06,440 --> 00:35:08,640 THAT THIS IS THE LEVEL OF BONE 908 00:35:08,640 --> 00:35:10,040 LOSS IN THE PLASMINOGEN 909 00:35:10,040 --> 00:35:13,720 DEFICIENT HOUSE AND WHEN SHE'S 910 00:35:13,720 --> 00:35:15,520 CROSSED TO THE FIBRINOGEN 911 00:35:15,520 --> 00:35:18,120 KNOCKOUT HAS RESCUE THAT'S 100%. 912 00:35:18,120 --> 00:35:19,440 SO, FIBRIN DOES DRIVE 913 00:35:19,440 --> 00:35:20,640 IMMUNOPATHOLOGY BUT WE WANTED TO 914 00:35:20,640 --> 00:35:22,600 KNOW HOW. 915 00:35:22,600 --> 00:35:25,280 SO WE STARTED TO CHARACTERIZE 916 00:35:25,280 --> 00:35:26,320 MUCOSAL LESIONS IN THESE MICE. 917 00:35:26,320 --> 00:35:29,200 AND WE'VE DONE A NUMBER OF 918 00:35:29,200 --> 00:35:29,480 STUDIES. 919 00:35:29,480 --> 00:35:33,120 I WILL SHOW YOU THIS AS AN 920 00:35:33,120 --> 00:35:33,360 EXAMPLE. 921 00:35:33,360 --> 00:35:43,680 HERE YOU SEE GINGIVAL TISSUES 922 00:35:43,680 --> 00:35:44,720 STAYED FOR FIBRINOGEN. 923 00:35:44,720 --> 00:35:46,080 THERE'S RECUTE. 924 00:35:46,080 --> 00:35:49,640 IN TISSUES THAT NEUTROPHILS COME 925 00:35:49,640 --> 00:35:51,520 IN CONTACT WITH FIBRIN BUT 926 00:35:51,520 --> 00:35:53,120 SURROUND DEPOSITS AND VALIDATED 927 00:35:53,120 --> 00:35:55,320 BY FLOW CYTOMETRY, RNA 928 00:35:55,320 --> 00:35:57,080 SEQUENCING, ALSO LOOKED AT 929 00:35:57,080 --> 00:35:59,000 INFILTRATION OF OTHER IMMUNE 930 00:35:59,000 --> 00:36:00,920 CELL SUBSETS AND SAW ONLY 931 00:36:00,920 --> 00:36:01,600 NEUTROPHILS, ESPECIALLY EARLY 932 00:36:01,600 --> 00:36:03,960 ON, THESE ARE THE ONLY CELLS 933 00:36:03,960 --> 00:36:05,680 THAT SIGNIFICANTLY INCREASE IN 934 00:36:05,680 --> 00:36:06,320 THE LESION. 935 00:36:06,320 --> 00:36:16,360 WHICH LED US TO THE QUESTION OF 936 00:36:16,360 --> 00:36:17,120 NEUTROPHIL-FIBRIN INTERACTION 937 00:36:17,120 --> 00:36:18,400 WHAT DRIVE BIOLOGY? 938 00:36:18,400 --> 00:36:22,520 FIBRIN HAS A BINDING SITE FOR 939 00:36:22,520 --> 00:36:26,520 NEUTROPHIL CD11B, THIS BINDING 940 00:36:26,520 --> 00:36:30,040 SITE IS A CRYPTIVE DOMAIN. 941 00:36:30,040 --> 00:36:31,360 IT DOESN'T EXPOSE THIS DOMAIN 942 00:36:31,360 --> 00:36:35,080 BUT WHEN IT'S LAID DOWN INTO A 943 00:36:35,080 --> 00:36:37,280 CLOT OR WITHIN THE TISSUES THIS 944 00:36:37,280 --> 00:36:39,920 DOMAIN IS EXPOSED IN MYELOID 945 00:36:39,920 --> 00:36:40,840 CELLS INCLUDING NEUTROPHILS 946 00:36:40,840 --> 00:36:41,120 COMBINED. 947 00:36:41,120 --> 00:36:43,280 WE WERE FORTUNATE THAT A 948 00:36:43,280 --> 00:36:44,720 COLLABORATOR OF THOMAS HAD MADE 949 00:36:44,720 --> 00:36:47,480 A MOUSE THAT HAS A SPECIFIC 950 00:36:47,480 --> 00:36:49,400 MUTATION IN THIS SITE. 951 00:36:49,400 --> 00:36:53,320 THESE MICE HAD NORMAL FIBRIN, 952 00:36:53,320 --> 00:36:54,520 NORMAL FIBRIN ACCUMULATION, 953 00:36:54,520 --> 00:36:58,800 NORMAL CLOTTING BUT FIBRIN 954 00:36:58,800 --> 00:37:03,920 CANNOT BIND MYELOID CELLS. 955 00:37:03,920 --> 00:37:05,520 COULD CROSS PLASMINOGEN KNOCKOUT 956 00:37:05,520 --> 00:37:06,960 MOUSE TO KNACKOUT AND SEE 957 00:37:06,960 --> 00:37:08,080 WHETHER THIS COULD RESCUE 958 00:37:08,080 --> 00:37:09,800 DISEASE, THIS WOULD TELL US 959 00:37:09,800 --> 00:37:13,320 WHETHER THIS SPECIFIC BINDING 960 00:37:13,320 --> 00:37:14,640 SITE IS WHAT DRIVES 961 00:37:14,640 --> 00:37:15,080 IMMUNOPATHOLOGY. 962 00:37:15,080 --> 00:37:18,720 WE WERE EXCITED WITH THE RESULT, 963 00:37:18,720 --> 00:37:21,720 BECAUSE WHEN SHE DID MAKE THIS 964 00:37:21,720 --> 00:37:25,240 CROSS, WE REALIZED THAT NOT ONLY 965 00:37:25,240 --> 00:37:28,960 IS THE RESCUE COMPLETE, BUT 966 00:37:28,960 --> 00:37:30,960 ACTUALLY THE RESCUE OF THIS 967 00:37:30,960 --> 00:37:32,520 PHENOTYPE WAS EVEN ABOVE AND 968 00:37:32,520 --> 00:37:35,480 BEYOND WHAT WE SEE IN WILDTYPE 969 00:37:35,480 --> 00:37:39,920 MICE, INDICATING THAT SOME OF 970 00:37:39,920 --> 00:37:41,240 THIS AGE-RELATED PERIODONTITIS 971 00:37:41,240 --> 00:37:42,880 BONE LOSS THAT HAPPENED WITH AGE 972 00:37:42,880 --> 00:37:47,400 IN MICE COULD BE RESCUED BECAUSE 973 00:37:47,400 --> 00:37:50,520 OF THE GAMMA ABLATION. 974 00:37:50,520 --> 00:37:52,920 SO THIS THEN ALSO WAS VERY 975 00:37:52,920 --> 00:37:54,240 IMPORTANT TO US, MORE STRIKING 976 00:37:54,240 --> 00:37:57,800 BECAUSE WHEN WE LOOKED AT THESE 977 00:37:57,800 --> 00:37:58,840 MICE FIBRIN WOULD STILL 978 00:37:58,840 --> 00:38:02,760 ACCUMULATE IN THE TISSUES TO THE 979 00:38:02,760 --> 00:38:05,120 SAME DEGREE APPROXIMATELY, AND 980 00:38:05,120 --> 00:38:05,760 NEUTROPHILS WOULD STILL 981 00:38:05,760 --> 00:38:07,520 ACCUMULATE TO ALMOST THE SAME 982 00:38:07,520 --> 00:38:09,840 DEGREE, TELLING US THAT YOU 983 00:38:09,840 --> 00:38:11,720 REALLY NEED THIS FUNCTIONAL 984 00:38:11,720 --> 00:38:14,640 INTERACTION BETWEEN FIBRIN AND 985 00:38:14,640 --> 00:38:17,680 NEUTROPHIL TO CD11B AND FIT 986 00:38:17,680 --> 00:38:18,840 GAMMA TO DRIVE IMMUNOPATHOLOGY, 987 00:38:18,840 --> 00:38:20,880 OTHERWISE EVEN THOUGH YOU HAVE 988 00:38:20,880 --> 00:38:22,840 THE SAME AMOUNT OF FIBRIN AND 989 00:38:22,840 --> 00:38:23,600 NEUTROPHILS, THEY ARE NOT 990 00:38:23,600 --> 00:38:28,080 ENGAGED IN A WAY THAT CAUSES A 991 00:38:28,080 --> 00:38:28,320 PROBLEM. 992 00:38:28,320 --> 00:38:31,320 AND SO, THEN OF COURSE THE NEXT 993 00:38:31,320 --> 00:38:33,120 QUESTION WAS TO UNDERSTAND WHAT 994 00:38:33,120 --> 00:38:37,840 HAPPENS AS A RESULT OF THE 995 00:38:37,840 --> 00:38:39,040 ENGAGEMENT, AND FOR THIS LAKMLAI 996 00:38:39,040 --> 00:38:40,360 HAS DONE TREMENDOUS AMOUNT OF 997 00:38:40,360 --> 00:38:41,760 WORK I'LL TRY TO SUMMARIZE IN A 998 00:38:41,760 --> 00:38:42,560 FEW SLIDES. 999 00:38:42,560 --> 00:38:44,360 SHE'S DONE A LOT OF EXPERIMENTS 1000 00:38:44,360 --> 00:38:46,880 IN VITRO AND IN VIVO, BUT SHE 1001 00:38:46,880 --> 00:38:49,840 FIRST DEVELOPED THIS IN VITRO 1002 00:38:49,840 --> 00:38:52,280 MODEL WHERE SHE WOULD CREATE 1003 00:38:52,280 --> 00:38:53,280 PLATES OF FIBRIN, FIBRIN WOULD 1004 00:38:53,280 --> 00:38:56,080 BE FROM A WILDTYPE MOUSE OR A 1005 00:38:56,080 --> 00:39:00,000 MOUSE THAT HAD A FIT GAMMA 1006 00:39:00,000 --> 00:39:02,840 MUTATION, AND WOULD THEN PUT 1007 00:39:02,840 --> 00:39:04,480 NEUTROPHILS IN FROM HUMAN OR 1008 00:39:04,480 --> 00:39:06,760 MOUSE, DID EXPERIMENTSES BOTH 1009 00:39:06,760 --> 00:39:09,280 WAYS, AND LOOKED AT NEUTROPHIL 1010 00:39:09,280 --> 00:39:11,280 BINDING AND FRACTIONALITY IN THE 1011 00:39:11,280 --> 00:39:15,920 SET OF THE TWO FIBRINS. 1012 00:39:15,920 --> 00:39:18,720 SO, THIS WOULD BE ABLE TO TELL 1013 00:39:18,720 --> 00:39:20,520 US WHAT TYPES OF NEUTROPHIL 1014 00:39:20,520 --> 00:39:24,120 FUNCTIONS ARE RELATED TO THE FIB 1015 00:39:24,120 --> 00:39:24,920 GAMMA ENGAGEMENT. 1016 00:39:24,920 --> 00:39:26,760 FIRST OF ALL, THE FIRST SET OF 1017 00:39:26,760 --> 00:39:30,640 DATA THAT SHE GOT WAS VERY CLEAR 1018 00:39:30,640 --> 00:39:32,920 THAT FIB GAMMA CD11B BINDING IS 1019 00:39:32,920 --> 00:39:34,360 IMPORTANT FOR NEUTROPHILS TO 1020 00:39:34,360 --> 00:39:35,520 EVEN ADHERE TO FIBRIN. 1021 00:39:35,520 --> 00:39:40,240 SO IF YOU HAD THE MUTATION A LOT 1022 00:39:40,240 --> 00:39:43,080 LESS NEUTROPHILS COULD WOULD 1023 00:39:43,080 --> 00:39:43,280 STICK. 1024 00:39:43,280 --> 00:39:45,480 ATTACHMENT OF NEUTROPHILS SEEMS 1025 00:39:45,480 --> 00:39:47,240 TO OCCUR MAJORLY THROUGH THIS 1026 00:39:47,240 --> 00:39:47,880 DOMAIN. 1027 00:39:47,880 --> 00:39:50,520 SHE ALSO BY DOING DIFFERENT 1028 00:39:50,520 --> 00:39:51,840 TYPES OF STIMULI REALIZED THAT 1029 00:39:51,840 --> 00:39:57,000 WHEN YOU HAVE THIS ENGAGEMENT, 1030 00:39:57,000 --> 00:39:58,240 NEUTROPHILS WILL SIGNIFICANTLY 1031 00:39:58,240 --> 00:39:59,440 PRODUCE MORE REACTIVE OXYGEN 1032 00:39:59,440 --> 00:40:02,160 SPECIES AND ALSO MAKE A LOT MORE 1033 00:40:02,160 --> 00:40:02,480 NET. 1034 00:40:02,480 --> 00:40:04,760 I'M NOT GOING TO SHOW MUCH OF 1035 00:40:04,760 --> 00:40:08,600 THE RAW DATA BUT I THOUGHT THAT 1036 00:40:08,600 --> 00:40:10,320 SHARING V BILL MIGHT BE A BETTER 1037 00:40:10,320 --> 00:40:12,200 WAY TO GIVE OVERVIEW OF THE 1038 00:40:12,200 --> 00:40:13,200 DATA. 1039 00:40:13,200 --> 00:40:16,440 IN THIS VIDEO YOU WILL SEE, 1040 00:40:16,440 --> 00:40:21,360 YOU'LL SEE NEUTROPHILS PLATED ON 1041 00:40:21,360 --> 00:40:25,880 WILDTYPE VERSUS KNOCK-IN FIBRIN, 1042 00:40:25,880 --> 00:40:28,600 WHAT IS SHOWN HERE IS STAINING 1043 00:40:28,600 --> 00:40:30,240 FOR BLUE FOR NUCLEI OF EVERY 1044 00:40:30,240 --> 00:40:32,440 CELL THAT'S PRESENT. 1045 00:40:32,440 --> 00:40:42,720 CELLS BECOME GREEN WHEN THEY ARE 1046 00:40:42,720 --> 00:40:44,120 PERMEALJZED. 1047 00:40:44,120 --> 00:40:45,120 WILDTYPE SIDE MORE NETTING 1048 00:40:45,120 --> 00:40:46,680 NEUTROPHILS AS OPPOSED TO 1049 00:40:46,680 --> 00:40:50,320 KNOCK-IN SIDE YOU HAVE MANY 1050 00:40:50,320 --> 00:40:52,960 FEWER SIGNIFICANTLY FEWER CELLS 1051 00:40:52,960 --> 00:40:53,280 FORMING NET. 1052 00:40:53,280 --> 00:40:55,600 AND SO THIS LED US TO CONCLUDE 1053 00:40:55,600 --> 00:40:58,800 THAT THIS ENGAGEMENT OF 1054 00:40:58,800 --> 00:41:00,360 NEUTROPHILS IS IMPORTANT NOT 1055 00:41:00,360 --> 00:41:05,000 ONLY FOR ADHESION BUT ALSO FOR 1056 00:41:05,000 --> 00:41:07,320 THEIR ACTIVATION AND PRODUCTION 1057 00:41:07,320 --> 00:41:08,720 OF ROS AND NETs. 1058 00:41:08,720 --> 00:41:10,320 NEXT WE WANTED TO ASK WHETHER 1059 00:41:10,320 --> 00:41:13,520 SOME OF THESE EFFECTOR FUNCTIONS 1060 00:41:13,520 --> 00:41:22,720 OF NEUTROPHILS ARE IMPORTANT FOR 1061 00:41:22,720 --> 00:41:23,280 IMMUNOPATHOLOGIST. 1062 00:41:23,280 --> 00:41:26,560 SHE SAW WITH VARIOUS EXPERIMENTS 1063 00:41:26,560 --> 00:41:30,480 WHEN SHE REMOVED NETs COULD 1064 00:41:30,480 --> 00:41:34,000 INHIBIT IMMUNOPATHOLOGY NOT 1065 00:41:34,000 --> 00:41:34,560 TOTALLY, BUT SIGNIFICANTLY, 1066 00:41:34,560 --> 00:41:36,120 INDICATING THAT THE PROCESS IS 1067 00:41:36,120 --> 00:41:37,320 AN IMPORTANT ONE DRIVING 1068 00:41:37,320 --> 00:41:40,000 IMMUNOPATHOLOGY BUT MAY NOT BE 1069 00:41:40,000 --> 00:41:42,240 THE COMPLETE STORY OF HOW 1070 00:41:42,240 --> 00:41:44,400 NEUTROPHILS AND FIB GAMMA 1071 00:41:44,400 --> 00:41:47,560 ENGAGEMENT LEADS TO DISEASE 1072 00:41:47,560 --> 00:41:47,920 HERE. 1073 00:41:47,920 --> 00:41:53,200 NOW, ALL OF THIS DATA HAS BEEN 1074 00:41:53,200 --> 00:41:55,240 VERY EXCITING TO US BECAUSE -- 1075 00:41:55,240 --> 00:41:57,800 FIRST BECAUSE IT STARTS TO 1076 00:41:57,800 --> 00:41:58,640 EXPLAIN POTENTIALLY WHY 1077 00:41:58,640 --> 00:42:00,640 IMMUNOPATHOLOGY IS OCCURRING IN 1078 00:42:00,640 --> 00:42:08,520 THE ORAL CAVITY, IN PATIENTS 1079 00:42:08,520 --> 00:42:09,920 WITH FIBRINOLYTIC DEFECTS. 1080 00:42:09,920 --> 00:42:12,440 WE ALSO STARTED CONSIDERING 1081 00:42:12,440 --> 00:42:13,280 THESE ARE BROADER -- PATHWAYS 1082 00:42:13,280 --> 00:42:15,520 THAT MIGHT BE IMPORTANT IN A 1083 00:42:15,520 --> 00:42:17,320 MORE BROAD SENSE. 1084 00:42:17,320 --> 00:42:19,560 WE'RE THINKING THAT IN THE 1085 00:42:19,560 --> 00:42:22,600 SETTING OF ANY WOUND, ANY 1086 00:42:22,600 --> 00:42:23,320 INJURY, YOU NEED FIBRIN OF 1087 00:42:23,320 --> 00:42:27,200 COURSE TO COME IN AND FORM A 1088 00:42:27,200 --> 00:42:30,080 CLOT, AND IT'S IMPORTANT THEN 1089 00:42:30,080 --> 00:42:33,920 THAT FIBRIN WILL BE ABLE TO 1090 00:42:33,920 --> 00:42:35,720 ATTACH NEUTROPHIL LOCALLY AND 1091 00:42:35,720 --> 00:42:37,520 ACTIVATE THEM LOCALLY IN ORDER 1092 00:42:37,520 --> 00:42:41,000 FOR NEUTROPHILS TO MEDIATE A 1093 00:42:41,000 --> 00:42:44,280 LOCAL FUNCTION THERE OF 1094 00:42:44,280 --> 00:42:47,560 PRODUCING ROS, NORMING 1095 00:42:47,560 --> 00:42:49,520 NORMING -- FORMING NET, TO CLEAR 1096 00:42:49,520 --> 00:42:50,920 THE WOUND FROM PATHOGEN. 1097 00:42:50,920 --> 00:42:52,120 WHEN IT'S CLEARED HEALING CAN 1098 00:42:52,120 --> 00:42:54,440 BEGIN TO OCCUR. 1099 00:42:54,440 --> 00:42:56,840 HOWEVER, ONE CAN SPECULATE THAT 1100 00:42:56,840 --> 00:42:59,160 IF FIBRIN IS CONSISTENTLY 1101 00:42:59,160 --> 00:43:01,160 DEPOSITED OR NOT REMOVED, THIS 1102 00:43:01,160 --> 00:43:05,200 CAN ALSO BECOME A PATHWAY THAT 1103 00:43:05,200 --> 00:43:07,520 BECOMES IMMUNOPATHOLOGIC AND 1104 00:43:07,520 --> 00:43:10,520 LEADS TO CHRONIC WOUNDS OR 1105 00:43:10,520 --> 00:43:11,560 TISSUE IMMUNOPATHOLOGY WHICH IS 1106 00:43:11,560 --> 00:43:15,080 WHAT WE THINK WE'RE SEEING HERE. 1107 00:43:15,080 --> 00:43:17,360 NOW, BEYOND THE BASIC BIOLOGICAL 1108 00:43:17,360 --> 00:43:20,160 CONCEPTS HERE WE ALSO WANTED TO 1109 00:43:20,160 --> 00:43:23,560 TAKE ANOTHER STEP AND SEE HOW 1110 00:43:23,560 --> 00:43:25,120 THIS PATHWAY COULD POTENTIALLY 1111 00:43:25,120 --> 00:43:27,080 FIT WITH GENERAL FORMS OF OUR 1112 00:43:27,080 --> 00:43:29,120 DISEASE OF INTEREST, WHICH IS 1113 00:43:29,120 --> 00:43:30,920 PERIODONTITIS DISEASE. 1114 00:43:30,920 --> 00:43:32,880 AND THE REASON WE STARTED 1115 00:43:32,880 --> 00:43:37,800 THINKING OF GENERAL FORMS OF 1116 00:43:37,800 --> 00:43:40,320 PERIODONTITIS, IT'S BEEN 1117 00:43:40,320 --> 00:43:42,600 APPRECIATED FOR YEARS THAT 1118 00:43:42,600 --> 00:43:46,880 NEUTROPHILS ARE ABUNDANT IN THE 1119 00:43:46,880 --> 00:43:48,560 LESIONS OF PERIODONTITIS, 1120 00:43:48,560 --> 00:43:49,120 ESPECIALLY YOUNGER ADULTS. 1121 00:43:49,120 --> 00:43:52,760 THIS IS DATA FROM OUR LAB, 1122 00:43:52,760 --> 00:43:56,280 LESIONS OF PERIODONTITIS, NUMBER 1123 00:43:56,280 --> 00:43:58,880 OF NEUTROPHILS BY FLOW 1124 00:43:58,880 --> 00:43:59,800 CYTOMETRY, THIS DATA IS 1125 00:43:59,800 --> 00:44:01,360 CONSISTENT WITH MANY MORE IN THE 1126 00:44:01,360 --> 00:44:03,320 FIELD FOR DECADES THAT HAVE SEEN 1127 00:44:03,320 --> 00:44:10,040 BY HISTOLOGY, TONS OF 1128 00:44:10,040 --> 00:44:11,320 NEUTROPHILS IN PERIODONTITIS, 1129 00:44:11,320 --> 00:44:12,960 SPECULATED NEUTROPHIL ACTIVATION 1130 00:44:12,960 --> 00:44:13,920 DRIVES DISEASE BUT HOW THIS 1131 00:44:13,920 --> 00:44:15,800 COULD BE HAPPENING IS SOMETHING 1132 00:44:15,800 --> 00:44:19,720 WE HAD NOT BEEN ABLE TO DELVE IN 1133 00:44:19,720 --> 00:44:20,520 SO FAR. 1134 00:44:20,520 --> 00:44:23,120 HOWEVER, FIBRIN IS ALSO 1135 00:44:23,120 --> 00:44:25,000 SOMETHING THAT WE APPRECIATE IS 1136 00:44:25,000 --> 00:44:28,240 PRESENT IN THE LESION OF THE 1137 00:44:28,240 --> 00:44:28,560 PERIODONTITIS. 1138 00:44:28,560 --> 00:44:29,160 WE KNOW INFLAMMATION CAUSES A 1139 00:44:29,160 --> 00:44:32,440 LOT OF BLEEDING SO THE IDEA THAT 1140 00:44:32,440 --> 00:44:34,640 FIBRIN AND NEUTROPHILS COME IN 1141 00:44:34,640 --> 00:44:37,120 CONTACT IN LESIONS OF 1142 00:44:37,120 --> 00:44:38,760 PERIODONTITIS IS ONE NATURALLY 1143 00:44:38,760 --> 00:44:42,280 VERY LOGICAL TO US BUT WE WANTED 1144 00:44:42,280 --> 00:44:44,000 TO GO FARTHER TO START TO THINK 1145 00:44:44,000 --> 00:44:44,320 OF. 1146 00:44:44,320 --> 00:44:46,840 SO WHAT GOT US EVEN MORE EXCITED 1147 00:44:46,840 --> 00:44:49,120 ABOUT THIS PROSPECT IS WHILE WE 1148 00:44:49,120 --> 00:44:52,520 WERE WORKING ON THE BASIC ENDS 1149 00:44:52,520 --> 00:44:55,360 ON THIS PROJECT THERE WAS A 1150 00:44:55,360 --> 00:44:58,400 LARGE GWAS STUDY THAT WAS 1151 00:44:58,400 --> 00:45:00,240 PERFORMED IN GERMANY WHERE THEY 1152 00:45:00,240 --> 00:45:03,240 LOOKED AT WHAT WAS THEN CALLED 1153 00:45:03,240 --> 00:45:05,400 AGREESIVE FORMS OF PERIODONTITIS 1154 00:45:05,400 --> 00:45:06,080 DISEASE, YOUNG ADULTS WITH 1155 00:45:06,080 --> 00:45:08,400 SEVERE DISEASE, AND THEY DID A 1156 00:45:08,400 --> 00:45:10,000 LARGE GWAS STUDY AND THE RESULT 1157 00:45:10,000 --> 00:45:12,280 OF THAT STUDY WAS THAT THE 1158 00:45:12,280 --> 00:45:14,720 GENETIC TRAIT THAT WAS MOST 1159 00:45:14,720 --> 00:45:16,960 CLOSELY ASSOCIATED WITH 1160 00:45:16,960 --> 00:45:17,880 AGGRESSIVE FORMS OF 1161 00:45:17,880 --> 00:45:19,240 PERIODONTITIS WAS PLASMINOGEN, 1162 00:45:19,240 --> 00:45:21,120 AROUND THE PLASMINOGEN GENE. 1163 00:45:21,120 --> 00:45:22,640 SO THAT EXCITED US VERY MUCH 1164 00:45:22,640 --> 00:45:23,880 BECAUSE IT HAPPENED AT THE SAME 1165 00:45:23,880 --> 00:45:26,720 TIME THAT WE WERE WORKING, AND 1166 00:45:26,720 --> 00:45:29,560 SO THAT ALSO INSTIGATED US TO GO 1167 00:45:29,560 --> 00:45:34,040 AND REACH OUT TO A FANTASTIC 1168 00:45:34,040 --> 00:45:36,240 COLLEAGUE, WHO HAS BEEN FOCUSING 1169 00:45:36,240 --> 00:45:37,720 ON GENOME IS OF ORAL DISEASES 1170 00:45:37,720 --> 00:45:40,680 FOR YEARS, INVOLVED IN THE GWAS 1171 00:45:40,680 --> 00:45:42,040 STUDY FOR PERIODONTITIS IN THE 1172 00:45:42,040 --> 00:45:42,680 U.S. 1173 00:45:42,680 --> 00:45:45,440 AND SO WE ASKED KIMON AND HIS 1174 00:45:45,440 --> 00:45:49,240 GROUP TO LOOK AT VARIATIONS 1175 00:45:49,240 --> 00:45:51,960 WITHIN THEIR COHORT, IN THE U.S. 1176 00:45:51,960 --> 00:45:53,640 COHORT WE HAD A MUCH SMALLER 1177 00:45:53,640 --> 00:45:56,000 NUMBER OF PATIENTS WITH 1178 00:45:56,000 --> 00:45:57,040 SEVERE -- WITH DIFFERENT TYPES 1179 00:45:57,040 --> 00:46:01,040 OF PERIODONTITIS, IN A WAY, SO 1180 00:46:01,040 --> 00:46:05,640 THEY DID TARGETED LOOKUP FOR 1181 00:46:05,640 --> 00:46:07,520 GENETIC POLYMORPHISMS AROUND THE 1182 00:46:07,520 --> 00:46:09,800 PLASMINOGEN LOCUS AND WHAT KIMON 1183 00:46:09,800 --> 00:46:12,840 AND TEAM REPORTED BACK WAS THAT 1184 00:46:12,840 --> 00:46:14,520 PLASMIOGEN VARIATIONS WERE VERY 1185 00:46:14,520 --> 00:46:17,240 MUCH ASSOCIATED WITH SEVERE 1186 00:46:17,240 --> 00:46:19,600 FORMS OF PERIODONTITIS BUT EVEN 1187 00:46:19,600 --> 00:46:22,120 VERY INTERESTINGLY ALSO VERY 1188 00:46:22,120 --> 00:46:25,880 MUCH AASSOCIATED WITH CARRIAGE 1189 00:46:25,880 --> 00:46:34,720 OF SPECIFIC ORAL MICROBE CALLED 1190 00:46:34,720 --> 00:46:36,120 AA HERE SIMILAR TO WHAT WAS 1191 00:46:36,120 --> 00:46:37,240 REPORTED IN THE GERMAN 1192 00:46:37,240 --> 00:46:37,680 POPULATION. 1193 00:46:37,680 --> 00:46:38,880 AT THIS POINT THERE WAS MORE FOR 1194 00:46:38,880 --> 00:46:43,160 US TO DO BUT WE'RE EXCITED WE 1195 00:46:43,160 --> 00:46:44,680 HAVE THIS INTERESTING GENOMIC 1196 00:46:44,680 --> 00:46:59,080 DATA IN THE COMMON FORMS OF 1197 00:46:59,080 --> 00:47:04,720 PERIONDONTIIS, HOW CAN MENDELIAN 1198 00:47:04,720 --> 00:47:05,960 SYNDROMES INFORM OUR 1199 00:47:05,960 --> 00:47:06,440 UNDERSTANDING. 1200 00:47:06,440 --> 00:47:09,080 USING VARIATION AS EXAMPLE IN A 1201 00:47:09,080 --> 00:47:11,800 WAY NOW THROUGH STUDY OF 1202 00:47:11,800 --> 00:47:13,080 MENDELIAN DISEASES WE HAVE A 1203 00:47:13,080 --> 00:47:16,560 TRAIT THAT WE CAN GO LOOK AT, AT 1204 00:47:16,560 --> 00:47:19,720 THE GENERAL POPULATION, THAT 1205 00:47:19,720 --> 00:47:22,120 COULD POTENTIALLY HELP US 1206 00:47:22,120 --> 00:47:23,480 STRATIFY DISEASE POPULATION. 1207 00:47:23,480 --> 00:47:24,720 NOW, THERE'S MORE FOR US TO DO. 1208 00:47:24,720 --> 00:47:27,520 WE HAVE TO REALLY SEE WHETHER 1209 00:47:27,520 --> 00:47:29,960 THE GENETIC VARIATIONS WE HAVE 1210 00:47:29,960 --> 00:47:31,120 IDENTIFIED HAVE A FUNCTIONAL 1211 00:47:31,120 --> 00:47:32,640 OUTPUT, AND THIS IS SOMETHING WE 1212 00:47:32,640 --> 00:47:34,520 NEED TO BE DOING. 1213 00:47:34,520 --> 00:47:36,640 BUT WE'RE HOPING THAT THESE KIND 1214 00:47:36,640 --> 00:47:40,320 OF STUDIES MAY HELP US STRATIFY 1215 00:47:40,320 --> 00:47:43,080 PATIENTS AND POTENTIALLY LEAD TO 1216 00:47:43,080 --> 00:47:44,400 THERAPEUTIC INTERVENTIONS THAT 1217 00:47:44,400 --> 00:47:46,040 ARE DIFFERENT FOR DIFFERENT 1218 00:47:46,040 --> 00:47:48,320 TYPES OF DISEASE SUBSETS. 1219 00:47:48,320 --> 00:47:49,960 IN CLOSING, I WANT TO LEAVE YOU 1220 00:47:49,960 --> 00:47:52,960 WITH THIS MESSAGE OF HOW WE'VE 1221 00:47:52,960 --> 00:47:57,480 TRIED TO DO THESE STUDIES WITHIN 1222 00:47:57,480 --> 00:48:00,000 THE NIH ENVIRONMENT, STUDYING 1223 00:48:00,000 --> 00:48:02,320 FROM MENDELIAN DISEASE, TRYING 1224 00:48:02,320 --> 00:48:04,200 TO DO BASIC STUDIES, FUNDAMENTAL 1225 00:48:04,200 --> 00:48:06,040 BIOLOGY AT THE ORAL CAVITY, 1226 00:48:06,040 --> 00:48:08,000 PAIRING BOTH HUMAN TISSUES AND 1227 00:48:08,000 --> 00:48:10,000 CELLS WITH PRE-CLINICAL AND 1228 00:48:10,000 --> 00:48:10,840 MECHANISTIC STUDIES IN MICE, 1229 00:48:10,840 --> 00:48:14,520 ALWAYS WITH THE HOPE OF TURNING 1230 00:48:14,520 --> 00:48:17,320 BACK INTO HUMAN INTERVENTION, 1231 00:48:17,320 --> 00:48:19,640 AND EVEN BETTER POTENTIALLY 1232 00:48:19,640 --> 00:48:20,680 EDUCATING AND INFORMING OF 1233 00:48:20,680 --> 00:48:23,840 UNDERSTANDING OF COMMON FORMS OF 1234 00:48:23,840 --> 00:48:24,160 DISEASE. 1235 00:48:24,160 --> 00:48:26,560 NOW, MAYBE THE MOST IMPORTANT OR 1236 00:48:26,560 --> 00:48:28,280 SECOND MOST IMPORTANT SLIDE 1237 00:48:28,280 --> 00:48:29,160 AFTER THANKING MY OWN GROUP, 1238 00:48:29,160 --> 00:48:32,040 WHICH HERE I DIDN'T HAVE ROOM TO 1239 00:48:32,040 --> 00:48:32,800 RETHANK, TO ACKNOWLEDGE 1240 00:48:32,800 --> 00:48:34,520 TREMENDOUS PARTNERSHIPS THAT WE 1241 00:48:34,520 --> 00:48:36,840 HAVE THROUGH THE YEAR. 1242 00:48:36,840 --> 00:48:39,040 AND SO THIS SLIDE DEPICTS REALLY 1243 00:48:39,040 --> 00:48:41,920 OUR MAJOR COLLABORATORS THAT 1244 00:48:41,920 --> 00:48:44,400 HAVE BEEN LONG-TERM PARTNERS, 1245 00:48:44,400 --> 00:48:45,360 HAVE ENRICHED OUR PROGRAM, 1246 00:48:45,360 --> 00:48:47,440 REALLY HELPED US SET UP AND 1247 00:48:47,440 --> 00:48:50,520 CONTINUE THROUGH THE YEARS BOTH 1248 00:48:50,520 --> 00:48:53,040 WITHIN NIDCR, WITHIN NIH, AND 1249 00:48:53,040 --> 00:48:54,320 YOU'VE HEARD OF MANY OF THE 1250 00:48:54,320 --> 00:48:56,880 SELECT ONES SPECIFICALLY. 1251 00:48:56,880 --> 00:48:58,920 AND IN THE EXTRAMURAL PROGRAM 1252 00:48:58,920 --> 00:49:00,000 AND INTERNATIONALLY. 1253 00:49:00,000 --> 00:49:02,520 I WANT TO ALSO DO A SPECIAL 1254 00:49:02,520 --> 00:49:05,440 THANK YOU TO MY MENTORING TENURE 1255 00:49:05,440 --> 00:49:07,120 TRACK COMMITTEE WHICH STARTED AS 1256 00:49:07,120 --> 00:49:10,920 A MENTORING COMMITTEE AND TURNED 1257 00:49:10,920 --> 00:49:11,920 INTO LONG-TERM COLLABORATORS, 1258 00:49:11,920 --> 00:49:13,440 PARTNERS, I WOULD SAY FRIENDS. 1259 00:49:13,440 --> 00:49:16,320 ALSO, I HAVE TO FINISH BY 1260 00:49:16,320 --> 00:49:18,960 THANKING THE TREMENDOUS SUPPORT 1261 00:49:18,960 --> 00:49:20,720 FROM THE NIDCR LEADERSHIP 1262 00:49:20,720 --> 00:49:22,880 STARTING WITH LARRY TABAK EARLY 1263 00:49:22,880 --> 00:49:26,800 ON, WHO ENCOURAGED ME TO GO THIS 1264 00:49:26,800 --> 00:49:29,040 DIRECTION, PREVIOUS SD AND 1265 00:49:29,040 --> 00:49:30,880 INSTITUTE DIRECTORS, AND OF 1266 00:49:30,880 --> 00:49:33,160 COURSE CURRENT LEADERSHIP, MATT 1267 00:49:33,160 --> 00:49:35,520 HOFFMAN, JANICE LEE, AND MARINA 1268 00:49:35,520 --> 00:49:35,920 D'SOUZA. 1269 00:49:35,920 --> 00:49:37,440 THANK YOU FOR YOUR ATTENTION. 1270 00:49:37,440 --> 00:49:39,840 I WILL STOP SHARING NOW. 1271 00:49:39,840 --> 00:49:42,280 >> NIKI, THANK YOU VERY MUCH, 1272 00:49:42,280 --> 00:49:43,880 FOR A FANTASTIC TALK. 1273 00:49:43,880 --> 00:49:47,120 FOR THOSE ON THE VIDEOCAST, THIS 1274 00:49:47,120 --> 00:49:49,520 IS MATT HOFFMAN, SCIENTIFIC 1275 00:49:49,520 --> 00:49:50,520 DIRECTOR OF NIDCR, HOSTING 1276 00:49:50,520 --> 00:49:50,800 QUESTIONS. 1277 00:49:50,800 --> 00:49:52,720 IF YOU WANT TO ASK A QUESTION, 1278 00:49:52,720 --> 00:49:55,120 JUST CLICK ON THE BUTTON ON THE 1279 00:49:55,120 --> 00:49:57,320 VIDEOCAST THAT SAYS SEND LIVE 1280 00:49:57,320 --> 00:49:58,400 FEEDBACK, THAT WILL COME 1281 00:49:58,400 --> 00:49:59,520 DIRECTLY TO ME. 1282 00:49:59,520 --> 00:50:01,120 NIKI, I'LL START WITH ONE OF THE 1283 00:50:01,120 --> 00:50:04,000 QUESTIONS THAT CAME UP THROUGH 1284 00:50:04,000 --> 00:50:06,800 YOUR TALK FROM HOWARD YOUNG WHO 1285 00:50:06,800 --> 00:50:11,000 IS ASKING HAVE YOU EVER 1286 00:50:11,000 --> 00:50:12,840 CONSIDERED USING IL-17 IN A 1287 00:50:12,840 --> 00:50:14,280 TOOTHPASTE FORMULATION TO TREAT 1288 00:50:14,280 --> 00:50:15,560 THE DISEASE, AND I GUESS THERE 1289 00:50:15,560 --> 00:50:25,440 WOULD BE A ROLE RANGE OF TYPES 1290 00:50:25,440 --> 00:50:26,480 OF ACTIMERS TO CONSIDER. 1291 00:50:26,480 --> 00:50:28,560 >> FOR LAD, THIS IS WHERE WE 1292 00:50:28,560 --> 00:50:31,200 STARTED, IT MADE SENSE TO USE 1293 00:50:31,200 --> 00:50:32,200 SYSTEMIC INTERVENTION BECAUSE 1294 00:50:32,200 --> 00:50:33,520 OBVIOUSLY ORAL MANIFESTATIONS 1295 00:50:33,520 --> 00:50:35,040 ARE NOT THE ONLY MANIFESTATIONS 1296 00:50:35,040 --> 00:50:36,120 THAT WE HAVE. 1297 00:50:36,120 --> 00:50:41,200 WHILE WE STARTED OUR STUDIES IN 1298 00:50:41,200 --> 00:50:43,120 THE ORAL CAVITY REALIZED 1299 00:50:43,120 --> 00:50:44,240 DYSREGULATION WAS WIDESPREAD. 1300 00:50:44,240 --> 00:50:45,600 FOR LAD HAVEN'T BEEN THINKING 1301 00:50:45,600 --> 00:50:48,840 THAT MUCH AT LOCAL FORMULATIONS. 1302 00:50:48,840 --> 00:50:51,120 HOWEVER, AS HOWARD IS STATING, 1303 00:50:51,120 --> 00:50:54,880 FOR COMMON FORMS OF 1304 00:50:54,880 --> 00:50:55,640 PERIODONTITIS A MORE LOCALIZED 1305 00:50:55,640 --> 00:50:58,000 APPROACH IS WHERE WE NEED TO 1306 00:50:58,000 --> 00:51:00,800 START AND THINK ABOUT, AND WE 1307 00:51:00,800 --> 00:51:01,720 HAVEN'T -- YOU KNOW, THIS IS 1308 00:51:01,720 --> 00:51:03,920 WHERE WE KNOW WE NEED TO BE. 1309 00:51:03,920 --> 00:51:06,160 BUT WE HAVEN'T DONE THE SPECIFIC 1310 00:51:06,160 --> 00:51:07,960 STEPS OF THINKING ABOUT THIS 1311 00:51:07,960 --> 00:51:11,560 PRACTICALLY FOR GENERAL FORMS OF 1312 00:51:11,560 --> 00:51:13,560 PERIODONTITIS. 1313 00:51:13,560 --> 00:51:17,760 YES, I APPRECIATE VERY MUCH THE 1314 00:51:17,760 --> 00:51:17,960 POINT. 1315 00:51:17,960 --> 00:51:23,600 >> ANOTHER QUESTION FROM PETER 1316 00:51:23,600 --> 00:51:25,640 YOOON. 1317 00:51:25,640 --> 00:51:27,960 CAN PROTEIN THAT LACKS CD11 SITE 1318 00:51:27,960 --> 00:51:29,200 BE APPLIED AS TREATMENT FOR 1319 00:51:29,200 --> 00:51:29,640 PERIODONTITIS. 1320 00:51:29,640 --> 00:51:32,880 >> THANK YOU FOR THE QUESTION. 1321 00:51:32,880 --> 00:51:34,200 ACTUALLY, ONE OF THE REASONS 1322 00:51:34,200 --> 00:51:36,160 THAT EXCITED US ABOUT THE 1323 00:51:36,160 --> 00:51:41,640 PROSPECT OF TARGETING THIS 1324 00:51:41,640 --> 00:51:46,000 PATHWAY IS THAT THERE IS 1325 00:51:46,000 --> 00:51:48,440 PRE-CLINICAL WORK USING FIBRIN 1326 00:51:48,440 --> 00:51:49,320 ANTIBODY THAT TARGETS 1327 00:51:49,320 --> 00:51:51,080 SPECIFICALLY THE FIB GAMMA 1328 00:51:51,080 --> 00:51:54,680 DOMAIN, THAT'S BEEN USED FOR 1329 00:51:54,680 --> 00:51:57,560 CLINICALLY FOR MULTIPLE 1330 00:51:57,560 --> 00:51:59,160 SCLEROSIS AND FOR RHEUMATOID 1331 00:51:59,160 --> 00:51:59,440 ARTHRITIS. 1332 00:51:59,440 --> 00:52:05,960 SO THE IDEA OF TARGETING THAT 1333 00:52:05,960 --> 00:52:07,840 SPECIFIC BINDING IS VERY 1334 00:52:07,840 --> 00:52:09,120 INTERESTING, EXCITING TO US. 1335 00:52:09,120 --> 00:52:10,680 >> OKAY. 1336 00:52:10,680 --> 00:52:11,560 SO, OBVIOUSLY EVERYONE'S 1337 00:52:11,560 --> 00:52:12,880 THINKING ABOUT TREATMENT. 1338 00:52:12,880 --> 00:52:14,280 WE HAVE ANOTHER QUESTION HERE 1339 00:52:14,280 --> 00:52:16,280 FROM STEVE HOLLAND WHO IS 1340 00:52:16,280 --> 00:52:19,680 SAYING, GREAT TALK, IN VIEW OF 1341 00:52:19,680 --> 00:52:22,520 THE ROLE OF NETs AND 1342 00:52:22,520 --> 00:52:26,200 PERIODONTAL DISEASE AND 1343 00:52:26,200 --> 00:52:30,320 PLASMINOGEN IS THERE ROOM FOR IN 1344 00:52:30,320 --> 00:52:31,200 GENERAL OR PLG IN PARTICULAR? 1345 00:52:31,200 --> 00:52:32,720 >> YEAH, SO THIS IS SOMETHING 1346 00:52:32,720 --> 00:52:36,360 THAT WE'RE THINKING OF AS WELL. 1347 00:52:36,360 --> 00:52:39,440 AGAIN, TRYING TO UNDERSTAND THE 1348 00:52:39,440 --> 00:52:42,040 COHORTS OF GENERAL POPULATION 1349 00:52:42,040 --> 00:52:42,720 PATIENTS WHERE THIS PATHWAY IS 1350 00:52:42,720 --> 00:52:45,560 IMPORTANT IS THE FIRST STEP. 1351 00:52:45,560 --> 00:52:49,640 BUT INHIBITING MITOSIS AND 1352 00:52:49,640 --> 00:52:52,360 NEUTROPHIL FUNCTION LOCALLY AND 1353 00:52:52,360 --> 00:52:56,640 OBVIOUSLY IT IS USED ALREADY 1354 00:52:56,640 --> 00:52:57,880 (INDISCERNIBLE) LESIONS, THAT 1355 00:52:57,880 --> 00:53:02,000 WOULD MAKE A LOT OF SENSE. 1356 00:53:02,000 --> 00:53:03,040 >> CAN I FOLLOW UP? 1357 00:53:03,040 --> 00:53:06,120 WHEN YOU WERE LOOKING AT THE 1358 00:53:06,120 --> 00:53:07,960 ROLE OF NEUTROPHIL NETs YOU 1359 00:53:07,960 --> 00:53:10,360 TALKED ABOUT THE ROLE OF 1360 00:53:10,360 --> 00:53:11,760 REACTIVE OXYGEN SPECIES. 1361 00:53:11,760 --> 00:53:14,320 SO, IS THAT ANOTHER AREA THAT 1362 00:53:14,320 --> 00:53:17,880 YOU'RE CONTINUING TO STUDY, OR 1363 00:53:17,880 --> 00:53:19,040 WHAT'S THE ROLE THERE? 1364 00:53:19,040 --> 00:53:20,720 >> THOSE ARE TIED TOGETHER, CAN 1365 00:53:20,720 --> 00:53:23,520 BE TIED TOGETHER. 1366 00:53:23,520 --> 00:53:27,600 SO, PART OF THE PROCESS INCLUDES 1367 00:53:27,600 --> 00:53:28,680 REACTIVE OXYGEN SPECIES, SO 1368 00:53:28,680 --> 00:53:31,720 COULD BE A CONTINUUM OR COULD BE 1369 00:53:31,720 --> 00:53:32,920 SEPARATE. 1370 00:53:32,920 --> 00:53:38,920 AND I WILL SAY THAT OUTSIDE OF 1371 00:53:38,920 --> 00:53:40,760 THE SETTING OF PLASMINOGEN 1372 00:53:40,760 --> 00:53:42,400 DEFICIENCY WE'VE BEEN 1373 00:53:42,400 --> 00:53:45,040 COLLABORATING WITH MARIANA AND 1374 00:53:45,040 --> 00:53:47,800 HER GROUP TO THINK OF MITOSIS 1375 00:53:47,800 --> 00:53:50,640 PATHWAYS IN THE SETTING OF 1376 00:53:50,640 --> 00:53:52,360 INFLAMMATORY BONE DISEASE 1377 00:53:52,360 --> 00:53:53,000 INCLUDING PERIODONTITIS, TRYING 1378 00:53:53,000 --> 00:53:54,640 TO LOOK AT THE GENERAL 1379 00:53:54,640 --> 00:54:04,680 POPULATION IN THE ROLE OF NETs 1380 00:54:04,680 --> 00:54:05,280 AND NEUTROPHIL FUNCTIONAL IN 1381 00:54:05,280 --> 00:54:06,440 PERIODONTITIS DISEASE IN 1382 00:54:06,440 --> 00:54:06,760 GENERAL. 1383 00:54:06,760 --> 00:54:11,160 WE'RE TRYING TO GO DOWN THOSE 1384 00:54:11,160 --> 00:54:12,880 PATHS, SOMETIMES I WON'T HAVE A 1385 00:54:12,880 --> 00:54:14,440 VERY SATISFYING ANSWER QUITE 1386 00:54:14,440 --> 00:54:14,760 YET. 1387 00:54:14,760 --> 00:54:17,600 >> THE NEXT QUESTION THAT'S COME 1388 00:54:17,600 --> 00:54:18,720 THROUGH FROM KATHERINE MACKEY, 1389 00:54:18,720 --> 00:54:20,280 THANK YOU FOR A WONDERFUL 1390 00:54:20,280 --> 00:54:21,640 INFORMATIVE TALK. 1391 00:54:21,640 --> 00:54:27,520 I'M A NEW ACI MORE FAMILIAR WITH 1392 00:54:27,520 --> 00:54:28,040 GUT MICROBIOME COMMUNITY 1393 00:54:28,040 --> 00:54:28,560 CHARACTERIZATION, DOES THE 1394 00:54:28,560 --> 00:54:31,120 TREATMENT OF SOME OF THESE 1395 00:54:31,120 --> 00:54:32,360 CLINICAL INFLAMMATORY CONDITIONS 1396 00:54:32,360 --> 00:54:33,760 WITH ANTIBIOTICS HAVE NEGATIVE 1397 00:54:33,760 --> 00:54:35,160 IMPLICATIONS FOR THE COMMENSAL 1398 00:54:35,160 --> 00:54:37,560 ORAL MICROBES AND CARRY 1399 00:54:37,560 --> 00:54:38,920 DOWNSTREAM NEGATIVE EFFECTS, IN 1400 00:54:38,920 --> 00:54:41,720 ADDITION TO THE INTENDED 1401 00:54:41,720 --> 00:54:45,120 ELIMINATION OF THE PERIODONTAL 1402 00:54:45,120 --> 00:54:45,760 PATHOGENS? 1403 00:54:45,760 --> 00:54:49,240 >> AGAIN, MY ANSWER MAY NOT BE 1404 00:54:49,240 --> 00:54:49,520 SATISFYING. 1405 00:54:49,520 --> 00:54:51,800 FOR LAD, ANTIBIOTICS DO HELP. 1406 00:54:51,800 --> 00:54:54,000 ALTHOUGH WE USE VERY BROAD 1407 00:54:54,000 --> 00:54:56,040 SPECTRUM ANTIBIOTICS AND DEPLETE 1408 00:54:56,040 --> 00:54:59,720 A LOT OF COMMENSAL, I THINK NET 1409 00:54:59,720 --> 00:55:00,720 DECREASE IN MICROBIAL BURDEN 1410 00:55:00,720 --> 00:55:04,320 SEEMS TO PLAY A ROLE AND TO HELP 1411 00:55:04,320 --> 00:55:06,200 RATHER THAN HAVE AT LEAST 1412 00:55:06,200 --> 00:55:08,720 CLINICALLY AND NEGATIVE 1413 00:55:08,720 --> 00:55:10,880 CONSEQUENCE BUT POINT IS WELL 1414 00:55:10,880 --> 00:55:13,360 TAKEN HOW DISTURBANCES BECAUSE 1415 00:55:13,360 --> 00:55:14,600 OF ANTIBIOTIC TREATMENTS MIGHT 1416 00:55:14,600 --> 00:55:17,320 BE DETRIMENTAL LONG TERM AND 1417 00:55:17,320 --> 00:55:18,960 REALLY ANTIBIOTICS, AS WE ALL 1418 00:55:18,960 --> 00:55:20,720 APPRECIATE, ESPECIALLY FOR THESE 1419 00:55:20,720 --> 00:55:25,120 TYPE OF DISEASES THAT ARE NOT 1420 00:55:25,120 --> 00:55:27,600 INFECTIONS, ARE CAUSED BY 1421 00:55:27,600 --> 00:55:28,600 COMMENSALS THAT SHIFT IN 1422 00:55:28,600 --> 00:55:30,120 PROPORTION, MIGHT NOT BE THE WAY 1423 00:55:30,120 --> 00:55:33,520 TO GO AND WE MIGHT HAVE TO THINK 1424 00:55:33,520 --> 00:55:35,160 ON THE MICROENVIRONMENT ALSO AT 1425 00:55:35,160 --> 00:55:37,680 MORE TARGETED APPROACHES. 1426 00:55:37,680 --> 00:55:39,320 >> THEN, NIKI, CAN YOU ALSO TELL 1427 00:55:39,320 --> 00:55:41,160 US FROM THE MICROBIOME 1428 00:55:41,160 --> 00:55:47,600 PERSPECTIVE, YOU MENTIONED A.A. 1429 00:55:47,600 --> 00:55:48,560 ACTINONYSIS IN YOUR PLASMINOGEN 1430 00:55:48,560 --> 00:55:48,800 STUDIES. 1431 00:55:48,800 --> 00:55:51,720 IS THERE A THOUGHT THAT SOME OF 1432 00:55:51,720 --> 00:55:52,720 THOSE SPECIFIC MICROBIAL 1433 00:55:52,720 --> 00:55:55,680 COMMUNITIES THAT ARE ASSOCIATED 1434 00:55:55,680 --> 00:55:59,920 WITH PERIODONTAL DISEASE MAY BE 1435 00:55:59,920 --> 00:56:03,720 RESPONDING TO UNDERLYING GENETIC 1436 00:56:03,720 --> 00:56:04,520 CONDITION OR UNDERLYING 1437 00:56:04,520 --> 00:56:05,360 PATHOLOGY RELATED? 1438 00:56:05,360 --> 00:56:06,840 >> IT'S A BIG QUESTION, MATT. 1439 00:56:06,840 --> 00:56:08,600 IN A GOOD WAY. 1440 00:56:08,600 --> 00:56:11,920 BUT SO WHEN WE THINK OF 1441 00:56:11,920 --> 00:56:13,240 GENETICS, THERE'S A COUPLE WAYS 1442 00:56:13,240 --> 00:56:16,720 ONE CAN THINK ABOUT IT. 1443 00:56:16,720 --> 00:56:19,480 SO DOES -- ARE YOU SUSCEPTIBLE 1444 00:56:19,480 --> 00:56:24,800 BECAUSE OF GENETICS TO 1445 00:56:24,800 --> 00:56:25,480 DECOLONIZE OR OVER-- BECOME 1446 00:56:25,480 --> 00:56:28,520 DYSBIOTIC OR ARE YOU RESPONDING 1447 00:56:28,520 --> 00:56:30,160 IN A PRO-INFLAMMATORY WAY, NO 1448 00:56:30,160 --> 00:56:32,120 MATTER WHAT YOUR STIMULUS IS? 1449 00:56:32,120 --> 00:56:36,320 SO THERE COULD BE DIFFERENT WAYS 1450 00:56:36,320 --> 00:56:39,560 BY WHICH YOU BECOME SUSCEPTIBLE. 1451 00:56:39,560 --> 00:56:44,080 A.A. IS A UNIQUE BUG ASSOCIATED 1452 00:56:44,080 --> 00:56:46,360 WITH SPECIFICALLY FORMS OF 1453 00:56:46,360 --> 00:56:48,480 PERIODONTITIS DISEASE COMPARED 1454 00:56:48,480 --> 00:56:49,440 TO RELATED COMMENSALS, 1455 00:56:49,440 --> 00:56:53,360 INTERESTING TO ZERO IN. 1456 00:56:53,360 --> 00:56:55,960 OBVIOUSLY IN THE PLASMINOGEN 1457 00:56:55,960 --> 00:56:56,640 DEFICIENCY TRAIT CORRELATES 1458 00:56:56,640 --> 00:56:58,240 CLOSELY SO WE HAVE TO PAY 1459 00:56:58,240 --> 00:57:01,960 ATTENTION TO THAT SPECIFIC BUG 1460 00:57:01,960 --> 00:57:03,880 AND ITS ROLE. 1461 00:57:03,880 --> 00:57:05,480 >> AND WHAT ABOUT PG? 1462 00:57:05,480 --> 00:57:12,360 HAVE YOU LOOKED AT DISEASE 1463 00:57:12,360 --> 00:57:17,320 SUSCEPTIBILITY FOR PG? 1464 00:57:17,320 --> 00:57:20,160 >> IN PLASMINOGEN TRAITS DATA 1465 00:57:20,160 --> 00:57:28,080 AVAILABLE HAD A LOT OF THE 1466 00:57:28,080 --> 00:57:30,760 CLASSIC PERIODONTAL PATHOGENS. 1467 00:57:30,760 --> 00:57:32,400 A.A. CORRELATED. 1468 00:57:32,400 --> 00:57:35,080 PG IS NOT ASSOCIATED SO THERE WE 1469 00:57:35,080 --> 00:57:36,880 DIDN'T HAVE AN ASSOCIATION. 1470 00:57:36,880 --> 00:57:39,920 NOT TO SAY THAT IT'S, YOU KNOW, 1471 00:57:39,920 --> 00:57:41,520 OBVIOUSLY WE KNOW IT'S 1472 00:57:41,520 --> 00:57:46,800 IMPLICATED IN MANY FORMS OF -- 1473 00:57:46,800 --> 00:57:48,480 CHRONIC FORM OF PERIODONTITIS. 1474 00:57:48,480 --> 00:57:50,480 >> CAN WE THINK ABOUT PATIENT 1475 00:57:50,480 --> 00:57:50,800 VARIABILITY? 1476 00:57:50,800 --> 00:57:53,760 YOU MENTIONED IN THE LAST SLIDE 1477 00:57:53,760 --> 00:57:54,400 ABOUT SUBCLASSIFYING PATIENTS. 1478 00:57:54,400 --> 00:57:56,920 HOW ARE YOU GOING TO DO THAT? 1479 00:57:56,920 --> 00:57:58,120 WHAT ARE FORESEEING IN THE 1480 00:57:58,120 --> 00:57:59,400 FUTURE CLINICALLY AS A WAY OF 1481 00:57:59,400 --> 00:58:00,080 DOING THAT? 1482 00:58:00,080 --> 00:58:02,560 >> I'LL TELL YOU WHAT OUR NEXT 1483 00:58:02,560 --> 00:58:03,840 STEPS ARE. 1484 00:58:03,840 --> 00:58:05,640 IT'S EASIER FOR ME TO THINK 1485 00:58:05,640 --> 00:58:07,280 SPECIFIC, I THINK IT'S EASIER TO 1486 00:58:07,280 --> 00:58:11,120 ANSWER WHEN YOU HAVE A SPECIFIC 1487 00:58:11,120 --> 00:58:12,720 PLAN. 1488 00:58:12,720 --> 00:58:17,760 WITH PLASMINOGEN, BECAUSE WE 1489 00:58:17,760 --> 00:58:18,160 HAVE GENETIC VARIATIONS WE'VE 1490 00:58:18,160 --> 00:58:19,360 BEEN TALKING TO EXTRAMURAL 1491 00:58:19,360 --> 00:58:20,800 COLLABORATORS TO LOOK ABOUT 1492 00:58:20,800 --> 00:58:22,800 GENOMIC DATA AVAILABLE AND TRY 1493 00:58:22,800 --> 00:58:26,880 TO LOOK AT THE PRESENCE OF THESE 1494 00:58:26,880 --> 00:58:27,720 GENOMIC -- GENETIC VARIATIONS, 1495 00:58:27,720 --> 00:58:28,960 HOW THEY -- WHAT TYPES OF 1496 00:58:28,960 --> 00:58:30,480 PATIENTS THEY SHOW UP IN. 1497 00:58:30,480 --> 00:58:33,000 BUT WE HAVE TO THEN ALSO SEE 1498 00:58:33,000 --> 00:58:35,240 WHETHER THE GENETIC VARIATION 1499 00:58:35,240 --> 00:58:38,880 HAS A FUNCTIONAL OUTPUT. 1500 00:58:38,880 --> 00:58:43,000 DOES THAT SNP REALLY END UP 1501 00:58:43,000 --> 00:58:45,600 LEADING TO PLASMINOGEN -- 1502 00:58:45,600 --> 00:58:46,960 REDUCED PLASMINOGEN ENZYMATIC 1503 00:58:46,960 --> 00:58:48,400 ACTIVITY OR PLASMINOGEN LEVELS? 1504 00:58:48,400 --> 00:58:49,840 AND CAN THAT PROVIDE FOR US 1505 00:58:49,840 --> 00:58:53,000 GROUPS OF PATIENTS THAT HAVE 1506 00:58:53,000 --> 00:58:54,880 THIS PLASMINOGEN-RELATED PROBLEM 1507 00:58:54,880 --> 00:58:57,960 THAT WE WOULD THEN THINK OF 1508 00:58:57,960 --> 00:58:59,800 TARGETING THAT SPECIFIC PATHWAY. 1509 00:58:59,800 --> 00:59:08,480 AND THAT IS NOT GOING TO BE 1510 00:59:08,480 --> 00:59:11,160 WIDESPREAD FOR ALL FORMS OF 1511 00:59:11,160 --> 00:59:12,360 PERIODONTITIS BUT WE SHOULD GO 1512 00:59:12,360 --> 00:59:16,000 DOWN THE LINE OF PATHWAYS THAT 1513 00:59:16,000 --> 00:59:17,160 MIGHT ALLOW US TO SUBCLASSIFY 1514 00:59:17,160 --> 00:59:18,360 FURTHER THIS CONDITION. 1515 00:59:18,360 --> 00:59:20,400 >> SO, NIKI, IN THE FUTURE WILL 1516 00:59:20,400 --> 00:59:23,680 WE BE DOING HOME TESTS SIMILAR 1517 00:59:23,680 --> 00:59:25,720 TO WHAT WE'VE DOING FOR 1518 00:59:25,720 --> 00:59:26,160 SARS-COV-2 RECENTLY? 1519 00:59:26,160 --> 00:59:26,560 >> I DON'T KNOW. 1520 00:59:26,560 --> 00:59:29,200 >> WHERE WE PUT A BIT OF SALIVA 1521 00:59:29,200 --> 00:59:32,800 IN A -- YOU'VE OBVIOUSLY 1522 00:59:32,800 --> 00:59:34,760 IDENTIFIED A NUMBER OF POTENTIAL 1523 00:59:34,760 --> 00:59:36,240 TARGETS RELATIVELY EASY TO 1524 00:59:36,240 --> 00:59:43,800 TRANSLATE INTO SOME HAND HELD 1525 00:59:43,800 --> 00:59:45,880 DEVICE TO GIVE PATIENTS SOME 1526 00:59:45,880 --> 00:59:48,280 IDEA WHAT MIGHT BE APPROPRIATE 1527 00:59:48,280 --> 00:59:49,160 TARGETED THERAPIES? 1528 00:59:49,160 --> 00:59:50,360 >> WE CAN SPECULATE THAT COULD 1529 00:59:50,360 --> 00:59:50,800 HAPPEN. 1530 00:59:50,800 --> 00:59:52,960 WE'RE NOT THERE YET. 1531 00:59:52,960 --> 00:59:55,160 I DON'T WANT TO JUMP INTO THAT 1532 00:59:55,160 --> 00:59:56,720 CONCLUSION QUITE YET. 1533 00:59:56,720 --> 00:59:57,240 >> THANKS VERY MUCH. 1534 00:59:57,240 --> 01:00:01,400 I WANT TO THANK THANK YOU VERY 1535 01:00:01,400 --> 01:00:02,800 MUCH AGAIN. 1536 01:00:02,800 --> 01:00:04,800 FASCINATING TAKE, GREAT 1537 01:00:04,800 --> 01:00:05,760 QUESTIONING. 1538 01:00:05,760 --> 01:00:08,120 I HAND BACK TO MICHAEL GOTTESMAN 1539 01:00:08,120 --> 01:00:12,000 TO CLOSE THE SESSION. 1540 01:00:12,000 --> 01:00:12,240 MICHAEL? 1541 01:00:12,240 --> 01:00:15,800 >> LET ME ECHO WHAT YOU SAID, 1542 01:00:15,800 --> 01:00:16,000 MATT. 1543 01:00:16,000 --> 01:00:18,600 THIS WAS A FANTASTIC LECTURE, 1544 01:00:18,600 --> 01:00:21,000 LEARNED AN ENORMOUS AMOUNT, I'M 1545 01:00:21,000 --> 01:00:23,600 SURE OTHER LISTENERS DID AS 1546 01:00:23,600 --> 01:00:23,800 WELL. 1547 01:00:23,800 --> 01:00:24,240 THANK YOU. 1548 01:00:24,240 --> 01:00:25,680 WE WISH YOU THE BEST OF LUCK AND 1549 01:00:25,680 --> 01:00:27,640 ALL THE SUPPORT YOU NEED TO 1550 01:00:27,640 --> 01:00:28,320 CONTINUE YOUR WORK. 1551 01:00:28,320 --> 01:00:29,720 THANK YOU VERY, VERY MUCH. 1552 01:00:29,720 --> 01:00:30,880 >> IT'S PLAN A PLEASURE AND 1553 01:00:30,880 --> 01:00:31,480 HONOR. 1554 01:00:31,480 --> 01:00:32,000 THANK YOU. 1555 01:00:32,000 --> 01:00:40,360 >> THANKS. 1556 01:00:40,360 --> 01:00:46,400 1557 01:00:46,400 --> 01:02:06,760