1 00:00:11,440 --> 00:00:13,640 Welcome to the Clinical Center Grand Rounds, 2 00:00:13,640 --> 00:00:17,440 a weekly series of educational lectures for physicians and 3 00:00:17,440 --> 00:00:20,080 health care professionals broadcast from the Clinical 4 00:00:20,080 --> 00:00:23,040 Center at the National Institutes of Health in 5 00:00:23,040 --> 00:00:24,840 Bethesda, MD. 6 00:00:24,840 --> 00:00:28,400 The NIH Clinical Center is the world's largest hospital totally 7 00:00:28,400 --> 00:00:32,080 dedicated to investigational research and leads the global 8 00:00:32,080 --> 00:00:35,040 effort in training today's investigators and discovering 9 00:00:35,040 --> 00:00:37,200 tomorrow's cures. 10 00:00:37,200 --> 00:00:46,680 Learn more by visiting us online at http://clinicalcenter.nih.gov 11 00:00:46,680 --> 00:00:48,600 OUR SPEAKER TODAY IS 12 00:00:48,600 --> 00:00:49,800 DR. ELIZABETA NEMETH, WHO IS A 13 00:00:49,800 --> 00:00:52,960 PROFESSOR OF MEDICINE IN THE 14 00:00:52,960 --> 00:00:53,720 DAVID GEFFEN SCHOOL OF MEDICINE 15 00:00:53,720 --> 00:00:56,680 AT UCLA, AND DIRECTOR OF THE 16 00:00:56,680 --> 00:01:01,040 UCLA CENTER FOR IRON DISORDERS. 17 00:01:01,040 --> 00:01:02,720 DR. NEMETH EARNED HER BACHELOR 18 00:01:02,720 --> 00:01:03,800 OF SCIENCE IN MOLECULAR BIOLOGY 19 00:01:03,800 --> 00:01:07,080 AT THE UNIVERSITY OF BELGRADE IN 20 00:01:07,080 --> 00:01:08,440 YUGOSLAVIA AND THEN EARNED A 21 00:01:08,440 --> 00:01:10,920 PH.D. IN CELL MOLECULAR AND 22 00:01:10,920 --> 00:01:13,040 NEUROSCIENCES AT THE UNIVERSITY 23 00:01:13,040 --> 00:01:13,480 OF HAWAII. 24 00:01:13,480 --> 00:01:17,240 SHE COMPLETED POSTDOCTORAL 25 00:01:17,240 --> 00:01:18,400 FELLOWSHIPS AT HAWAII AND THEN 26 00:01:18,400 --> 00:01:19,920 AT CEDARS-SINAI MEDICAL CENTER 27 00:01:19,920 --> 00:01:22,520 IN LOS ANGELES BEFORE JOINING 28 00:01:22,520 --> 00:01:24,080 UCLA IN 2001. 29 00:01:24,080 --> 00:01:29,240 AS MANY OF YOU WILL KNOW, IN HER 30 00:01:29,240 --> 00:01:30,280 INVESTIGATIONS, SHE HAS 31 00:01:30,280 --> 00:01:33,680 UNDERTAKEN THE STUDY OF IRON 32 00:01:33,680 --> 00:01:35,880 HOMEOSTASIS AND ITS DISORDERS 33 00:01:35,880 --> 00:01:38,760 WITH SPECIFIC FOCUS ON THE 34 00:01:38,760 --> 00:01:41,760 FUNCTION OF THE HEPATIC PEPTIDE 35 00:01:41,760 --> 00:01:45,000 HORMONE AND MORE RECENTLY ON ITS 36 00:01:45,000 --> 00:01:48,280 RECEPTOR, THE IRON TRANSPORTER. 37 00:01:48,280 --> 00:01:52,280 HER WORK HAS HELPED DEFINE THE 38 00:01:52,280 --> 00:01:57,480 REGULATION OF HEPCIDIN, AND 39 00:01:57,480 --> 00:01:58,080 ERYTHROPOIESIS. 40 00:01:58,080 --> 00:02:00,880 IT HAS ALSO DESCRIBED THE ROLE 41 00:02:00,880 --> 00:02:04,320 IN DIFFERENT IRON DISORDERS 42 00:02:04,320 --> 00:02:06,800 INCLUDING HEREDITARY 43 00:02:06,800 --> 00:02:07,800 HEMOCHROMATOSIS, THALASSEMIA AND 44 00:02:07,800 --> 00:02:09,520 THE ANEMIA OF INFLAMMATION. 45 00:02:09,520 --> 00:02:12,480 IT HAS ELUCIDATED A MECHANISM OF 46 00:02:12,480 --> 00:02:22,320 ACTION AS THE LIGAND DESCRIBED 47 00:02:22,320 --> 00:02:27,080 THE HORMONE ERYTHROPHERONE AND 48 00:02:27,080 --> 00:02:29,000 ALSO DEVELOPED NOVEL POTENTIAL 49 00:02:29,000 --> 00:02:30,360 HEPCIDIN TARGETED CANDIDATES FOR 50 00:02:30,360 --> 00:02:35,360 THE TREATMENT OF IRON DISORDERS. 51 00:02:35,360 --> 00:02:38,200 IN IN ADDITION TO BEING THE FOUNDER 52 00:02:38,200 --> 00:02:40,480 AND DIRECTOR OF THE UCLA CENTER 53 00:02:40,480 --> 00:02:42,120 FOR IRON DISORDERS, DR. NEMETH 54 00:02:42,120 --> 00:02:45,840 IS ALSO DIRECTOR OF A PROGRAM AT 55 00:02:45,840 --> 00:02:47,160 UCLA FOR JUNIOR FACULTY. 56 00:02:47,160 --> 00:02:49,280 SHE'S A MEMBER OF THE NIH 57 00:02:49,280 --> 00:02:50,680 MOLECULAR AND CELLULAR 58 00:02:50,680 --> 00:02:52,520 HEMATOLOGY STUDY SECTION AND IS 59 00:02:52,520 --> 00:02:54,920 CURRENTLY PRESIDENT OF THE 60 00:02:54,920 --> 00:02:58,880 INTERNATIONAL BIOIRON SOCIETY. 61 00:02:58,880 --> 00:03:04,320 IN 2021, SHE RECEIVED A PRIZE 62 00:03:04,320 --> 00:03:06,480 FROM THE AMERICAN SOCIETY OF 63 00:03:06,480 --> 00:03:07,600 HEMATOLOGY JUST A FEW MONTHS 64 00:03:07,600 --> 00:03:10,880 AGO, WHICH IS AWARDED FOR 65 00:03:10,880 --> 00:03:11,840 OUTSTANDING CAREER CONTRIBUTIONS 66 00:03:11,840 --> 00:03:17,040 TO HEMATOLOGY, AND I THINK THAT 67 00:03:17,040 --> 00:03:19,640 PRIZE TO MANY OF US WAS A VERY 68 00:03:19,640 --> 00:03:20,560 WELL DESERVED HONOR CONSIDERING 69 00:03:20,560 --> 00:03:22,040 THE BODY OF HER WORK OVER THE 70 00:03:22,040 --> 00:03:24,320 LAST 20 YEARS. 71 00:03:24,320 --> 00:03:26,800 HER TALK TODAY IS ENTITLED FROM 72 00:03:26,800 --> 00:03:29,120 ANEMIA TO IRON OVERLOAD AND 73 00:03:29,120 --> 00:03:30,120 INFECTION, THE PATHOBIOLOGY OF 74 00:03:30,120 --> 00:03:30,800 IRON. 75 00:03:30,800 --> 00:03:33,680 PLEASE WELCOME DR. NEMETH. 76 00:03:33,680 --> 00:03:34,840 >> THANK YOU VERY MUCH, 77 00:03:34,840 --> 00:03:35,800 DR. SCHECHTER AND COLLEAGUES. 78 00:03:35,800 --> 00:03:39,200 IT'S TRULY AN HONOR TO GIVE THIS 79 00:03:39,200 --> 00:03:41,360 LECTURE. 80 00:03:41,360 --> 00:03:43,800 I WILL TRY TO SUMMARIZE THE 81 00:03:43,800 --> 00:03:45,960 ADVANCES WE'VE MADE OVER THE 82 00:03:45,960 --> 00:03:48,240 LAST 20 YEARS IN UNDERSTANDING 83 00:03:48,240 --> 00:03:49,320 REALLY THE MOLECULAR 84 00:03:49,320 --> 00:03:50,240 UNDERPINNINGS OF IRON PHYSIOLOGY 85 00:03:50,240 --> 00:03:53,200 AND HOW THAT EXPLAINS 86 00:03:53,200 --> 00:03:54,400 PATHOGENESIS OF DIFFERENT IRON 87 00:03:54,400 --> 00:03:55,120 DISORDERS. 88 00:03:55,120 --> 00:03:59,280 MY DISCLOSURES ARE I'M 89 00:03:59,280 --> 00:04:00,920 ON THE ADVISORY BOARD FOR 90 00:04:00,920 --> 00:04:03,760 ALL THESE LISTED, I'M ALSO A 91 00:04:03,760 --> 00:04:04,320 STOCK SHAREHOLDER. 92 00:04:04,320 --> 00:04:07,160 THESE ARE RELATED TO HEPCIDIN 93 00:04:07,160 --> 00:04:08,480 DIAGNOSTICS OR THERAPEUTICS, AND 94 00:04:08,480 --> 00:04:10,480 ALL MY GRABBED SUPPORT COMES 95 00:04:10,480 --> 00:04:10,880 FROM NIH. 96 00:04:10,880 --> 00:04:14,600 SO THANK YOU. 97 00:04:14,600 --> 00:04:17,920 HERE ARE LEARNING OBJECTIVES FOR 98 00:04:17,920 --> 00:04:18,120 TODAY. 99 00:04:18,120 --> 00:04:19,520 TO UNDERSTAND THE PATHOGENESIS 100 00:04:19,520 --> 00:04:22,320 OF IRON OVERLOAD DISORDERS, 101 00:04:22,320 --> 00:04:24,520 UNDERSTAND THE PATHOGENESIS OF 102 00:04:24,520 --> 00:04:25,560 INFLAMMATION AND UNDERSTAND THE 103 00:04:25,560 --> 00:04:31,400 ROLE OF IRON IN HOST DEFENSE. 104 00:04:31,400 --> 00:04:32,520 I WILL START VERY BROADLY. 105 00:04:32,520 --> 00:04:34,040 JUST TO UNDERSTAND WHY DO WE 106 00:04:34,040 --> 00:04:36,760 REALLY NEED IRON? 107 00:04:36,760 --> 00:04:40,320 WHY IS IT SO ESSENTIAL? 108 00:04:40,320 --> 00:04:42,520 THE COMMONLY KNOWN FUNCTIONS OF 109 00:04:42,520 --> 00:04:44,160 IRON IS IN OXYGEN TRANSPORT AND 110 00:04:44,160 --> 00:04:46,000 STORAGE AS WELL AS IN ATP 111 00:04:46,000 --> 00:04:47,720 SYNTHESIS, SO IRON IS ACTUALLY 112 00:04:47,720 --> 00:04:52,520 THE VERY AXE OM TO WHICH OXYGEN 113 00:04:52,520 --> 00:04:53,840 ATTACHES FOR TRANSPORT AND 114 00:04:53,840 --> 00:04:54,840 STORAGE OF OXYGEN. 115 00:04:54,840 --> 00:04:58,760 AND IRON IS ALSO THE VERY ATOM 116 00:04:58,760 --> 00:04:59,840 ALONG WHICH ELECTRON TRANSPORT 117 00:04:59,840 --> 00:05:03,320 IS BEING CONDUCTED IN 118 00:05:03,320 --> 00:05:04,400 MITOCHONDRIAL RESPIRATORY 119 00:05:04,400 --> 00:05:04,680 COMPLEXES. 120 00:05:04,680 --> 00:05:05,960 BUT IN ADDITION TO THESE, IRON 121 00:05:05,960 --> 00:05:08,800 IS INVOLVED IN MANY, MANY OTHER 122 00:05:08,800 --> 00:05:11,200 VITAL CELLULAR PROCESSES, FROM 123 00:05:11,200 --> 00:05:14,520 OXYGEN SENSING DNA SYNTHESIS AND 124 00:05:14,520 --> 00:05:20,640 REPAIR TO METABOLISM OF AMINO 125 00:05:20,640 --> 00:05:23,200 ACIDS, ET CETERA. 126 00:05:23,200 --> 00:05:24,200 SO ONE WONDERS WHY AARON IS 127 00:05:24,200 --> 00:05:25,120 INVOLVED IN MANY PROCESSES. 128 00:05:25,120 --> 00:05:27,840 FROM A CHEMICAL PER PERSPECTIVE, THE 129 00:05:27,840 --> 00:05:29,360 EXPLANATION IS THAT IRON 130 00:05:29,360 --> 00:05:30,480 ACTUALLY HAS A VERY VERSATILE 131 00:05:30,480 --> 00:05:32,000 CHEMISTRY IN THAT IT CAN VERY 132 00:05:32,000 --> 00:05:33,120 REGULARLY BOTH RELEASE AN 133 00:05:33,120 --> 00:05:34,320 ELECTRON AND ACCEPT AN ELECTRON, 134 00:05:34,320 --> 00:05:37,240 SO IT CAN MEDIATE EITHER 135 00:05:37,240 --> 00:05:38,000 OXIDATION OR REDUCTION 136 00:05:38,000 --> 00:05:39,120 REACTIONS. 137 00:05:39,120 --> 00:05:41,320 BUT FROM THE EVOLUTIONARY 138 00:05:41,320 --> 00:05:42,400 PERSPECTIVE, IT IS THOUGHT THAT 139 00:05:42,400 --> 00:05:44,360 IRON WAS ACTUALLY ESSENTIAL FOR 140 00:05:44,360 --> 00:05:49,280 THE VERY START OF LIFE. 141 00:05:49,280 --> 00:05:50,920 INITIALLY, LIFE STARTED IN THE 142 00:05:50,920 --> 00:05:53,400 EARLY SEAS, THEY WERE VERY 143 00:05:53,400 --> 00:05:56,200 IRON-RICH AND OXYGEN-POOR AND 144 00:05:56,200 --> 00:06:00,080 THEY'RE REFERRED TO AS FERR, OH 145 00:06:00,080 --> 00:06:04,440 US OUS 146 00:06:04,440 --> 00:06:06,520 PARADISE. 147 00:06:06,520 --> 00:06:07,840 MORE AND MORE COMPLEX MOLECULES 148 00:06:07,840 --> 00:06:09,480 FROM VERY SIMPLE MOLECULES AND 149 00:06:09,480 --> 00:06:13,200 GASES, AND THAT AS THESE 150 00:06:13,200 --> 00:06:16,920 MOLECULES BECAME MORE 151 00:06:16,920 --> 00:06:18,760 COMPLEX, -- MORE AND MORE 152 00:06:18,760 --> 00:06:21,560 REACTIONS AND THAT MAY BE ONE OF 153 00:06:21,560 --> 00:06:22,600 THE EXPLANATIONS WHY IRON IS SO 154 00:06:22,600 --> 00:06:26,080 EVER PRESENT IF IN LIFE. 155 00:06:26,080 --> 00:06:29,520 THERE IS PRACTICALLY ALL OF THE 156 00:06:29,520 --> 00:06:30,680 LIVING ORGANISMS REQUIRE IRON. 157 00:06:30,680 --> 00:06:32,640 HOWEVER, IRON DISORDERS ARE VERY 158 00:06:32,640 --> 00:06:34,160 COMMON GLOBALLY. 159 00:06:34,160 --> 00:06:39,320 IF WE LOOK AT IRON INSUFFICIENCY 160 00:06:39,320 --> 00:06:42,400 FORMS, IRON DEFICIENCY ANEMIA 161 00:06:42,400 --> 00:06:45,760 WOULD BE THE PRIMARY ONE. 162 00:06:45,760 --> 00:06:46,400 WORLD HEALTH ORGANIZATION LISTS 163 00:06:46,400 --> 00:06:47,840 THAT AMONG THE FIVE GREATEST 164 00:06:47,840 --> 00:06:49,360 CAUSE OF YEARS LIVED WITH 165 00:06:49,360 --> 00:06:50,320 DISABILITY. 166 00:06:50,320 --> 00:06:52,080 AND IT IS PARTICULARLY PREVALENT 167 00:06:52,080 --> 00:06:53,720 AMONG WOMEN AND CHILDREN IN LOW 168 00:06:53,720 --> 00:07:00,720 AND MIDDLE INCOME COUNTRIES. 169 00:07:00,720 --> 00:07:03,200 HIGHLY COMMON ALSO IS ANEMIA OF 170 00:07:03,200 --> 00:07:05,600 INFLAMMATION OR ANEMIA OF 171 00:07:05,600 --> 00:07:07,920 CHRONIC DISEASE, IRON 172 00:07:07,920 --> 00:07:10,760 MALDISTRIBUTION. 173 00:07:10,760 --> 00:07:13,040 FREQUENTLY IRON DEFICIENCY AND 174 00:07:13,040 --> 00:07:14,240 ANEMIA ARE CO-PRESENT. 175 00:07:14,240 --> 00:07:15,880 ALSO MILLIONS OF PEOPLE 176 00:07:15,880 --> 00:07:17,960 WORLDWIDE ARE AFFECTED BY IRON 177 00:07:17,960 --> 00:07:18,720 EXCESS. 178 00:07:18,720 --> 00:07:22,320 THE MOST PROMINENT DISORDERS ARE 179 00:07:22,320 --> 00:07:25,320 HEMOCHROMATOSIS, WHICH IS THE 180 00:07:25,320 --> 00:07:32,440 MOST COMMON -- MOST NOTABLE IN 181 00:07:32,440 --> 00:07:36,400 NORTHERN EUROPEAN ORIGIN, AND 182 00:07:36,400 --> 00:07:38,120 IRON LOADING ANEMIAS. 183 00:07:38,120 --> 00:07:39,520 WE WILL GO THROUGH THE 184 00:07:39,520 --> 00:07:42,520 PATHOGENESIS OF BOTH OF THESE. 185 00:07:42,520 --> 00:07:44,520 SO THE WAY SYSTEMIC IRON 186 00:07:44,520 --> 00:07:45,680 HOMEOSTASIS IS MAINTAINED IN 187 00:07:45,680 --> 00:07:48,440 HUMANS IS ACTUALLY THROUGH THE 188 00:07:48,440 --> 00:07:49,880 RECYCLING ECONOMY. 189 00:07:49,880 --> 00:07:52,480 AND THAT IS BECAUSE DURING THE 190 00:07:52,480 --> 00:07:54,280 EVOLUTION, AS OXYGEN -- THE 191 00:07:54,280 --> 00:07:55,520 OXYGEN CONTENT BECAME MUCH 192 00:07:55,520 --> 00:07:57,360 HIGHER IN ATMOSPHERE, IRON 193 00:07:57,360 --> 00:07:58,960 BECAME MUCH LESS AVAILABLE AND 194 00:07:58,960 --> 00:08:01,200 SO LIVING ORGANISMS HAVE EVOLVED 195 00:08:01,200 --> 00:08:06,120 TO RECYCLE IRON. 196 00:08:06,120 --> 00:08:09,640 FLOOB IF WE LOOK AT THE TOTAL 197 00:08:09,640 --> 00:08:19,760 IRON -- IN IN THE BODY, IT'S 3 TO 198 00:08:19,760 --> 00:08:22,320 4 GRAMS, THE LARGEST IS IN RED 199 00:08:22,320 --> 00:08:23,080 CELLS, HEMOGLOBIN, APPROXIMATELY 200 00:08:23,080 --> 00:08:24,360 TWO THIRDS OF THE TOTAL IRON 201 00:08:24,360 --> 00:08:24,720 AMOUNT. 202 00:08:24,720 --> 00:08:27,440 AS I MENTIONED, IRON ECONOMIES 203 00:08:27,440 --> 00:08:29,400 ARE RECYCLING ONE, SO YOU WILL 204 00:08:29,400 --> 00:08:32,400 APPRECIATE THAT EVERY DAY, WE 205 00:08:32,400 --> 00:08:34,520 ABSORB VERY LITTLE IRON, ONLY 206 00:08:34,520 --> 00:08:36,400 1 TO 2 MILLIGRAMS, WHICH IS LESS 207 00:08:36,400 --> 00:08:38,280 THAN .1% OF TOTAL BODY IRON. 208 00:08:38,280 --> 00:08:39,720 SO WE ABSORB VERY LITTLE AND 209 00:08:39,720 --> 00:08:42,720 THAT IS REALLY TO COMPENSATE FOR 210 00:08:42,720 --> 00:08:43,440 THESE UNREGULATED IRON LOSSES 211 00:08:43,440 --> 00:08:47,040 THAT OCCUR BY SLOUGHING OF 212 00:08:47,040 --> 00:08:47,760 GASTROINTESTINAL CELLS OR SKIN 213 00:08:47,760 --> 00:08:52,000 CELLS OR MINOR BLEEDS. 214 00:08:52,000 --> 00:08:53,760 THE MAJOR REALLY FLOW OF IRON IN 215 00:08:53,760 --> 00:08:58,160 THE BODY IS THROUGH THE BONE 216 00:08:58,160 --> 00:08:58,640 MARROW, APPROXIMATELY 217 00:08:58,640 --> 00:08:59,920 20 MILLIGRAMS A DAY IS TAKEN UP 218 00:08:59,920 --> 00:09:01,480 TO SYNTHESIZE NEW RED BLOOD 219 00:09:01,480 --> 00:09:02,320 CELLS. 220 00:09:02,320 --> 00:09:05,120 AND THAT IRON IS THEN PRESENT AS 221 00:09:05,120 --> 00:09:08,320 A COMPONENT OF HEMOGLOBIN IN RED 222 00:09:08,320 --> 00:09:09,760 BLOOD CELLS, THEY LIVE 223 00:09:09,760 --> 00:09:11,080 APPROXIMATELY FOR 120 DAYS, 224 00:09:11,080 --> 00:09:12,120 THAT'S FOUR MONTHS, AND THEN 225 00:09:12,120 --> 00:09:15,880 THEY GET RECYCLED BY MACROPHAGES 226 00:09:15,880 --> 00:09:18,080 IN THE SPLEEN AND THE LIVER AND 227 00:09:18,080 --> 00:09:18,680 APPROXIMATELY 20 MILLIGRAMS A 228 00:09:18,680 --> 00:09:20,480 DAY IS RECYCLED BACK INTO 229 00:09:20,480 --> 00:09:20,760 CIRCULATION. 230 00:09:20,760 --> 00:09:22,880 AND YOU WILL APPRECIATE THE 231 00:09:22,880 --> 00:09:24,440 PLASMA IRON LEVELS ARE ACTUALLY 232 00:09:24,440 --> 00:09:26,640 PRETTY LOW, ONLY 3 TO 233 00:09:26,640 --> 00:09:29,120 4 MILLIGRAMS, BUT A MUCH LARGER 234 00:09:29,120 --> 00:09:31,280 FLOW OF IRON GOES THROUGH IT 235 00:09:31,280 --> 00:09:33,080 EVERY DAY, SO REALLY PLASMA IRON 236 00:09:33,080 --> 00:09:34,360 COMPARTMENT TURNS OVER SEVERAL 237 00:09:34,360 --> 00:09:38,240 TIMES A DAY. 238 00:09:38,240 --> 00:09:40,880 THAT IS WHY IT IS SUCH A 239 00:09:40,880 --> 00:09:41,600 DRAMATIC COMPARTMENT THAT CAN 240 00:09:41,600 --> 00:09:43,520 CHANGE OVER RELATIVELY EASILY. 241 00:09:43,520 --> 00:09:44,320 DEPENDING ON WHETHER WE HAVE 242 00:09:44,320 --> 00:09:45,880 IRON SURPLUS OR IRON DEFICIENCY, 243 00:09:45,880 --> 00:09:47,320 WE CAN STORE IRON IN THE LIVER, 244 00:09:47,320 --> 00:09:48,920 WHICH IS THE MAJOR STORAGE ORGAN 245 00:09:48,920 --> 00:09:50,560 AND USUALLY CAN HAVE UP TO 246 00:09:50,560 --> 00:09:52,200 1-GRAM OF IRON STORED. 247 00:09:52,200 --> 00:09:53,600 WOMEN USUALLY HAVE LESS. 248 00:09:53,600 --> 00:09:55,520 AND WHEN WE NEED IT, WE MOBILIZE 249 00:09:55,520 --> 00:09:57,680 IT OUT OF THE LIVER FOR 250 00:09:57,680 --> 00:09:59,880 PROCESSES. 251 00:09:59,880 --> 00:10:02,800 SO HOW IS THIS SYSTEMIC IRON 252 00:10:02,800 --> 00:10:04,000 HOMEOSTASIS REGULATE AND 253 00:10:04,000 --> 00:10:04,320 MAINTAINED? 254 00:10:04,320 --> 00:10:06,440 IT'S MAINTAINED BY REGULATING 255 00:10:06,440 --> 00:10:08,160 FLOWS OF IRON INTO PLASMA. 256 00:10:08,160 --> 00:10:11,600 AND THAT IS DONE THROUGH THE 257 00:10:11,600 --> 00:10:13,880 PROTEIN CALLED THEIR OWE PORE 258 00:10:13,880 --> 00:10:17,040 TIN, WHICH IS THE ONLY KNOWN 259 00:10:17,040 --> 00:10:18,800 CELLULAR IRON EXPORTER, THE ONLY 260 00:10:18,800 --> 00:10:20,000 CONDUIT FOR IRON TO ENTER 261 00:10:20,000 --> 00:10:20,600 PLASMA. 262 00:10:20,600 --> 00:10:24,680 SO PHARAOH PORE TIN IS EXPRESSED 263 00:10:24,680 --> 00:10:26,240 ON -- THAT ABSORB IRON FROM THE 264 00:10:26,240 --> 00:10:28,360 DIET. 265 00:10:28,360 --> 00:10:32,320 IT'S EXPRESSED ON STLE NICK 266 00:10:32,320 --> 00:10:33,360 MACROPHAGES THAT RECYCLE OLD RED 267 00:10:33,360 --> 00:10:35,200 BLOOD CELLS AND IT'S ALSO 268 00:10:35,200 --> 00:10:36,600 EXPRESSED ON HEPATOCYTES THAT 269 00:10:36,600 --> 00:10:37,720 STORE IRON. 270 00:10:37,720 --> 00:10:39,520 SO IS THE ONLY WAY FOR IRON TO 271 00:10:39,520 --> 00:10:52,160 ENTER PLASMA. 272 00:10:52,160 --> 00:10:53,200 THEREBY CONTROLS FLOWS OF IRON 273 00:10:53,200 --> 00:10:56,360 INTO PLASMA. 274 00:10:56,360 --> 00:11:00,200 SO HEPCIDIN IS THIS REALLY SMALL 275 00:11:00,200 --> 00:11:01,520 PEPTIDE, 25 AMINO ASIDES LONG, 276 00:11:01,520 --> 00:11:02,720 PRODUCED IN VERY LARGE 277 00:11:02,720 --> 00:11:04,040 QUANTITIES IN THE LIVER, AND ITS 278 00:11:04,040 --> 00:11:06,760 PRODUCTION IS REGULATED, WHICH 279 00:11:06,760 --> 00:11:09,400 IN TURN HIGHLY REGULATED AND 280 00:11:09,400 --> 00:11:11,280 THAT, IN TURN, REGULATES IRON 281 00:11:11,280 --> 00:11:11,920 FLOWS. 282 00:11:11,920 --> 00:11:13,000 IT'S ALSO VERY RAPIDLY CLEARED 283 00:11:13,000 --> 00:11:15,080 IN THE KIDNEYS, BECAUSE IT IS SO 284 00:11:15,080 --> 00:11:17,920 SMALL. 285 00:11:17,920 --> 00:11:22,960 SO THIS IS HOW HEPCIDIN CONTROLS 286 00:11:22,960 --> 00:11:23,720 IRON FLOWS. 287 00:11:23,720 --> 00:11:25,600 HEPCIDIN IS A LIGAND FOR 288 00:11:25,600 --> 00:11:26,920 FERROPORTIN, SO FERROPORTIN IS 289 00:11:26,920 --> 00:11:29,720 THIS TRANS MEMBRANE 12 MULTIPASS 290 00:11:29,720 --> 00:11:33,680 TRANS MEMBRANE PROTEIN THAT HAS 291 00:11:33,680 --> 00:11:35,120 A CENTRAL CAVITY THROUGH WHICH 292 00:11:35,120 --> 00:11:36,920 IRON IS EXPORTED FROM INSIDE A 293 00:11:36,920 --> 00:11:38,720 CELL TO OUTSIDE OF THE CELL, AND 294 00:11:38,720 --> 00:11:40,360 HEPCIDIN IS A SMALL PEPTIDE 295 00:11:40,360 --> 00:11:42,080 WHICH INSERTS ITSELF INTO THE 296 00:11:42,080 --> 00:11:44,280 CENTRAL CAVITY OF FERROPORTIN, 297 00:11:44,280 --> 00:11:47,560 AND THUS OCCLUDES FERROPORTIN 298 00:11:47,560 --> 00:11:48,680 AND PREVENTS FURTHER IRON 299 00:11:48,680 --> 00:11:48,920 EXPORT. 300 00:11:48,920 --> 00:11:50,920 IN ADDITION TO THAT, THIS 301 00:11:50,920 --> 00:11:56,160 BINDING, THE DIRECT INTERACTION 302 00:11:56,160 --> 00:11:59,720 CAUSES EU BIC WHICH NATION AND 303 00:11:59,720 --> 00:12:00,920 THAT LEADS TO DESTRUCTION OF 304 00:12:00,920 --> 00:12:02,320 BOTH LIGAND AND THE RECEPTOR. 305 00:12:02,320 --> 00:12:05,360 SO IF WE LOOK IN THE CELLULAR 306 00:12:05,360 --> 00:12:07,800 MODEL, HERE ARE CELLS EXPRESSING 307 00:12:07,800 --> 00:12:09,320 FERROPORTIN TAGGED WITH 308 00:12:09,320 --> 00:12:11,360 FLUORESCENT GREEN PROTEIN GFP. 309 00:12:11,360 --> 00:12:13,480 IN THE ABSENCE OF HEPCIDIN, 310 00:12:13,480 --> 00:12:14,920 FERROPORTIN IS ON THE CELL 311 00:12:14,920 --> 00:12:17,160 SURFACE AND IT EXPORTS IRON. 312 00:12:17,160 --> 00:12:19,800 BUT WHEN HEPCIDIN IS ADDED, 313 00:12:19,800 --> 00:12:20,920 FERROPORTIN IS RAPIDLY 314 00:12:20,920 --> 00:12:22,520 INTERNALIZED AND DEGRADED AND 315 00:12:22,520 --> 00:12:26,360 THEN EXPORTED OUT OF THE CELL 316 00:12:26,360 --> 00:12:26,800 STOCKS. 317 00:12:26,800 --> 00:12:29,000 SO HOW THAT EXPLAINS HOW 318 00:12:29,000 --> 00:12:30,440 HEPCIDIN CONTROLS INTESTINAL 319 00:12:30,440 --> 00:12:33,240 IRON ABSORPTION. 320 00:12:33,240 --> 00:12:35,080 WHEN HEPCIDIN IS LOW, 321 00:12:35,080 --> 00:12:37,960 FERROPORTIN IS EXPRESSED ON THE 322 00:12:37,960 --> 00:12:44,840 MEMBRANE OF THE DUE DUODENAL 323 00:12:44,840 --> 00:12:45,600 ENTEROSITES. 324 00:12:45,600 --> 00:12:49,200 ON IRON IS GOING TO BE DIRECTLY 325 00:12:49,200 --> 00:12:50,800 EXPORTED INTO BLOOD. 326 00:12:50,800 --> 00:12:53,640 BUT WHEN HEPCIDIN IS HIGH, EVEN 327 00:12:53,640 --> 00:12:55,800 IF WE CONTINUE TAKING IRON ON 328 00:12:55,800 --> 00:12:57,520 THE APICAL SIDE, THAT IRON IS 329 00:12:57,520 --> 00:13:01,400 JUST GETTING STUCK WITHIN 330 00:13:01,400 --> 00:13:03,920 DUODENAL ENTEROCYTES AND THESE 331 00:13:03,920 --> 00:13:07,840 ARE SHORT LIVED CELLS, THEY GET 332 00:13:07,840 --> 00:13:10,680 SLOUGHED OFF IN TWO TO THREE 333 00:13:10,680 --> 00:13:15,760 DAYS, SO HEPCIDIN WILL -- HIGH 334 00:13:15,760 --> 00:13:17,240 HEPCIDIN, LOWER IRON TRANSPORT 335 00:13:17,240 --> 00:13:22,480 INTO BLOOD. 336 00:13:22,480 --> 00:13:26,080 THE SIMILAR PRINCIPLE APPLIES, 337 00:13:26,080 --> 00:13:31,400 SO WHEN HEPCIDIN IS LOW, AS 338 00:13:31,400 --> 00:13:32,720 MACROPHAGES EXTRACT IRON FROM 339 00:13:32,720 --> 00:13:34,480 HEMOGLOBIN, THAT IRON CAN BE 340 00:13:34,480 --> 00:13:36,000 READILY EXPORTED THROUGH 341 00:13:36,000 --> 00:13:36,920 FERROPORTIN WHICH IS EXPRESSED 342 00:13:36,920 --> 00:13:38,960 ON THE SURFACE OF MACROPHAGES, 343 00:13:38,960 --> 00:13:45,840 BUT WHEN HEPCIDIN IS HIGH, EVEN 344 00:13:45,840 --> 00:13:47,120 THOUGH PHAGOCYTOSIS CONTINUES, 345 00:13:47,120 --> 00:13:49,000 IRON IS GOING TO GET SEQUESTERED 346 00:13:49,000 --> 00:13:52,320 WITHIN FERRATIN AND IRON WILL 347 00:13:52,320 --> 00:13:54,520 NOT BE EXPORTED INTO PLASMA. 348 00:13:54,520 --> 00:13:57,920 SO IF WE NOW PUT IT ALL TOGETHER 349 00:13:57,920 --> 00:13:59,800 ON AN ORGANIZE LEVEL, WHEN 350 00:13:59,800 --> 00:14:01,680 HEPCIDIN IS ELEVATED, THAT WILL 351 00:14:01,680 --> 00:14:03,400 TARGET FERROPORTIN ON ALL OF THE 352 00:14:03,400 --> 00:14:04,800 TARGET SITES THAT HANDLE MAJOR 353 00:14:04,800 --> 00:14:09,960 IRON FLOWS, NARE FERROPORTIN WILL BE 354 00:14:09,960 --> 00:14:11,680 DESTROYED AND THAT DECREASES 355 00:14:11,680 --> 00:14:12,520 IRON FLOWS INTO PLASMA. 356 00:14:12,520 --> 00:14:14,000 AS I MENTIONED, THIS PLASMA 357 00:14:14,000 --> 00:14:15,520 COMPARTMENT IS VERY SMALL, AND 358 00:14:15,520 --> 00:14:17,680 IT'S CONSTANTLY GETTING UTILIZED 359 00:14:17,680 --> 00:14:18,800 BY THE BONE MARROW AND OTHER 360 00:14:18,800 --> 00:14:20,440 CELLS IN THE BODY, SO IT'S GOING 361 00:14:20,440 --> 00:14:22,600 TO GET VERY RAPIDLY DEPLETED, 362 00:14:22,600 --> 00:14:25,840 AND THAT EXPLAINS HOW HYPOTHAT 363 00:14:25,840 --> 00:14:30,720 WILL -- OCCURS. 364 00:14:30,720 --> 00:14:32,560 THIS IS AN EXAMPLE IN MICE, HOW 365 00:14:32,560 --> 00:14:37,720 WE CAN DO THIS IN A VERY -- YOU 366 00:14:37,720 --> 00:14:38,880 CAN APPRECIATE WITHIN JUST ONE 367 00:14:38,880 --> 00:14:41,880 HOUR, WE CAN ACHIEVE THIS 368 00:14:41,880 --> 00:14:49,440 PROFOUND PIE HOE FAIR HYPOFERREMIA. 369 00:14:49,440 --> 00:14:53,000 SO IN A WAY, HEPCIDIN IS TO IRON 370 00:14:53,000 --> 00:15:01,320 WHAT INSULIN IS TO GLUCOSE. 371 00:15:01,320 --> 00:15:04,120 SO HEPCIDIN REGULATION IS REALLY 372 00:15:04,120 --> 00:15:05,200 COMPLEX AND THAT IS RESPONSIBLE 373 00:15:05,200 --> 00:15:10,120 FOR CONTROLLING THESE IRON FLOWS 374 00:15:10,120 --> 00:15:11,600 AND MAINTAINING SYSTEMIC IRON 375 00:15:11,600 --> 00:15:12,280 HOMEOSTASIS. 376 00:15:12,280 --> 00:15:14,320 I'M GOING TO COVER THREE MAJOR 377 00:15:14,320 --> 00:15:14,760 CIRCUITRY. 378 00:15:14,760 --> 00:15:16,560 ONE OF THEM IS HEPCIDIN 379 00:15:16,560 --> 00:15:17,080 REGULATION BY IRON. 380 00:15:17,080 --> 00:15:19,840 SO THIS IS A CLASSICAL ENDOCRINE 381 00:15:19,840 --> 00:15:20,320 ME 382 00:15:20,320 --> 00:15:21,440 MECHANISM WHERE A HORMONE 383 00:15:21,440 --> 00:15:23,120 CONTROLS A SUBSTRATE AND 384 00:15:23,120 --> 00:15:23,960 SUBSTRATE IN TURN CONTROLS THE 385 00:15:23,960 --> 00:15:24,400 HORMONE. 386 00:15:24,400 --> 00:15:26,040 SO IT'S A FEEDBACK MECHANISM. 387 00:15:26,040 --> 00:15:28,320 THE SAME AS EXISTS FOR, FOR 388 00:15:28,320 --> 00:15:30,120 EXAMPLE, INSULIN AND GLUCOSE. 389 00:15:30,120 --> 00:15:32,080 AND IN CASE FOR HEPCIDIN, BOTH 390 00:15:32,080 --> 00:15:34,160 PLASMA IRON, SO CIRCULATING IRON 391 00:15:34,160 --> 00:15:35,480 AS WELL AS LIVER STORES CAN 392 00:15:35,480 --> 00:15:39,320 CONTROL HEPCIDIN PRODUCTION. 393 00:15:39,320 --> 00:15:41,040 THIS JUST ENSURES WHEN WE HAVE 394 00:15:41,040 --> 00:15:42,320 ENOUGH IRON, HEPCIDIN IS GOING 395 00:15:42,320 --> 00:15:44,200 TO BE INCREASED AND PREVENT 396 00:15:44,200 --> 00:15:48,400 FURTHER ABSORPTION OF IRON. 397 00:15:48,400 --> 00:15:52,200 AS COULD BE EXPECTED, 398 00:15:52,200 --> 00:15:53,000 ERYTHROPOIESIS ALSO RELEASES A 399 00:15:53,000 --> 00:15:54,760 FACTOR THAT CONTROLS HEPCIDIN, 400 00:15:54,760 --> 00:15:57,920 BECAUSE IT IS SUCH AN 401 00:15:57,920 --> 00:15:59,240 IRON-INTENSIVE PRO CYST THAT IT 402 00:15:59,240 --> 00:16:00,480 NEEDS TO HAVE MEANS TO 403 00:16:00,480 --> 00:16:01,520 COMMUNICATE WHEN IT NEEDS MORE 404 00:16:01,520 --> 00:16:03,280 IRON TO PRODUCE MORE RED BLOOD 405 00:16:03,280 --> 00:16:03,600 CELLS. 406 00:16:03,600 --> 00:16:05,120 AND THE THIRD CIRCUITRILY TALK 407 00:16:05,120 --> 00:16:07,520 ABOUT IS HEPCIDIN REGULATION BY 408 00:16:07,520 --> 00:16:09,640 INFLAMMATION, AND THIS IS PART 409 00:16:09,640 --> 00:16:13,400 OF HOST DEFENSE MECHANISM. 410 00:16:13,400 --> 00:16:16,400 SO IF WE LOOK AT HEPCIDIN 411 00:16:16,400 --> 00:16:18,360 REGULATION BY IRON AT A BASIC 412 00:16:18,360 --> 00:16:19,520 PHYSIOLOGY, HERE'S AN EXAMPLE OF 413 00:16:19,520 --> 00:16:21,480 A VOLUNTEER THAT INGESTED A 414 00:16:21,480 --> 00:16:23,320 SINGLE IRON PILL AND WE LOOKED 415 00:16:23,320 --> 00:16:28,240 AT A TIME COURSE OF SERUM 416 00:16:28,240 --> 00:16:30,120 HEPCIDIN, INGESTED, INCREASES 417 00:16:30,120 --> 00:16:31,000 RAPIDLY AND THEN IT STARTS 418 00:16:31,000 --> 00:16:32,720 COMING DOWN, AND THE REASON WE 419 00:16:32,720 --> 00:16:35,000 HAVE THIS RETURN OF SERUM IRON 420 00:16:35,000 --> 00:16:37,440 TO BASELINE IS BECAUSE HEPCIDIN 421 00:16:37,440 --> 00:16:38,840 IS INCREASED. 422 00:16:38,840 --> 00:16:41,920 SO AS IRON STARTS INCREASING IN 423 00:16:41,920 --> 00:16:44,200 CIRCULATION, THAT IS A STIMULUS 424 00:16:44,200 --> 00:16:47,040 FOR HEPCIDIN TO ALSO INCREASE. 425 00:16:47,040 --> 00:16:48,760 AS HEPCIDIN GOES UP, IT CAUSES 426 00:16:48,760 --> 00:16:50,400 IRON TO START COMING DOWN AND 427 00:16:50,400 --> 00:16:51,920 THEN HEPCIDIN CAN START COMING 428 00:16:51,920 --> 00:16:52,360 DOWN TOO. 429 00:16:52,360 --> 00:16:53,920 SO THIS IS THAT CLASSICAL 430 00:16:53,920 --> 00:16:55,200 ENDOCRINE FEEDBACK MECHANISM 431 00:16:55,200 --> 00:16:58,920 WHERE SUBSTRATE AND HORMONE 432 00:16:58,920 --> 00:17:01,760 REGULATE EACH OTHER TO ENSURE 433 00:17:01,760 --> 00:17:05,720 THAT SERUM IRON IS IN THE 434 00:17:05,720 --> 00:17:08,640 HOMEOSTATIC RANGE, 10 TO 30 435 00:17:08,640 --> 00:17:09,280 MICROMOLAR. 436 00:17:09,280 --> 00:17:10,920 NOW, WHAT IS THE MOLECULAR 437 00:17:10,920 --> 00:17:11,800 MECHANISM UNDERPINNING THIS? 438 00:17:11,800 --> 00:17:14,320 THAT ACTUALLY HAS BEEN ONE OF 439 00:17:14,320 --> 00:17:17,840 THE MOST DIFFICULT TOPICS IN THE 440 00:17:17,840 --> 00:17:19,320 IRON FIELD AND IT HAS TAKEN 20 441 00:17:19,320 --> 00:17:20,320 YEARS TO MAKE THIS SCHEMA. 442 00:17:20,320 --> 00:17:23,640 SO IT TURNS OUT THAT AT THE 443 00:17:23,640 --> 00:17:26,360 CENTER OF HEPCIDIN REGULATION BY 444 00:17:26,360 --> 00:17:28,320 IRON IS THE BONE MORPHOGENETIC 445 00:17:28,320 --> 00:17:29,640 PATHWAY. 446 00:17:29,640 --> 00:17:33,280 THE SPECIFIC LIGANDS THAT 447 00:17:33,280 --> 00:17:35,440 REGULAR HEPCIDIN -- 2 AND 6, AND 448 00:17:35,440 --> 00:17:37,800 THEY BIND TO CERTAIN PROTEIN 449 00:17:37,800 --> 00:17:39,600 RECEPTORS AND THERE IS ALSO A 450 00:17:39,600 --> 00:17:46,560 CO-RECEPTOR AND THIS CORY CORE 451 00:17:46,560 --> 00:17:47,680 RECEPTOR ENSURES THAT CERTAIN 452 00:17:47,680 --> 00:17:49,120 LIGANDS AND CERTAIN RECEPTORS 453 00:17:49,120 --> 00:17:53,480 ARE GOING TO COME TOGETHER. 454 00:17:53,480 --> 00:17:57,400 SO -- THROUGH STIMULATING -- S 455 00:17:57,400 --> 00:17:58,920 DESCRIPTION FACTORS INCREASE 456 00:17:58,920 --> 00:18:01,880 HEPCIDIN TRANSCRIPTION. 457 00:18:01,880 --> 00:18:02,960 RELATIVELY RECENT TWIST TO THE 458 00:18:02,960 --> 00:18:05,600 STORY IS THAT THESE BMP LIGANDS 459 00:18:05,600 --> 00:18:08,480 ACTUALLY ARE PRODUCED BY LIVER 460 00:18:08,480 --> 00:18:11,400 SIGN 461 00:18:11,400 --> 00:18:12,720 SINUSOIDAL -- IT'S ACTUALLY THE 462 00:18:12,720 --> 00:18:13,520 ENDOTHELIUM. 463 00:18:13,520 --> 00:18:15,480 NOW HOW DOES IRON SENSING COME 464 00:18:15,480 --> 00:18:18,400 INTO THIS? 465 00:18:18,400 --> 00:18:20,400 THERE IS AN INCREASE IN IRON 466 00:18:20,400 --> 00:18:23,120 STORES, IT TURNS OUT THAT 467 00:18:23,120 --> 00:18:27,560 ENDOTHELIUM PRODUCES MORE 468 00:18:27,560 --> 00:18:30,560 BMPs, BMP2 AND 6, AND THAT POE 469 00:18:30,560 --> 00:18:32,400 10 SHAITS PHOSPHORYLATION AND -- 470 00:18:32,400 --> 00:18:33,080 INCITING TRANSCRIPTION. 471 00:18:33,080 --> 00:18:34,360 HOWEVER, WE DON'T YET KNOW 472 00:18:34,360 --> 00:18:36,400 EXACTLY HOW THESE IRON STORES 473 00:18:36,400 --> 00:18:37,960 ARE SENSED, WHAT IS THE IRON 474 00:18:37,960 --> 00:18:39,640 FORM THAT IS BEING SENSED, IS IT 475 00:18:39,640 --> 00:18:42,320 BEING SENSED IN HEPATOCYTES OR 476 00:18:42,320 --> 00:18:43,400 ENDOTHELIAL CELLS, SO THIS IS 477 00:18:43,400 --> 00:18:44,760 ALL BEING WORKED OUT AND IT ONE 478 00:18:44,760 --> 00:18:46,000 OF THE MAJOR QUESTIONS IN THE 479 00:18:46,000 --> 00:18:51,840 FIELD. 480 00:18:51,840 --> 00:18:54,800 I ALSO MENTIONED PLASMA IRON CAN 481 00:18:54,800 --> 00:18:58,520 REGULATE HELP SIGH DIN, THROUGH 482 00:18:58,520 --> 00:19:00,320 TRANSPARENT RECEPTOR 1 AND 2. 483 00:19:00,320 --> 00:19:02,640 1 IS THE CLASSICAL RECEPTOR THAT 484 00:19:02,640 --> 00:19:03,960 TAKES UP IRON INTO EVERY CELL IN 485 00:19:03,960 --> 00:19:07,800 THE BODY, AND IN HEPATOSITES, 486 00:19:07,800 --> 00:19:08,440 TRANSPARENT RECEPTOR ONE REACTS 487 00:19:08,440 --> 00:19:11,280 WITH HFE, WHICH IS THE MOLECULE 488 00:19:11,280 --> 00:19:15,320 THAT'S THE MOST COMMON CAUSE OF 489 00:19:15,320 --> 00:19:18,400 HEMA CHROMATOCYST IN HUMANS. 490 00:19:18,400 --> 00:19:20,480 RECEPTOR 2 IS THE HOMOLOGUE OF 491 00:19:20,480 --> 00:19:21,920 TRANSPARENT RECEPTOR 1 AND IT 492 00:19:21,920 --> 00:19:23,200 DOESN'T PARTICIPATE IN TAKING UP 493 00:19:23,200 --> 00:19:25,840 IRON, BUT RATHER PARTICIPATES IN 494 00:19:25,840 --> 00:19:26,600 IRON SENSING. 495 00:19:26,600 --> 00:19:34,040 SO WHAT HAPPENS WHEN -- BINDING 496 00:19:34,040 --> 00:19:36,960 TO RECEPTOR 1 DISPLACES HFE, AND 497 00:19:36,960 --> 00:19:40,040 HFE THEN INTERACTS WITH THE BONE 498 00:19:40,040 --> 00:19:44,640 MORPHOGENETIC PROTEIN RECEPTORS. 499 00:19:44,640 --> 00:19:45,600 BINDING STABILIZES THE PROTEIN 500 00:19:45,600 --> 00:19:50,400 AND WE THINK IT MAY ALSO 501 00:19:50,400 --> 00:19:52,360 INTERACT WITH PROTEIN RECEPTORS. 502 00:19:52,360 --> 00:19:53,280 SO WHAT HAPPENS IS THAT 503 00:19:53,280 --> 00:19:55,480 PROPORTIONAL TO THE PLASMA IRON, 504 00:19:55,480 --> 00:19:59,640 THERE IS THE FORMATION OF THIS 505 00:19:59,640 --> 00:20:02,720 SUPER COMPLEX AROUND -- PROTEIN 506 00:20:02,720 --> 00:20:04,400 RECEPTORS WHICH THEN 507 00:20:04,400 --> 00:20:09,320 POTENTIATES -- SIGNALING 508 00:20:09,320 --> 00:20:10,520 AND -- -- INCREASE IN STORED 509 00:20:10,520 --> 00:20:11,640 IRON AND INCREASE IN PLASMA IRON 510 00:20:11,640 --> 00:20:14,720 LEADS TO POTENTIATION OF PROTEIN 511 00:20:14,720 --> 00:20:17,200 SIGNALING WHICH THEN INKREASES 512 00:20:17,200 --> 00:20:19,280 HEPCIDIN TRANSCRIPTION. 513 00:20:19,280 --> 00:20:21,120 SO WHY ARE THESE DETAILS 514 00:20:21,120 --> 00:20:21,680 RELEVANT? 515 00:20:21,680 --> 00:20:23,520 WELL, THAT EXPLAINS PATHOGENESIS 516 00:20:23,520 --> 00:20:26,720 OF HEREDITARY HEMOCHROMATOSIS OR 517 00:20:26,720 --> 00:20:31,200 AS WE NOW LIKE TO CALL IT, JUST 518 00:20:31,200 --> 00:20:31,560 HEMOCHROMATOSIS. 519 00:20:31,560 --> 00:20:33,280 SO WHAT IS THE MOLECULAR BASIS? 520 00:20:33,280 --> 00:20:35,600 IT IS THE MUTATIONS IN HFE, THIS 521 00:20:35,600 --> 00:20:38,960 IS THE MOST COMMON FORM, MU 522 00:20:38,960 --> 00:20:42,000 HUMAN RELATIONS IN TRANSPARENT 523 00:20:42,000 --> 00:20:45,880 RECEPTOR TWO, RECENTLY IN 524 00:20:45,880 --> 00:20:49,280 BMP6 WHERE HE DESCRIBED -- 525 00:20:49,280 --> 00:20:51,160 AND -- SO MUTATIONS IN ANY OF 526 00:20:51,160 --> 00:20:52,920 THESE REGULATORS OF HEPCIDIN OR 527 00:20:52,920 --> 00:20:55,080 HEPCIDIN ITSELF ARE RESPONSIBLE 528 00:20:55,080 --> 00:21:00,680 FOR A MAJORITY OF THE FORMS OF 529 00:21:00,680 --> 00:21:01,320 HEREDITARY HEMOCHROMATOSIS. 530 00:21:01,320 --> 00:21:04,520 WHAT HAPPENS MOLECULARLY OR 531 00:21:04,520 --> 00:21:06,280 PATHOPHYSIOLOGY IS THERE'S 532 00:21:06,280 --> 00:21:08,320 SENSING OF IRON SO HEPCIDIN WILL 533 00:21:08,320 --> 00:21:12,480 NOT BE APPROPRIATELY RESPONSIVE, 534 00:21:12,480 --> 00:21:13,920 WHICH THEN LEADS TO IRON 535 00:21:13,920 --> 00:21:15,320 OVERLOAD. 536 00:21:15,320 --> 00:21:19,760 NOW, WHY IS IRON BAD, WHY IS TOO 537 00:21:19,760 --> 00:21:20,600 MUCH IRON BAD? 538 00:21:20,600 --> 00:21:23,600 WHEN THERE'S EXCESSIVE IRON AB 539 00:21:23,600 --> 00:21:29,120 SORMINGS, PLASMA TRANS FERRIN 540 00:21:29,120 --> 00:21:30,520 GETS -- AS I MENTIONED THAT'S A 541 00:21:30,520 --> 00:21:33,920 SMALL COMPARTMENT SO THIS IS 542 00:21:33,920 --> 00:21:38,920 VERY -- IF THERE'S EXCESSIVE -- 543 00:21:38,920 --> 00:21:40,120 WHAT HAPPENS IS THE NEW FORM OF 544 00:21:40,120 --> 00:21:41,920 IRON APPEARS IN CIRCULATION, 545 00:21:41,920 --> 00:21:45,160 WHICH WE REFER TO AS 546 00:21:45,160 --> 00:21:45,840 NON-TRANSPARENT-BOUND IRON BUT 547 00:21:45,840 --> 00:21:48,360 IT'S REALLY IRON BOUND TO SMALL 548 00:21:48,360 --> 00:21:51,040 ORGANIC MOLECULES OR MAYBE 549 00:21:51,040 --> 00:21:52,320 LOOSELY BOUND TO ALBUMEN. 550 00:21:52,320 --> 00:21:55,400 SO WHEN THIS FORM APPEARS, THERE 551 00:21:55,400 --> 00:22:03,240 WILL BE UP TAKE OF THAT 552 00:22:03,240 --> 00:22:08,320 NON-TRANSFERIN LN -BOUND IRON, AND 553 00:22:08,320 --> 00:22:12,520 THESE TRANSPORTERS USUALLY UNDER 554 00:22:12,520 --> 00:22:13,000 PHYSIOLOGICAL CONDITIONS 555 00:22:13,000 --> 00:22:18,320 TRANSPORT OTHER METALS BUT WHEN 556 00:22:18,320 --> 00:22:20,120 THEY AREN'T PRESENT IN EXCESSIVE 557 00:22:20,120 --> 00:22:21,920 AMOUNTS, THOSE TRANSPORTERS WILL 558 00:22:21,920 --> 00:22:24,800 ALSO TAKE UP -- AND WILL LOAD 559 00:22:24,800 --> 00:22:25,680 THESE ORGANS. 560 00:22:25,680 --> 00:22:30,480 YOU CAN APPRECIATE IN LIVER AND 561 00:22:30,480 --> 00:22:32,360 HEART IRON UPLOADING, HIGHLY 562 00:22:32,360 --> 00:22:32,760 ABNORMAL. 563 00:22:32,760 --> 00:22:35,320 ONCE THIS EXCESS FREE IRON IS 564 00:22:35,320 --> 00:22:36,520 ACCUMULATED, IT WILL CATALYZE 565 00:22:36,520 --> 00:22:38,800 GENERATION OF HARMFUL OXYGEN 566 00:22:38,800 --> 00:22:39,080 RADICALS. 567 00:22:39,080 --> 00:22:43,080 YOU CAN SEE THIS EXAMPLE OF 568 00:22:43,080 --> 00:22:44,120 FENTON REACTION AND THEY WILL 569 00:22:44,120 --> 00:22:46,760 NOW DAMAGE ALL OF THE VITAL CELL 570 00:22:46,760 --> 00:22:49,280 STRUCTURES: DNA, RNA, PROTEINS, 571 00:22:49,280 --> 00:22:51,120 CELL MEMBRANES. 572 00:22:51,120 --> 00:22:55,040 SO THEN ON THE ORGANISMAL LEVEL, 573 00:22:55,040 --> 00:22:57,680 YOU CAN -- MAY SUFFER SOME 574 00:22:57,680 --> 00:22:59,520 DAMAGE, SO LIVER IS USUALLY THE 575 00:22:59,520 --> 00:23:02,040 PRIMARY ORGAN THAT WILL GET 576 00:23:02,040 --> 00:23:03,400 DAMAGED BECAUSE THAT IS THE ONE 577 00:23:03,400 --> 00:23:04,760 THAT EXPRESSES MOST OF THESE 578 00:23:04,760 --> 00:23:05,720 TRANSPORTERS AND WILL TAKE UP 579 00:23:05,720 --> 00:23:08,440 MOST OF THE IRON. 580 00:23:08,440 --> 00:23:11,440 AND SO THERE MAY BE HEPATIC FAY 581 00:23:11,440 --> 00:23:13,160 BRO CYST AND IN SOME PATIENTS 582 00:23:13,160 --> 00:23:15,480 DEVELOPMENT OF CIRRHOSIS AND 583 00:23:15,480 --> 00:23:16,320 EVEN CANCER. 584 00:23:16,320 --> 00:23:17,720 CARDIOMYOPATHY MAY OCCUR. 585 00:23:17,720 --> 00:23:19,320 THERE COULD BE ANTERIOR 586 00:23:19,320 --> 00:23:25,240 PITUITARY FAILURE, DIABETES, 587 00:23:25,240 --> 00:23:26,320 HYPOGONADISM, ET CETERA. 588 00:23:26,320 --> 00:23:28,400 SO ANY ORGAN THAT ENDS UP HAVING 589 00:23:28,400 --> 00:23:29,280 EXCESSIVE IRON ACCUMULATION WILL 590 00:23:29,280 --> 00:23:30,720 BE DAMAGED. 591 00:23:30,720 --> 00:23:32,440 NOW WHICH ORGANS WILL ACCUMULATE 592 00:23:32,440 --> 00:23:34,720 IT WILL DEPEND ON THE SEVERITY 593 00:23:34,720 --> 00:23:36,160 OF IRON OVERLOADS. 594 00:23:36,160 --> 00:23:38,440 AND HERE IS AN EXAMPLE OF THE 595 00:23:38,440 --> 00:23:40,800 MOST SEVERE FORM OF 596 00:23:40,800 --> 00:23:42,040 HEMOCHROMATOSIS, WHICH USED TO 597 00:23:42,040 --> 00:23:43,560 BE CALLED JUVENILE 598 00:23:43,560 --> 00:23:44,360 HEMOCHROMATOSIS. 599 00:23:44,360 --> 00:23:46,200 IN THIS CASE, IT WAS A 600 00:23:46,200 --> 00:23:47,520 25-YEAR-OLD MAN, HE PRESENTED 601 00:23:47,520 --> 00:23:50,000 WITH ABDOMINAL PAIN, 602 00:23:50,000 --> 00:23:51,160 HEPATOMEGALY, SYMPTOMS OF HEART 603 00:23:51,160 --> 00:23:52,840 FAILURE, AND HEART BIOPSY WAS 604 00:23:52,840 --> 00:24:00,600 PERFORMED AND THEN SOME -- CLOSE TO 605 00:24:00,600 --> 00:24:03,480 100%, VERY HIGH FERRATIN, WHERE 606 00:24:03,480 --> 00:24:04,440 NORMAL RANGE IS HERE. 607 00:24:04,440 --> 00:24:06,720 HE HAD EVIDENCE OF DIABETES AND 608 00:24:06,720 --> 00:24:08,440 LIVER DAMAGE. 609 00:24:08,440 --> 00:24:10,480 AND UNFORTUNATELY, TWO DAYS 610 00:24:10,480 --> 00:24:11,680 AFTER DIAGNOSIS, THE PATIENT 611 00:24:11,680 --> 00:24:15,360 DIED FROM HEART FAILURE. 612 00:24:15,360 --> 00:24:16,920 SO THIS SEVERE FORM OF 613 00:24:16,920 --> 00:24:18,240 HEMOCHROMATOSIS CAN BE 614 00:24:18,240 --> 00:24:20,440 ACTUALL LETHAL. 615 00:24:20,440 --> 00:24:21,600 ON AUTOPSY, LARGE AMOUNTS OF 616 00:24:21,600 --> 00:24:22,920 IRON IN THE HEART WERE FOUND, 617 00:24:22,920 --> 00:24:26,520 THE LIVER, THE PANCREAS, LYMPH 618 00:24:26,520 --> 00:24:29,360 NODES, TESTES, ADRENAL GLANDS, 619 00:24:29,360 --> 00:24:30,920 AND NO MATURE SPERMS WERE 620 00:24:30,920 --> 00:24:31,400 OBSERVED. 621 00:24:31,400 --> 00:24:34,640 SO CLASSICAL HEMOCHROMATOSIS. 622 00:24:34,640 --> 00:24:38,680 SO SPECIFIC, IN THIS SPECIFIC 623 00:24:38,680 --> 00:24:46,520 PATIENT, HEMOJU VE LIN ENSURES 624 00:24:46,520 --> 00:24:48,080 RECEPTORS WILL COME TOGETHER AND 625 00:24:48,080 --> 00:24:50,520 IT'S ESSENTIAL FOR HEPCIDIN 626 00:24:50,520 --> 00:24:50,800 PRODUCTION. 627 00:24:50,800 --> 00:24:54,160 SO THEN TO SUMMARIZE THE 628 00:24:54,160 --> 00:24:57,360 PATHOGENESIS OF HEMOCHROMATOSIS, 629 00:24:57,360 --> 00:24:59,920 IT IS CAUSED BY MUTATIONS IN 630 00:24:59,920 --> 00:25:04,520 HEPCIDIN REGULATORS OR HEPCIDIN 631 00:25:04,520 --> 00:25:06,520 ITSELF LEADING TO HEPCIDIN 632 00:25:06,520 --> 00:25:06,920 DEFICIENCY. 633 00:25:06,920 --> 00:25:09,960 THERE IS A VARIETY OF DEGREES OF 634 00:25:09,960 --> 00:25:10,400 HEPCIDIN DEFICIENCY. 635 00:25:10,400 --> 00:25:12,400 THERE IS ABSOLUTE OR RELATIVE 636 00:25:12,400 --> 00:25:13,600 HEPCIDIN DEFICIENCY, AND THE 637 00:25:13,600 --> 00:25:15,320 SEVERITY OF DISEASE WILL DEPEND 638 00:25:15,320 --> 00:25:16,880 ON THE SEVERITY OF HEPCIDIN 639 00:25:16,880 --> 00:25:22,240 DEFICIENCY. 640 00:25:22,240 --> 00:25:23,720 AND THAT UNLEASHES IRON FLOWS 641 00:25:23,720 --> 00:25:24,320 INTO PLASMA. 642 00:25:24,320 --> 00:25:25,720 I DIDN'T MENTION BUT AS YOU CAN 643 00:25:25,720 --> 00:25:28,120 EXPECT, THERE CAN ALSO BE A FORM 644 00:25:28,120 --> 00:25:29,320 OF HEMOCHROMATOSIS RESULTING 645 00:25:29,320 --> 00:25:31,920 FROM MUTATIONS IN HEPCIDIN 646 00:25:31,920 --> 00:25:33,600 RECEPTOR, SO THIS IS A RARE FORM 647 00:25:33,600 --> 00:25:35,000 OF HEMOCHROMATOSIS, AND THE GAIN 648 00:25:35,000 --> 00:25:37,080 OF FUNCTION MUTATIONS IN 649 00:25:37,080 --> 00:25:38,560 FERROPORTIN THAT RESULT IN 650 00:25:38,560 --> 00:25:40,240 RESISTANCE TO HEPCIDIN. 651 00:25:40,240 --> 00:25:43,960 SO AGAIN, YOU CAN THINK OF THIS 652 00:25:43,960 --> 00:25:46,840 AS AN EQUIVALENCE TO INSULIN AND 653 00:25:46,840 --> 00:25:47,920 GLUCOSE SYSTEM, WHERE YOU CAN 654 00:25:47,920 --> 00:25:50,480 HAVE INSULIN RESISTANCE OR 655 00:25:50,480 --> 00:25:53,760 INSULIN DEFICIENCY RESULTING IN 656 00:25:53,760 --> 00:25:54,200 DIABETES. 657 00:25:54,200 --> 00:25:56,280 IT IS THE SAME THING IN HEMOCROW 658 00:25:56,280 --> 00:25:58,560 SEW CYST, HEPCIDIN DEFICIENCY OR 659 00:25:58,560 --> 00:26:00,320 RESISTANCE TO HEPCIDIN THAT 660 00:26:00,320 --> 00:26:01,320 RESULTS IN HEMOCHROMATOSIS. 661 00:26:01,320 --> 00:26:04,920 SO THE MAJORITY OF FORMS ARE 662 00:26:04,920 --> 00:26:08,960 HELP SIGH 663 00:26:08,960 --> 00:26:12,200 HEPCIDIN-DEFICIENT FORM, 664 00:26:12,200 --> 00:26:12,920 CONSTANTLY INCREASED -- WHICH 665 00:26:12,920 --> 00:26:15,080 WILL LEAD TO TOTAL BODY ON 666 00:26:15,080 --> 00:26:15,640 OVERLOAD. 667 00:26:15,640 --> 00:26:18,360 THERE IS SATURATION OF IRON PLAS 668 00:26:18,360 --> 00:26:23,720 FER F. -- 669 00:26:23,720 --> 00:26:26,120 WILL LOAD THE LIVER, THE HEART 670 00:26:26,120 --> 00:26:28,720 AND -- ET CETERA. 671 00:26:28,720 --> 00:26:30,520 AND SO AS YOU CAN APPRECIATE 672 00:26:30,520 --> 00:26:34,000 THEN, HEPCIDIN ITSELF COULD BE 673 00:26:34,000 --> 00:26:36,840 USEFUL AS THERAPY IN 674 00:26:36,840 --> 00:26:38,040 HEMOCHROMATOSIS SIMILAR TO HOW 675 00:26:38,040 --> 00:26:40,920 INSULIN IS USED FOR DIABETES. 676 00:26:40,920 --> 00:26:42,640 SO THAT WAS THE DISCUSSION ABOUT 677 00:26:42,640 --> 00:26:44,400 HEPCIDIN REGULATION BY IRON. 678 00:26:44,400 --> 00:26:44,800 AND 679 00:26:44,800 --> 00:26:45,800 WHAT GOES WRONG IN THAT 680 00:26:45,800 --> 00:26:46,320 CIRCUITRY. 681 00:26:46,320 --> 00:26:48,000 NOW I'M GOING TO TALK ABOUT HELP 682 00:26:48,000 --> 00:26:50,600 SIGH DIN REGULATION BY 683 00:26:50,600 --> 00:26:52,600 ERYTHROPOIESIS AND DISEASES 684 00:26:52,600 --> 00:26:58,440 ASSOCIATED WITH THAT CIRCUITRY. 685 00:26:58,440 --> 00:26:59,680 ERYTHROPOIESIS ITSELF IS AN 686 00:26:59,680 --> 00:27:00,400 INCREDIBLY INTENSE PROCESS. 687 00:27:00,400 --> 00:27:02,360 IF YOU LOOK AT THE SHEER NUMBER 688 00:27:02,360 --> 00:27:11,120 OF EE RIRT ROW SITINGS -- WE MAKE APPROXI MATELY 689 00:27:11,120 --> 00:27:12,120 2.5 MILLION ERYTHROCYTES PER 690 00:27:12,120 --> 00:27:13,640 SECOND, AND EACH OF THOSE NEEDS 691 00:27:13,640 --> 00:27:16,040 OVER A BILLION ATOMS OF IRON TO 692 00:27:16,040 --> 00:27:17,040 SYNTHESIZE HEMOGLOBIN. 693 00:27:17,040 --> 00:27:18,920 SO INCREDIBLY INTENSE PROCESS, 694 00:27:18,920 --> 00:27:21,080 AND YOU CAN APPRECIATE THAT IRON 695 00:27:21,080 --> 00:27:26,760 SUPPLY HAS TO BE COORDINATED 696 00:27:26,760 --> 00:27:28,120 WITH -- ACTIVITIMENT SO FOR THE 697 00:27:28,120 --> 00:27:29,920 LAST 50 YEARS, IT HAS BEEN 698 00:27:29,920 --> 00:27:31,560 ASSUMED AND ALSO DEMONSTRATED 699 00:27:31,560 --> 00:27:37,360 INDIRECTLY THAT THERE IS -- BUT 700 00:27:37,360 --> 00:27:40,120 WE HAVE RECENTLY DISCOVERED THE 701 00:27:40,120 --> 00:27:42,080 REGULATOR OR A REGULATOR THAT 702 00:27:42,080 --> 00:27:44,800 ENABLES COMMUNICATION BETWEEN 703 00:27:44,800 --> 00:27:46,120 ERYTHROPOETIC ACTIVITY IN IRON. 704 00:27:46,120 --> 00:27:47,880 PART OF THAT OF COURSE IS 705 00:27:47,880 --> 00:27:50,240 REGULATION OF HEPCIDIN, SO 706 00:27:50,240 --> 00:27:52,200 HEPCIDIN HAS TO BE SUPPRESSED TO 707 00:27:52,200 --> 00:27:53,920 ALLOW MORE IRON TO BE AVAILABLE. 708 00:27:53,920 --> 00:27:57,600 SO YOU CAN SEE HERE AFTER 709 00:27:57,600 --> 00:27:59,720 PHLEBOTOMY OR EPO 710 00:27:59,720 --> 00:28:02,040 ADMINISTRATION, HEPCIDIN IS 711 00:28:02,040 --> 00:28:02,800 PROFOUNDLY SUPPRESSED RAPIDLY, 712 00:28:02,800 --> 00:28:03,680 SO MORE THAN TENFOLD. 713 00:28:03,680 --> 00:28:06,160 WHAT WE WANTED TO DO WAS TO 714 00:28:06,160 --> 00:28:11,200 IDENTIFY A FACTOR THAT WOULD 715 00:28:11,200 --> 00:28:12,640 HAVE THE -- WE ANALYZED BONE 716 00:28:12,640 --> 00:28:15,560 MARROW IN THE MICE WHERE THIS 717 00:28:15,560 --> 00:28:16,800 ADVANCED ACTIVITY IS OCCURRING 718 00:28:16,800 --> 00:28:18,920 AND LOOK FOR SECRETED PROTEINS 719 00:28:18,920 --> 00:28:21,520 THAT WILL HAVE PROFILES -- 720 00:28:21,520 --> 00:28:22,800 EXPRESSION PROFILES OPPOSITE OF 721 00:28:22,800 --> 00:28:24,960 WHAT HAPPENS TO HEPCIDIN. 722 00:28:24,960 --> 00:28:27,360 AND SURPRISINGLY, WE IDENTIFIED 723 00:28:27,360 --> 00:28:29,720 ONLY ONE SECRETED PROTEIN THAT 724 00:28:29,720 --> 00:28:31,760 FITS THIS DESCRIPTION, THIS 725 00:28:31,760 --> 00:28:33,720 IDEA, AND WE EVENTUALLY NAMED IT 726 00:28:33,720 --> 00:28:39,960 EE RIR ROW FAIR ON, BECAUSE IT'S 727 00:28:39,960 --> 00:28:42,920 PRODUCED BY ERYTHROBLASTS, FERR 728 00:28:42,920 --> 00:28:44,680 IS BECAUSE IT REGULATES IRON, 729 00:28:44,680 --> 00:28:46,920 AND ONE BECAUSE IT'S A HORMONE. 730 00:28:46,920 --> 00:28:56,120 SO WE CALL IT FOR SHORT -- IT'S 731 00:28:56,120 --> 00:29:00,480 A MEMBER OF THIS LARGER GROUP OF 732 00:29:00,480 --> 00:29:02,880 TNF-LIKE PROTEINS THAT'S ALSO A 733 00:29:02,880 --> 00:29:03,120 MEMBER. 734 00:29:03,120 --> 00:29:04,720 WE STILL DON'T UNDERSTAND THE 735 00:29:04,720 --> 00:29:06,360 COMPONENTS OF THE STRUCTURE THAT 736 00:29:06,360 --> 00:29:08,120 ARE IMPORTANT FOR ITS ACTIVITY 737 00:29:08,120 --> 00:29:10,520 BUT WE DO KNOW THAT IT IS A 738 00:29:10,520 --> 00:29:11,160 STRESS HORMONE. 739 00:29:11,160 --> 00:29:15,440 ITS EXPRESS IS VERY LOW AT LACE 740 00:29:15,440 --> 00:29:17,720 LINE BUT AFTER EE POE INJECTION, 741 00:29:17,720 --> 00:29:19,040 THERE'S A HUGE INCREASE IN PRO 742 00:29:19,040 --> 00:29:22,120 TUCKS OF ERYTHROFERRONE. 743 00:29:22,120 --> 00:29:24,400 WHAT IT DOES IS ENABLE HEPCIDIN 744 00:29:24,400 --> 00:29:25,720 SUPPRESSION. 745 00:29:25,720 --> 00:29:28,240 SO HERE'S WILD TYPE MICE AFTER 746 00:29:28,240 --> 00:29:29,440 PHLEBOTOMY, YOU CAN SEE THERE'S 747 00:29:29,440 --> 00:29:31,680 A HUGE SUPPRESSION OF HEPCIDIN, 748 00:29:31,680 --> 00:29:37,400 MORE THAN TENFOLD, BUT SO THE 749 00:29:37,400 --> 00:29:39,320 CONSEQUENCE OF THIS AS FAR AS WE 750 00:29:39,320 --> 00:29:45,600 KNOW SO FAR IS THAT IF -- THERE 751 00:29:45,600 --> 00:29:48,440 IS NO HEPCIDIN REPRESSION AND 752 00:29:48,440 --> 00:29:49,760 DELAYED RECOVERY OF ANEMIA. 753 00:29:49,760 --> 00:29:52,160 THERE ARE OTHER WAYS FOR AN 754 00:29:52,160 --> 00:29:53,800 ORGANISM TO RECOVER FROM ANEMIA, 755 00:29:53,800 --> 00:29:57,120 SO EVENTUALLY THIS IMPAIRMENT IS 756 00:29:57,120 --> 00:29:59,400 OVERCOME BUT THERE'S CERTAINLY A 757 00:29:59,400 --> 00:30:00,440 DELAYED RECOVERY. 758 00:30:00,440 --> 00:30:04,400 SO THIS WAS PROBABLY TO ENABLE 759 00:30:04,400 --> 00:30:11,640 RAPID RECOVERY IN NOW, HOW DOES 760 00:30:11,640 --> 00:30:12,080 ERFE ACT? 761 00:30:12,080 --> 00:30:18,880 AGAIN IT TARGETS THIS PATHWAY, 762 00:30:18,880 --> 00:30:22,560 SO ERFE IS ACTUALLY A TRAP FOR 763 00:30:22,560 --> 00:30:25,400 BMPs, PARTICULARLY FOR 2 AND 6 BUT IT CAN ALSO BIND SOME 764 00:30:25,400 --> 00:30:26,720 OTHER BMPs. 765 00:30:26,720 --> 00:30:31,000 SO ONCE ERFE TRACKS THESE 766 00:30:31,000 --> 00:30:33,280 BMPs, SMAD PHOSPHORYLATION IS 767 00:30:33,280 --> 00:30:35,040 DECREASED AND TRANSCRIPTION IS 768 00:30:35,040 --> 00:30:35,920 SUPPRESSED. 769 00:30:35,920 --> 00:30:41,840 THAT IS THE WAY IT POTENTLY -- 770 00:30:41,840 --> 00:30:46,400 SO PHYSIOLOGICAL ROLE OF -- IS 771 00:30:46,400 --> 00:30:47,920 TO ENABLE MORE IRON TO REACH THE 772 00:30:47,920 --> 00:30:48,840 BONE MARROW AND IT'S PART OF 773 00:30:48,840 --> 00:30:50,960 THIS NOW AS WE UNDERSTAND 774 00:30:50,960 --> 00:30:52,080 THREE-HORMONE CIRCUITRY TO 775 00:30:52,080 --> 00:30:55,040 RESPOND TO ANEMIA, OR AFTER 776 00:30:55,040 --> 00:30:55,480 HEMORRHAGE. 777 00:30:55,480 --> 00:31:00,480 SO IF THERE IS ANEMIA OR HIGH 778 00:31:00,480 --> 00:31:03,080 POX YAM. 779 00:31:03,080 --> 00:31:09,320 EPO IS THE THE MAIN STIMULUS 780 00:31:09,320 --> 00:31:11,640 FOR -- IN THE LIVER TO DECREASE 781 00:31:11,640 --> 00:31:13,360 HEPCIDIN PRODUCTION, AND THEN IN 782 00:31:13,360 --> 00:31:16,400 TURN, ENABLES MORE IRON TO BE 783 00:31:16,400 --> 00:31:20,520 AVAILABLE FOR ERYTHROPOIESIS. 784 00:31:20,520 --> 00:31:23,240 TO ENSURE THAT BONE MARROW IS 785 00:31:23,240 --> 00:31:24,440 GOING TO GET A SUFFICIENT AMOUNT 786 00:31:24,440 --> 00:31:26,240 OF IRON. 787 00:31:26,240 --> 00:31:27,920 BUT THERE IS THE DARK SIDE TO 788 00:31:27,920 --> 00:31:29,920 THIS CIRCUITRY AS WELL, AND THAT 789 00:31:29,920 --> 00:31:35,440 HAPPENS IN HEMOTBLOA HEMOGLOBINOPATHIES. 790 00:31:35,440 --> 00:31:35,920 HERE'S, FOR EXAMPLE, A 791 00:31:35,920 --> 00:31:37,880 PRESENTATION OF A PATIENT THAT 792 00:31:37,880 --> 00:31:41,160 WAS IRON OVERLOADED BUT EVEN 793 00:31:41,160 --> 00:31:42,800 WITHOUT TRANSFUSIONS, SO IT WAS 794 00:31:42,800 --> 00:31:43,760 A 61-YEAR-OLD MAN. 795 00:31:43,760 --> 00:31:46,640 HE HAD A DIAGNOSIS OF BETA 796 00:31:46,640 --> 00:31:49,000 THALASSEMIA, BUT HE HAD THIS 797 00:31:49,000 --> 00:31:54,360 MILD ELEVATION OF SERUM 798 00:31:54,360 --> 00:31:55,480 TRANSAMINASES, BUT 799 00:31:55,480 --> 00:31:57,520 INTERESTINGLY, WAS NOT 800 00:31:57,520 --> 00:32:00,120 TRANSFUSED MUCH AT ALL, ONLY 801 00:32:00,120 --> 00:32:01,760 3 UNITS OF PACKED RED BLOOD 802 00:32:01,760 --> 00:32:04,400 CELLS, AND HE WAS MAINTAINING 803 00:32:04,400 --> 00:32:06,520 HEMOGLOBIN IN A RANGE OF CLOSE 804 00:32:06,520 --> 00:32:09,520 TO 10, BUT HE ACTUALLY WAS 805 00:32:09,520 --> 00:32:12,400 IRON-OVERLOADED, HE HAD AN 806 00:32:12,400 --> 00:32:15,680 ENLARGED LIVER, MRI SHOWED A 807 00:32:15,680 --> 00:32:17,440 HIGH AMOUNT IN HIS LIVER AND HE 808 00:32:17,440 --> 00:32:19,280 HAD NO OTHER CONFOUNDING FACTORS 809 00:32:19,280 --> 00:32:21,480 THAT COULD EXPLAIN THIS IRON 810 00:32:21,480 --> 00:32:21,760 OVERLOAD. 811 00:32:21,760 --> 00:32:26,400 SO THESE PATIENTS, PATIENTS WITH 812 00:32:26,400 --> 00:32:28,320 ANEMIA, SUCH AS BETA 813 00:32:28,320 --> 00:32:29,480 THALASSEMIA, THEY DO DEVELOP 814 00:32:29,480 --> 00:32:31,400 IRON OVERLOAD EVEN WHEN NOT 815 00:32:31,400 --> 00:32:33,080 TRANSFUSED, BUT IF THEY'RE 816 00:32:33,080 --> 00:32:35,280 TRANSFUSED, IRON OVERLOAD 817 00:32:35,280 --> 00:32:35,800 WORSENS EVEN MORE. 818 00:32:35,800 --> 00:32:39,640 SO DISEASES IN THIS CATEGORY 819 00:32:39,640 --> 00:32:42,800 ANEMIA FROM INEFFECTIVE 820 00:32:42,800 --> 00:32:46,320 ERYTHROPOIESIS ARE THALASSEMIA, 821 00:32:46,320 --> 00:32:47,160 THE ONE THAT THE PATIENT HAD, 822 00:32:47,160 --> 00:32:49,320 BUT THERE'S ALSO BETA 823 00:32:49,320 --> 00:32:52,040 THALASSEMIA MAJOR OR TRANSFUSION 824 00:32:52,040 --> 00:32:57,280 DEPENDENT BAY THAT THALASSEMIA. 825 00:32:57,280 --> 00:33:02,000 OTHERS OTHER REALLY, THEY ALL 826 00:33:02,000 --> 00:33:04,120 HYPERABSORB IRON IF THEY'RE NOT 827 00:33:04,120 --> 00:33:05,280 TRANSFUSED, AND THEIR 828 00:33:05,280 --> 00:33:08,400 PATHOGENESIS OF IRON OVERLOAD 829 00:33:08,400 --> 00:33:10,640 PHENOCOPIES THAT HE HEREDITARY -- 830 00:33:10,640 --> 00:33:12,520 AND WE CALL THEM IRON LOADING 831 00:33:12,520 --> 00:33:12,920 ANEMIAS. 832 00:33:12,920 --> 00:33:14,920 THERE IS SUPPRESSION OF 833 00:33:14,920 --> 00:33:16,640 HEPCIDIN, SO HEPCIDIN IS 834 00:33:16,640 --> 00:33:18,280 RELATIVELY LOW CONSIDER THE 835 00:33:18,280 --> 00:33:21,760 SEVERITY OF IRON OVERLOAD, AND 836 00:33:21,760 --> 00:33:23,400 HEPCIDIN IS LOW BECAUSE OF 837 00:33:23,400 --> 00:33:27,560 OVERPRODUCTION OF EE RIRT ROE 838 00:33:27,560 --> 00:33:31,200 FERRONE, BY EXUBERANTLY 839 00:33:31,200 --> 00:33:32,640 PROLIFERATING ERYTHROBLASTS AND 840 00:33:32,640 --> 00:33:40,160 THAT IN TERMS -- YOUR HEALTHY 841 00:33:40,160 --> 00:33:45,480 SUBJECTS HAVE VERY LOW LEVELS 842 00:33:45,480 --> 00:33:46,840 OF -- THALASSEMIA HAS MUCH 843 00:33:46,840 --> 00:33:53,600 HIGHER LEVELS OF EE ERYTHROFERRONE. 844 00:33:53,600 --> 00:33:55,120 RIGHT BEFORE THE TRANSFUSION 845 00:33:55,120 --> 00:33:56,080 CYCLE, THERE IS A MUCH HIGHER 846 00:33:56,080 --> 00:34:01,720 CYCLE OF ERYTHROFERRON,, BUT 847 00:34:01,720 --> 00:34:06,920 THEN TRANS FUSIONS WRM -- 848 00:34:06,920 --> 00:34:07,680 ERYTHROPOIESIS CAN SUPPRESS IT. 849 00:34:07,680 --> 00:34:11,160 YOU CAN ALSO SEE -- WHEN 850 00:34:11,160 --> 00:34:13,240 ERYTHROFAIRN IS HIGH, HEPCIDIN 851 00:34:13,240 --> 00:34:15,640 WILL BE PROFOUNDLY SUPPRESSED. 852 00:34:15,640 --> 00:34:17,160 SO THE WAY WE NOW UNDERSTAND 853 00:34:17,160 --> 00:34:19,920 PATHOGENESIS OF IRON LOADING IN 854 00:34:19,920 --> 00:34:22,960 THESE ANEMIAS IS THAT THERE IS 855 00:34:22,960 --> 00:34:25,160 HIGH LEVEL OF EPO IN THESE 856 00:34:25,160 --> 00:34:27,320 CONDITIONS WHICH STIMULATES THE 857 00:34:27,320 --> 00:34:28,640 BONE MARROW, EXPANDS THE NUMBER 858 00:34:28,640 --> 00:34:31,120 OF ERYTHROID PRECURSORS, AND 859 00:34:31,120 --> 00:34:34,240 THEY PRODUCE VERY LARGE AMOUNT 860 00:34:34,240 --> 00:34:36,400 OF ERYTHROFAIR OWN, HORMONE, 861 00:34:36,400 --> 00:34:38,520 WHICH CAUSES HEPCIDIN 862 00:34:38,520 --> 00:34:41,480 SUPPRESSION AND RELATIVE 863 00:34:41,480 --> 00:34:43,120 HEPCIDIN DEFICIENCY, AND NOW IT 864 00:34:43,120 --> 00:34:45,400 LOOKS THE SAME AS FOR 865 00:34:45,400 --> 00:34:45,760 HEMOCHROMATOSIS. 866 00:34:45,760 --> 00:34:52,440 THERE IS EXCESSIVE IRON FLOWS, 867 00:34:52,440 --> 00:34:54,800 TRANS FERRIN GETS SATURATED, 868 00:34:54,800 --> 00:34:58,600 NON- -- APPEARS AND THAT LOADS 869 00:34:58,600 --> 00:35:02,440 LIVER, HEART AND THEN THE 870 00:35:02,440 --> 00:35:06,560 PREGLANDS. 871 00:35:06,560 --> 00:35:07,920 IT HAS BEEN SPECULATED NOW BEING 872 00:35:07,920 --> 00:35:09,000 TRIED WHETHER WE CAN USE 873 00:35:09,000 --> 00:35:11,720 HEPCIDIN AGONISTS TO CORRECT 874 00:35:11,720 --> 00:35:13,360 THIS EFFICIENCY AND PREVENT IRON 875 00:35:13,360 --> 00:35:15,240 OVERLOAD OR POTENTIALLY USE ER 876 00:35:15,240 --> 00:35:17,200 IF E ANTAGONISTS, WHETHER THAT 877 00:35:17,200 --> 00:35:20,720 COULD SER SERVE AS USEFUL THERAPY TO 878 00:35:20,720 --> 00:35:24,720 PREVENT AN OVERLOAD. 879 00:35:24,720 --> 00:35:25,840 THE LAST CIRCUITRY I WILL TALK 880 00:35:25,840 --> 00:35:29,320 ABOUT IS HELP SEIDEN REGULATION 881 00:35:29,320 --> 00:35:29,920 BY INFLAMMATION. 882 00:35:29,920 --> 00:35:32,920 THIS IS VERY IMPORTANT FOR HOST 883 00:35:32,920 --> 00:35:33,280 DEFENSE. 884 00:35:33,280 --> 00:35:36,800 EARLY ON WE NOTICED IT IS 885 00:35:36,800 --> 00:35:38,120 DRAMATICALLY -- HE WAS A SUBJECT 886 00:35:38,120 --> 00:35:42,360 THAT HAD -- AND SEPSIS, MORE 887 00:35:42,360 --> 00:35:43,920 THAN 100 FOLD ELEVATED, AND AS 888 00:35:43,920 --> 00:35:45,760 THE PATIENT WAS TREATED WITH 889 00:35:45,760 --> 00:35:46,720 ANTIBIOTICS, HEPCIDIN WENT DOWN 890 00:35:46,720 --> 00:35:50,120 TO THE NORMAL RANGE. 891 00:35:50,120 --> 00:35:51,400 WE CAN MODEL THIS IN MICE AS 892 00:35:51,400 --> 00:35:52,720 WELL, AND WE HAVE SHOWN USING 893 00:35:52,720 --> 00:35:54,240 MOUSE MODELS THAT INTERLEUKIN 894 00:35:54,240 --> 00:35:56,480 6 IS THE CRITICAL MEDIATOR OF 895 00:35:56,480 --> 00:35:59,720 THIS HEPCIDIN REGULATION BY 896 00:35:59,720 --> 00:36:03,240 INFLAMMATION, SO IT'S REALLY A 897 00:36:03,240 --> 00:36:04,440 TYPE 2 PHASE REACTANT. 898 00:36:04,440 --> 00:36:07,160 HERE'S AN EXAMPLE OF A BACTERIAL 899 00:36:07,160 --> 00:36:07,440 INFECTION. 900 00:36:07,440 --> 00:36:08,800 WHEN WE LOOK AT WILD TYPE MICE, 901 00:36:08,800 --> 00:36:12,080 THERE IS SEVERAL THOUSAND FOLD 902 00:36:12,080 --> 00:36:17,440 INCREASE OF HEPCIDIN PRODUCTION 903 00:36:17,440 --> 00:36:19,400 BUT NOT -- FOR THIS RESPONSE. 904 00:36:19,400 --> 00:36:22,120 AND IT HAS BEEN SPECULATED ALSO 905 00:36:22,120 --> 00:36:23,880 ALL ALONG THAT IN WOULD BE 906 00:36:23,880 --> 00:36:25,720 IMPORTANT FOR INNATE IMMUNITY, 907 00:36:25,720 --> 00:36:30,320 AND THEY HAD -- INFECTION PREND, 908 00:36:30,320 --> 00:36:34,280 THAT WOULD INCREASE HEPCIDIN, 909 00:36:34,280 --> 00:36:36,200 HELP SIGH BIN AGAINST 910 00:36:36,200 --> 00:36:38,080 EXTRACELLULAR INFECTIONS BY 911 00:36:38,080 --> 00:36:39,080 LIMITING EXTRACELLULAR IRON 912 00:36:39,080 --> 00:36:40,840 AVAILABILITY AND THAT COULD BE 913 00:36:40,840 --> 00:36:43,560 PACK TIER YOE STATIC POTENTIALLY 914 00:36:43,560 --> 00:36:45,320 AND ALLOW THE REST OF THE IMMUNE 915 00:36:45,320 --> 00:36:46,840 SYSTEM TO GET RID OF THE 916 00:36:46,840 --> 00:36:47,920 PATHOGENS. 917 00:36:47,920 --> 00:36:50,520 BUT AT THE SAME TIME, ONE COULD 918 00:36:50,520 --> 00:36:54,440 SPECULATE THAT -- COULD 919 00:36:54,440 --> 00:36:55,960 POTENTIALLY PROMOTE 920 00:36:55,960 --> 00:36:56,840 INTERCELLULAR INFECTIONS WHICH 921 00:36:56,840 --> 00:37:00,000 ARE COUNTERPRODUCTIVE, SO BY 922 00:37:00,000 --> 00:37:02,880 TARGETING FERROPORTIN -- 923 00:37:02,880 --> 00:37:05,320 THEORETICALLY HIGH HEPCIDIN 924 00:37:05,320 --> 00:37:11,720 COULD POTENTIATE GROWTH OF -- 925 00:37:11,720 --> 00:37:13,320 ORGANISMS. 926 00:37:13,320 --> 00:37:16,840 THE ROLE IN INNATE HI MEUD IT. 927 00:37:16,840 --> 00:37:21,120 WE DECIDED TO -- LOOKED AT THE 928 00:37:21,120 --> 00:37:22,800 SPECTRUM OF PATHOGENS SO WE 929 00:37:22,800 --> 00:37:32,440 LOOKED AT SOME CLASSICALLY 930 00:37:32,440 --> 00:37:34,120 SIDEROPHILIC WHICH ARE KNOWN PO 931 00:37:34,120 --> 00:37:36,120 EXPERIENCE IN OUR OVERLOADED 932 00:37:36,120 --> 00:37:37,840 PATIENTS. 933 00:37:37,840 --> 00:37:44,080 OVERLOADED, YOU CAN LOOK AT -- 934 00:37:44,080 --> 00:37:46,120 I'M JUST GOING TO BRIEFLY 935 00:37:46,120 --> 00:37:47,720 SUMMARIZE, THERE WAS NO EFFECT 936 00:37:47,720 --> 00:37:52,600 ON GRAM POSITIVE STEF LOW COCCUS 937 00:37:52,600 --> 00:37:57,520 AUREUS OR MICRO BACK HERE YA 938 00:37:57,520 --> 00:37:59,520 AND -- THAT IS NOT TO SAY THAT 939 00:37:59,520 --> 00:38:01,760 THESE PATHOGENS DON'T NEED IRON. 940 00:38:01,760 --> 00:38:04,640 ALL OF THE BACK FEAR YA USES 941 00:38:04,640 --> 00:38:05,280 IRON, ET CETERA. 942 00:38:05,280 --> 00:38:08,480 IT IS JUST THAT THE HOST 943 00:38:08,480 --> 00:38:09,640 MANIPULATION -- LEVELS DO NOT 944 00:38:09,640 --> 00:38:11,120 AFFECT THE VIRULENCE OF THESE 945 00:38:11,120 --> 00:38:14,720 BACTERIA. 946 00:38:14,720 --> 00:38:16,240 BUT, HEPCIDIN AND IRON VARIATION 947 00:38:16,240 --> 00:38:18,880 VERY MUCH AFFECTED THE VIRULENCE 948 00:38:18,880 --> 00:38:20,720 GROWTH OF GRAM-NEGATIVE 949 00:38:20,720 --> 00:38:24,400 ORGANISMS AS WELL AS THE 950 00:38:24,400 --> 00:38:26,880 SIDEROPHIRIC ONES WHICH ARE ALSO 951 00:38:26,880 --> 00:38:27,400 GRAM-NEGATIVE. 952 00:38:27,400 --> 00:38:31,560 SO WE ACTUALLY -- NATURALLY 953 00:38:31,560 --> 00:38:33,000 UNLOADED AND WE LOOKED AT SIR 954 00:38:33,000 --> 00:38:35,520 VIAL, AND REALLY THE DIFFERENCE 955 00:38:35,520 --> 00:38:36,920 WAS DRAMATIC. 956 00:38:36,920 --> 00:38:38,000 AS BIG A DIFFERENCE IN SURVIVAL 957 00:38:38,000 --> 00:38:39,120 AS WE HAVE SEEN. 958 00:38:39,120 --> 00:38:41,400 ALL OF THE WILD TYPE MICE IN 959 00:38:41,400 --> 00:38:50,000 THESE MODELS, E. COLI, THEY ALL 960 00:38:50,000 --> 00:39:01,200 FAIR BETTER, HAD MUCH -- THE 961 00:39:01,200 --> 00:39:02,320 DEATH WAS EXTREMELY RAPID, 962 00:39:02,320 --> 00:39:03,440 WITHIN HALF A DAY. 963 00:39:03,440 --> 00:39:05,640 THIS BACK TIER YON REPLICATED 964 00:39:05,640 --> 00:39:06,840 EVERY 10 MINUTES IN THE PRESENCE 965 00:39:06,840 --> 00:39:08,480 OF EXCESS IRON. 966 00:39:08,480 --> 00:39:12,720 SO FROM THIS PERSPECTIVE, EVEN 967 00:39:12,720 --> 00:39:15,760 E. COLI AND KLEBSIELLA COULD BE 968 00:39:15,760 --> 00:39:22,560 CONSIDERED SIDERO -- AND IN ALL 969 00:39:22,560 --> 00:39:25,800 OF THESE INFECTIONS, 970 00:39:25,800 --> 00:39:26,520 TREATMENT -- AGONISTS COMPLETELY 971 00:39:26,520 --> 00:39:28,120 RESCUED MICE FROM MORTALITY. 972 00:39:28,120 --> 00:39:30,880 SO IT IS ALL ABOUT EXTRACELLULAR 973 00:39:30,880 --> 00:39:33,160 IRON AVAILABILITY THAT PROMOTES 974 00:39:33,160 --> 00:39:35,080 RAPID GROWTH IN THESE PACKAGES. 975 00:39:35,080 --> 00:39:37,760 AND THIS IS CONSISTENT WITH 976 00:39:37,760 --> 00:39:38,760 CLINICAL OBSERVATIONS, SO HERE 977 00:39:38,760 --> 00:39:41,280 IS AN EXAMPLE, A CASE REPORT OF 978 00:39:41,280 --> 00:39:42,760 PREVIOUSLY HEALTHY 59-YEAR-OLD 979 00:39:42,760 --> 00:39:45,520 WOMAN. 980 00:39:45,520 --> 00:39:47,720 SHE ATE RAW SEAFOOD AT A 981 00:39:47,720 --> 00:39:48,440 RESTAURANT. 982 00:39:48,440 --> 00:39:49,520 AND THEN SHE DEVELOPED 983 00:39:49,520 --> 00:39:49,800 INFECTION. 984 00:39:49,800 --> 00:39:53,720 SHE WAS HOSPITALIZED, LEG WAS 985 00:39:53,720 --> 00:39:54,640 AMPUTATED, SHE REQUIRED 986 00:39:54,640 --> 00:39:55,840 OPERATIONS TO SAVE HER ARM. 987 00:39:55,840 --> 00:39:58,040 YOU ACTUALLY HEAR THESE 988 00:39:58,040 --> 00:39:59,320 ANECDOTAL STORIES ABOUT PEOPLE 989 00:39:59,320 --> 00:40:01,720 WHO ATE RAW SEAFOOD AND DIED 990 00:40:01,720 --> 00:40:04,560 RAPIDLY OR WERE FISHING OR 991 00:40:04,560 --> 00:40:06,680 CRABBING AND THEN GOT SCRATCHED, 992 00:40:06,680 --> 00:40:09,400 DEVELOPED A SEVERE INFECTION OR 993 00:40:09,400 --> 00:40:11,360 HAD TATTOOS AND WENT SWIMMING 994 00:40:11,360 --> 00:40:16,400 AND DEVELOPED SEVERE INFECTION. 995 00:40:16,400 --> 00:40:17,520 IN THOSE DRAMATIC CASES AS WELL 996 00:40:17,520 --> 00:40:21,320 AS IN THIS CASE, PATIENTS ARE 997 00:40:21,320 --> 00:40:26,920 INFECTED WITH VIBRIO VULNIFICUS, 998 00:40:26,920 --> 00:40:29,360 PRESENT IN WARM COASTAL WATERS 999 00:40:29,360 --> 00:40:32,120 AND IS PRESENT IN RAW SEAFOOD. 1000 00:40:32,120 --> 00:40:39,560 THIS PATIENT UNBEKNOWNSTED TO 1001 00:40:39,560 --> 00:40:46,840 HER HAD HEMOCHROMATOSIS, AND 1002 00:40:46,840 --> 00:40:49,760 THIS BE UNFORTUNATELY HAS VERY 1003 00:40:49,760 --> 00:40:50,480 HIGH MORTALITY. 1004 00:40:50,480 --> 00:40:52,680 NOW WHAT IS THE MECHANISM BY 1005 00:40:52,680 --> 00:40:55,800 WHICH HEPCIDIN PROTECTS AGAINST 1006 00:40:55,800 --> 00:40:56,080 INFECTION? 1007 00:40:56,080 --> 00:40:57,160 WE HAVE LOOKED AT MULTIPLE 1008 00:40:57,160 --> 00:40:58,680 POINTS, WE WANTED TO SEE IF IT 1009 00:40:58,680 --> 00:41:03,640 AFFECTS INITIALLY INNATE IMMUNE 1010 00:41:03,640 --> 00:41:04,920 RESPONSE, HEPCIDIN DID NOT 1011 00:41:04,920 --> 00:41:05,320 AFFECT THAT. 1012 00:41:05,320 --> 00:41:08,520 IT DID NOT EXERT DIRECT 1013 00:41:08,520 --> 00:41:09,640 ANTIMICROBIAL ACTIVITY EITHER 1014 00:41:09,640 --> 00:41:11,680 AND IT PURELY FUNCTIONS BY 1015 00:41:11,680 --> 00:41:12,800 CONTROLLING IERNL CONCENTRATIONS 1016 00:41:12,800 --> 00:41:13,240 IN CIRCULATION. 1017 00:41:13,240 --> 00:41:15,600 SO EVEN WHEN WE TAKE HELP SIGH 1018 00:41:15,600 --> 00:41:18,040 DIB KNOCKOUT MICE, IF WE IRON 1019 00:41:18,040 --> 00:41:21,600 DEPLETE THEM, TO PREVENT PREBS 1020 00:41:21,600 --> 00:41:24,480 PRESENCE OF THIS -- IT'S ALL 1021 00:41:24,480 --> 00:41:28,400 ABOUT CIRCULATING IRON IN TBRAM 1022 00:41:28,400 --> 00:41:29,080 GRAM-NEGATIVE INFECTIONS. 1023 00:41:29,080 --> 00:41:30,160 BUT WHAT WAS SURPRISING US IS 1024 00:41:30,160 --> 00:41:32,400 WHY WOULD IT MAKE SUCH A 1025 00:41:32,400 --> 00:41:35,520 DIFFERENCE WHETHER IRON TRANS 1026 00:41:35,520 --> 00:41:38,760 FERRIN LEVELS ARE DIFFERENT? 1027 00:41:38,760 --> 00:41:41,200 IN HEALTHY SUBJECTS, IRON IS 1028 00:41:41,200 --> 00:41:47,640 BOUND TO TRANS FERRIN, IT HAS 1029 00:41:47,640 --> 00:41:49,720 EXTREMELY -- TO MOST MICROBES 1030 00:41:49,720 --> 00:41:54,080 EXCEPT FOR THE ONES THAT 1031 00:41:54,080 --> 00:41:55,520 ACTUALLY HAVE RECEPTORS FOR 1032 00:41:55,520 --> 00:42:01,320 TRANS FAIRN. 1033 00:42:01,320 --> 00:42:03,600 WE KNOW THERE'S 1034 00:42:03,600 --> 00:42:04,200 NON-TRANSFERRIN-BOUND IRON AND 1035 00:42:04,200 --> 00:42:06,760 THAT IRON IS PRESENT WHEN 1036 00:42:06,760 --> 00:42:07,320 TRANSFERRIN IS THE RANGE OF 1037 00:42:07,320 --> 00:42:11,160 MOTION EXCEEDS MAYBE 70 TO 80%. 1038 00:42:11,160 --> 00:42:14,680 HERE ARE A NUMBER OF CONDITIONS, 1039 00:42:14,680 --> 00:42:17,520 WHAT HAPPENS, AFTER TRANSFUSION, 1040 00:42:17,520 --> 00:42:21,760 HEMOLYSIS OR BONE MARROW LESION. 1041 00:42:21,760 --> 00:42:23,720 THIS ONE COULD BE EASILY 1042 00:42:23,720 --> 00:42:25,520 ACCESSIBLE TO MICROBES, SO WE 1043 00:42:25,520 --> 00:42:27,800 WANTED TO SEE WHICH OF THESE 1044 00:42:27,800 --> 00:42:30,520 FORMS ENHANCES GROWTH OF THE 1045 00:42:30,520 --> 00:42:30,760 PATHOGENS. 1046 00:42:30,760 --> 00:42:33,720 AND TURNS OUT IT IS THIS 1047 00:42:33,720 --> 00:42:34,240 NON-TRANSPARENT -- IRON. 1048 00:42:34,240 --> 00:42:36,320 WHEN WE DID EX VIVO EXPERIMENTS 1049 00:42:36,320 --> 00:42:37,880 WHERE WE SUPPLEMENTED HUMAN 1050 00:42:37,880 --> 00:42:38,880 PLASMA WITH INCREASING 1051 00:42:38,880 --> 00:42:42,160 CONCENTRATIONS OF IRON, WE 1052 00:42:42,160 --> 00:42:44,640 MANAGED TO GRADUALLY SATURATE 1053 00:42:44,640 --> 00:42:45,800 TRANSFERRIN, AND THEN WE WOULD 1054 00:42:45,800 --> 00:42:51,480 EITHER NOT HAVE NTBI PRESENT. 1055 00:42:51,480 --> 00:42:54,520 FOR EXAMPLE, WHEN WE LOOKED 1056 00:42:54,520 --> 00:42:57,880 AT -- IN THE ABSENCE OF 1057 00:42:57,880 --> 00:42:59,640 NON-TRANSFERRIN-BOUND IRON, 1058 00:42:59,640 --> 00:43:01,880 THERE'S NO -- REALLY RAPID 1059 00:43:01,880 --> 00:43:03,720 GROWTH BUT NOT -- ON PRESENCE. 1060 00:43:03,720 --> 00:43:05,720 IF WE ADD THE SAME AMOUNT OF 1061 00:43:05,720 --> 00:43:10,400 IRON IN THE FORM OF 1062 00:43:10,400 --> 00:43:11,080 HOLOTRANSFERRIN, IT DOES NOT 1063 00:43:11,080 --> 00:43:15,800 GROW AT ALL. 1064 00:43:15,800 --> 00:43:17,720 SIMILARLY, HERE IS INCREASING 1065 00:43:17,720 --> 00:43:27,840 PLASMA IRON LEVELS BEFORE 1066 00:43:27,840 --> 00:43:30,520 NON-TRANSFERRIN, IT GROWS 1067 00:43:30,520 --> 00:43:34,320 RAPIDLY ONLY IN THE PRESENCE OF 1068 00:43:34,320 --> 00:43:36,400 NON-TRANS FAIRNT -- THE WAY WE 1069 00:43:36,400 --> 00:43:37,920 NOW UNDERSTAND THE FUNCTION OF 1070 00:43:37,920 --> 00:43:39,920 HEPCIDIN IN INNATE IMMUNITY IS 1071 00:43:39,920 --> 00:43:42,200 THAT DURING INFECTION, THERE IS 1072 00:43:42,200 --> 00:43:45,800 INCREASED RISK OF GENERATING 1073 00:43:45,800 --> 00:43:48,400 THIS NON- -- FOR TWO REASONS. 1074 00:43:48,400 --> 00:43:51,920 ONE, MACROPHAGES ARE 1075 00:43:51,920 --> 00:43:56,240 PHAGOCYTOSING ERYTHROCYTES -- SO 1076 00:43:56,240 --> 00:43:58,760 THERE'S POTENTIAL FOR INCREASED 1077 00:43:58,760 --> 00:44:00,640 OUR DELIVERY TO PLASMA FROM 1078 00:44:00,640 --> 00:44:05,000 THESE MACROPHAGES. 1079 00:44:05,000 --> 00:44:10,240 BUTST RESULTING IN BACKING UP OF 1080 00:44:10,240 --> 00:44:14,520 IRON IN PLASMA. 1081 00:44:14,520 --> 00:44:16,440 SO WHEN HEPCIDIN IS INDUCED 1082 00:44:16,440 --> 00:44:18,720 EARLY IN INFECTION, YOU WILL 1083 00:44:18,720 --> 00:44:23,240 KEEP ON TSH IT LANDLORD NOT 1084 00:44:23,240 --> 00:44:25,120 APPEAR FOR INCREASED TRANSPARENT 1085 00:44:25,120 --> 00:44:25,920 SITUATION. 1086 00:44:25,920 --> 00:44:28,520 AND WE ACTUALLY DID SEE THIS IN 1087 00:44:28,520 --> 00:44:31,040 MOUSE MODELS, THAT THAT IS 1088 00:44:31,040 --> 00:44:35,200 EXACTLY WHAT HEPCIDIN DOES. 1089 00:44:35,200 --> 00:44:37,160 IF WE LOOK AT WILD TYPE MICE WHO 1090 00:44:37,160 --> 00:44:39,040 HAVE SEVERE INFLAMMATION, YOU 1091 00:44:39,040 --> 00:44:40,680 CAN SEE THIS IS MY SERUM IRON 1092 00:44:40,680 --> 00:44:41,880 BEFORE INFLAMMATION, THIS IS 1093 00:44:41,880 --> 00:44:42,720 AFTER INFLAMMATION. 1094 00:44:42,720 --> 00:44:45,040 YOU CAN APPRECIATE IF THERE IS 1095 00:44:45,040 --> 00:44:46,520 HYPOTHEIR EMIA, BUT IF WE LOOK 1096 00:44:46,520 --> 00:44:48,120 AT HEPCIDIN KNOCKOUT MICE BEFORE 1097 00:44:48,120 --> 00:44:49,960 AND AFTER INFLAMMATION, THERE IS 1098 00:44:49,960 --> 00:44:52,240 AN INCREASE IN IRON RELEASE INTO 1099 00:44:52,240 --> 00:44:52,560 CIRCULATION. 1100 00:44:52,560 --> 00:44:54,640 SO INDEED, HEPCIDIN IS THE 1101 00:44:54,640 --> 00:44:56,320 FACTOR THAT PREVENTS THIS 1102 00:44:56,320 --> 00:45:00,000 EXCESSIVE IRON RELEASE INTO 1103 00:45:00,000 --> 00:45:03,400 CIRCULATION. 1104 00:45:03,400 --> 00:45:04,920 SO TO THE BEST OF OUR KNOWLEDGE, 1105 00:45:04,920 --> 00:45:07,400 THE ROLE OF HELP SIGH BIN IN 1106 00:45:07,400 --> 00:45:08,320 INNATE IMMUNITY IS TO BLOCK 1107 00:45:08,320 --> 00:45:12,520 PRODUCTION OF THIS TRANS -- IRON 1108 00:45:12,520 --> 00:45:14,200 AND DEPENDS ON GROWTH OF THAT 1109 00:45:14,200 --> 00:45:16,120 FORM OF IRON. 1110 00:45:16,120 --> 00:45:17,400 BUT DISEASES THAT ARE ASSOCIATED 1111 00:45:17,400 --> 00:45:19,480 WITH INCREASED PRODUCTION OR 1112 00:45:19,480 --> 00:45:27,520 PRESENCE OF NON- -- FUN DPAL FUNGAL 1113 00:45:27,520 --> 00:45:29,080 INFORECASTS AND THOSE PRESENT AS 1114 00:45:29,080 --> 00:45:32,600 IMPAIRED HEPCIDIN PRO DUCK, SO 1115 00:45:32,600 --> 00:45:33,480 HEMOCHROMATOSIS, DIFFERENT IRON 1116 00:45:33,480 --> 00:45:34,880 LOADING ANEMIAS, CHRONIC LIVER 1117 00:45:34,880 --> 00:45:35,920 DISEASE WHERE HEPCIDIN 1118 00:45:35,920 --> 00:45:41,880 PRODUCTION IS ALSO IMPAIRED. 1119 00:45:41,880 --> 00:45:43,400 OR THESE CONDITIONS ARE 1120 00:45:43,400 --> 00:45:44,720 ASSOCIATED WITH DECREASED IRON 1121 00:45:44,720 --> 00:45:46,920 CONSUMPTION BECAUSE OF IMPAIRED 1122 00:45:46,920 --> 00:45:48,400 ERYTHROPOIESIS, SO THAT WILL BE 1123 00:45:48,400 --> 00:45:51,040 AFTER CHEMOTHERAPY, WHEN 1124 00:45:51,040 --> 00:45:52,320 ERYTHROPOIESIS IS SUPPRESSED, 1125 00:45:52,320 --> 00:45:53,440 IRON WILL BACK UP IN 1126 00:45:53,440 --> 00:45:54,960 CIRCULATION, AND THERE'S INDEED 1127 00:45:54,960 --> 00:45:58,520 HIGH RISK OF GRAM-NEGATIVE 1128 00:45:58,520 --> 00:46:01,440 SEPSIS WHEN IT'S PRESENT. 1129 00:46:01,440 --> 00:46:02,920 ALSO AFTER BONE MARROW ABLATION, 1130 00:46:02,920 --> 00:46:07,440 THERE'S HIGHER RISK OF INVASIVE 1131 00:46:07,440 --> 00:46:10,600 FUNGAL INFECTION, ASPERGILLUS 1132 00:46:10,600 --> 00:46:13,240 CAN USE -- AND RABDLY INCREASE 1133 00:46:13,240 --> 00:46:14,120 ITS GROWTH. 1134 00:46:14,120 --> 00:46:17,840 AND ALSO THERE IS RISK WITH 1135 00:46:17,840 --> 00:46:21,680 EXOGENOUS -- WITH TRANSFUSION. 1136 00:46:21,680 --> 00:46:23,520 SO I MENTIONED THAT HEPCIDIN IS 1137 00:46:23,520 --> 00:46:25,280 AN ESSENTIAL COMPONENT OF HOST 1138 00:46:25,280 --> 00:46:27,880 DEFENSE, BUT TO CONTROL THIS 1139 00:46:27,880 --> 00:46:29,200 IRON AVAILABILITY PATHOGENS, BUT 1140 00:46:29,200 --> 00:46:30,640 THERE IS A DOWNSIDE TO IT. 1141 00:46:30,640 --> 00:46:32,440 WHEN WE HAVE A PRESENCE OF 1142 00:46:32,440 --> 00:46:33,560 INFLAMMATORY DISORDERS, THIS 1143 00:46:33,560 --> 00:46:39,040 MECHANISM BECOMES MALADAPTIVE. 1144 00:46:39,040 --> 00:46:40,040 THIS IRON RESTRICTION THEN CAN 1145 00:46:40,040 --> 00:46:43,160 CONTRIBUTE TO ANEMIA -- A 1146 00:46:43,160 --> 00:46:43,400 DEVELOP. 1147 00:46:43,400 --> 00:46:51,920 ANEMIA OF INFLAMMATION. 1148 00:46:51,920 --> 00:46:52,920 IRON RESTRICTION IS ONLY ONE 1149 00:46:52,920 --> 00:46:53,920 COMPONENT. 1150 00:46:53,920 --> 00:46:57,120 DIRECT EFFECT ON REDUCING RED 1151 00:46:57,120 --> 00:47:00,120 BLOOD CELL LIFESPAN IS ANOTHER, 1152 00:47:00,120 --> 00:47:02,920 DECREASED EPO PRODUCTION IN THE 1153 00:47:02,920 --> 00:47:05,480 KIDNEYS AND SUPPRESSING 1154 00:47:05,480 --> 00:47:07,120 ERYTHROID DIFFERENTIATION, BUT 1155 00:47:07,120 --> 00:47:10,720 IRON RESTRICTION IS A MAJOR 1156 00:47:10,720 --> 00:47:11,480 CONTRIBUTOR. 1157 00:47:11,480 --> 00:47:14,080 THIS IS OF COURSE MEDIATED BY 1158 00:47:14,080 --> 00:47:17,120 HELP 1159 00:47:17,120 --> 00:47:17,520 HEPCIDIN EXCESS. 1160 00:47:17,520 --> 00:47:19,200 THIS WAS SHOWN IN CHRONIC KIDNEY 1161 00:47:19,200 --> 00:47:22,600 DISEASE, IN MANY IB FLAM INFLAMMATORY 1162 00:47:22,600 --> 00:47:24,600 DISORDERS FROM AUTOIMMUNE 1163 00:47:24,600 --> 00:47:26,440 DISEASES, INFECTIONS, CRITICAL 1164 00:47:26,440 --> 00:47:27,640 CARE PATIENTS, BURN PATIENTS HAD 1165 00:47:27,640 --> 00:47:31,000 EXTREMELY HIGH LEVELS. 1166 00:47:31,000 --> 00:47:32,120 EVEN MODERATE ELEVATION WAS 1167 00:47:32,120 --> 00:47:32,920 OBSERVED IN OBESITY. 1168 00:47:32,920 --> 00:47:34,120 AND THEN MULTIPLE FORMS OF 1169 00:47:34,120 --> 00:47:35,840 CANCER HAVE ELEVATED HEPCIDIN, 1170 00:47:35,840 --> 00:47:38,920 AND ALL OF THESE PATIENTS ARE AT 1171 00:47:38,920 --> 00:47:40,440 HIGH RISK OF DEVELOPING ANEMIA 1172 00:47:40,440 --> 00:47:41,200 OF INFLAMMATION. 1173 00:47:41,200 --> 00:47:46,160 AND YOU CAN APPRECIATE HERE THAT 1174 00:47:46,160 --> 00:47:49,080 IN COMPARISON TO -- THIS 1175 00:47:49,080 --> 00:47:52,200 SELECTION OF PATIENTS HAD MUCH 1176 00:47:52,200 --> 00:47:55,800 ELEVATED HEPCIDIN LEVELS. 1177 00:47:55,800 --> 00:47:58,880 SO THE WAY HIGH HEPCIDIN 1178 00:47:58,880 --> 00:48:00,400 CONTRIBUTES, THERE IS INCREASED 1179 00:48:00,400 --> 00:48:03,040 HEPCIDIN PRODUCTION BY IL-6 1180 00:48:03,040 --> 00:48:05,120 PRIMARILY WHICH TARGETS 1181 00:48:05,120 --> 00:48:05,880 FERROPORTIN. 1182 00:48:05,880 --> 00:48:07,720 NOW IRON FLOWS ARE RESTRICTED, 1183 00:48:07,720 --> 00:48:10,000 THIS PLASMA COMPARTMENT GETS 1184 00:48:10,000 --> 00:48:12,800 RAPIDLY DEPLETED SO HYPOFAIR 1185 00:48:12,800 --> 00:48:15,400 EMIA RESULTS AND AS THERE'S 1186 00:48:15,400 --> 00:48:18,560 CHRONIC HYPOFERREMIA, THAT 1187 00:48:18,560 --> 00:48:23,640 EVENTUALLY LEADS TO -- AND OR 1188 00:48:23,640 --> 00:48:27,720 HYPOTHERAPY -- IS BLOCKING -- AN 1189 00:48:27,720 --> 00:48:29,280 TAG NIGMS COULD BE USED FOR 1190 00:48:29,280 --> 00:48:30,400 TREATMENT OF ANEMIA AND 1191 00:48:30,400 --> 00:48:30,720 INFRAMATION. 1192 00:48:30,720 --> 00:48:34,280 SO 1193 00:48:34,280 --> 00:48:35,080 INFLAMMATION. 1194 00:48:35,080 --> 00:48:36,840 SO TO SUMMARIZE WHAT I TOLD YOU 1195 00:48:36,840 --> 00:48:38,320 ABOUT ADVANCES MADE IN THE LAST 1196 00:48:38,320 --> 00:48:41,240 TWO AT THE CADE ABOUT SYSTEMIC 1197 00:48:41,240 --> 00:48:42,960 IRON REGULATION IS THAT IT IS 1198 00:48:42,960 --> 00:48:44,480 MEDIATED BY THE INTERACTION 1199 00:48:44,480 --> 00:48:48,400 BETWEEN HEPCIDIN, ITS RECEPTOR 1200 00:48:48,400 --> 00:48:50,560 FERROPORTIN TO CONTROL IRON 1201 00:48:50,560 --> 00:48:51,560 DELIVERY TO BLOOD PLASMA. 1202 00:48:51,560 --> 00:48:55,520 NOW WE CAN EXPLAIN IRON OVERLOAD 1203 00:48:55,520 --> 00:48:57,360 SITUATIONS WHICH RESULTS FROM JE 1204 00:48:57,360 --> 00:49:02,600 DME TICK HEPCIDIN REFRISCH SEE, 1205 00:49:02,600 --> 00:49:06,360 WHERE EXCESSIVE INTERFERON HAS 1206 00:49:06,360 --> 00:49:08,800 GENERATED. 1207 00:49:08,800 --> 00:49:09,840 FOR IRON RESTRICTED CONDITIONS, 1208 00:49:09,840 --> 00:49:13,200 WE NOW KNOW THAT IRON 1209 00:49:13,200 --> 00:49:15,280 RESTRICTION IS ANEMIA PARTIALLY 1210 00:49:15,280 --> 00:49:21,840 CALLED BY INFLAMMATORY -- 1211 00:49:21,840 --> 00:49:23,480 HEPCIDIN IS IMPORTANT FOR 1212 00:49:23,480 --> 00:49:25,040 RESISTANCE TO CERTAIN PART JENS 1213 00:49:25,040 --> 00:49:31,760 AND SO CERTAIN 1214 00:49:31,760 --> 00:49:34,680 PATHOGENS -- GRAM NEGATIVES. 1215 00:49:34,680 --> 00:49:36,040 THE CLINICAL -- IT CAN BE 1216 00:49:36,040 --> 00:49:39,520 TARGETED FOR DRUG LEADS AND A 1217 00:49:39,520 --> 00:49:40,640 NUMBER OF POTENTIAL THERAPEUTICS 1218 00:49:40,640 --> 00:49:43,720 ARE UNDER DEVELOPMENT AND ARE IN 1219 00:49:43,720 --> 00:49:44,360 PHASE 2 TRIALS. 1220 00:49:44,360 --> 00:49:44,880 SO THANK YOU VERY MUCH. 1221 00:49:44,880 --> 00:49:47,960 THIS IS THE UCLA CENTER FOR IRON 1222 00:49:47,960 --> 00:49:49,120 DISORDERS AND ALL MY COLLEAGUES 1223 00:49:49,120 --> 00:49:50,480 WHO ARE INVOLVED IN THIS WORK. 1224 00:49:50,480 --> 00:49:57,080 SO THANK YOU. 1225 00:49:57,080 --> 00:49:58,120 >> THANK YOU. 1226 00:49:58,120 --> 00:49:58,920 THERE ARE SEVERAL QUESTIONS THAT 1227 00:49:58,920 --> 00:50:01,840 HAVE BEEN SUBMITTED, AS WELL AS 1228 00:50:01,840 --> 00:50:04,840 I HAVE A FEW QUESTIONS. 1229 00:50:04,840 --> 00:50:06,920 LET ME BEGIN BY ASKING, YOU 1230 00:50:06,920 --> 00:50:10,400 ALLUDED TO HEPCIDIN AGONISTS AND 1231 00:50:10,400 --> 00:50:11,040 ANTAGONISTS. 1232 00:50:11,040 --> 00:50:15,000 CAN HEPCIDIN ITSELF OR A 1233 00:50:15,000 --> 00:50:16,720 SYNTHETIC PEPTIDE SIMILAR TO BE 1234 00:50:16,720 --> 00:50:19,800 USED THERAPEUTICALLY AS SUCH? 1235 00:50:19,800 --> 00:50:20,400 >> YES. 1236 00:50:20,400 --> 00:50:24,840 >> DOES IT -- ARE THE 1237 00:50:24,840 --> 00:50:27,480 PHARMACOKINETICS ADEQUATE FOR 1238 00:50:27,480 --> 00:50:27,760 UTILIZATION? 1239 00:50:27,760 --> 00:50:30,120 >> SO A DRUG -- SO THERE ARE 1240 00:50:30,120 --> 00:50:33,280 MULTIPLE FORMS OF HEPCIDIN 1241 00:50:33,280 --> 00:50:37,520 AGONISM, AND THEY SPAN FROM FULL 1242 00:50:37,520 --> 00:50:40,160 LINK HEPCIDIN TO SLIGHTLY 1243 00:50:40,160 --> 00:50:42,960 SMALLER HEPCIDIN TO MINI 1244 00:50:42,960 --> 00:50:44,160 HEPCIDIN, WHICH IS A SMALL 1245 00:50:44,160 --> 00:50:47,120 PEPTIDE, TO SORT OF A MICRO 1246 00:50:47,120 --> 00:50:48,320 HEPCIDIN WHICH IS JUST A SMALL 1247 00:50:48,320 --> 00:50:49,000 MOLECULE. 1248 00:50:49,000 --> 00:50:51,480 SO EVERYTHING EXISTS IN THE 1249 00:50:51,480 --> 00:50:53,840 PIPELINE FROM SMALL TO FULL 1250 00:50:53,840 --> 00:50:55,160 LENGTH HEPCIDIN, AND THE 1251 00:50:55,160 --> 00:50:57,160 CONSIDERATION IS, WILL THAT BE 1252 00:50:57,160 --> 00:50:58,760 RAPID CLEAR THAT IT HAS TO BE 1253 00:50:58,760 --> 00:51:03,280 INJECTED CONTINUOUSLY. 1254 00:51:03,280 --> 00:51:05,680 SO THE MINI AND MIDI HEPCIDINS 1255 00:51:05,680 --> 00:51:06,960 HAVE BEEN ENGINEERED IN SUCH A 1256 00:51:06,960 --> 00:51:09,680 WAY THAT THEY CAN PERSIST LONGER 1257 00:51:09,680 --> 00:51:11,560 IN CIRCULATION. 1258 00:51:11,560 --> 00:51:13,120 EVEN FULL LENGTH HEPCIDIN SEEMS 1259 00:51:13,120 --> 00:51:14,520 TO HAVE BEEN FORMULATED IN SUCH 1260 00:51:14,520 --> 00:51:15,920 A WAY THAT IT CAN LAST A LITTLE 1261 00:51:15,920 --> 00:51:16,400 BIT LONGER. 1262 00:51:16,400 --> 00:51:18,120 SO IN THIS CASE, FORMULATION 1263 00:51:18,120 --> 00:51:20,920 ACTUALLY HELPS TO PROLONG ITS 1264 00:51:20,920 --> 00:51:22,200 PRESENCE IN CIRCULATION. 1265 00:51:22,200 --> 00:51:26,200 AND THEN THE SMALL MOLECULES GET 1266 00:51:26,200 --> 00:51:26,960 TAKEN RAPIDLY. 1267 00:51:26,960 --> 00:51:28,840 SO MULTIPLE APPROACHES HAVE BEEN 1268 00:51:28,840 --> 00:51:29,920 TAKEN. 1269 00:51:29,920 --> 00:51:33,240 SO FAR ONLY SMALL MOLECULES ARE 1270 00:51:33,240 --> 00:51:35,400 CURRENTLY AVAILABLE BUT -- 1271 00:51:35,400 --> 00:51:39,040 OTHERWISE THEY'RE BEING INJECTED 1272 00:51:39,040 --> 00:51:40,520 SUBCUTANEOUSLY AND ARE IN 1273 00:51:40,520 --> 00:51:41,240 CLINICAL TRIALS. 1274 00:51:41,240 --> 00:51:41,760 >> THANK YOU. 1275 00:51:41,760 --> 00:51:43,080 LET ME ASK ONE FURTHER QUESTION. 1276 00:51:43,080 --> 00:51:46,160 YOU MENTIONED THAT INEFFECTIVE 1277 00:51:46,160 --> 00:51:51,720 ERYTHROPOIESIS CAUSES EXCESS 1278 00:51:51,720 --> 00:51:52,480 ERYTHROFERRONE. 1279 00:51:52,480 --> 00:51:58,240 HOW IS ERYTHROFERRONE PRODUCTION 1280 00:51:58,240 --> 00:51:59,480 LINKED TO ERYTHROPOIESIS, PER 1281 00:51:59,480 --> 00:52:01,840 SE, OR INEFFECTIVE 1282 00:52:01,840 --> 00:52:02,600 ERYTHROPOIESIS IN PARTICULAR? 1283 00:52:02,600 --> 00:52:07,400 >> SO THE CELLS THAT PRODUCE EE 1284 00:52:07,400 --> 00:52:10,080 RIR ROW FERRONE ARE PRECURSORS 1285 00:52:10,080 --> 00:52:12,920 AND THEY'RE VERY EXPANDED. 1286 00:52:12,920 --> 00:52:14,680 IT'S THE BODY'S ATTEMPT TO MAKE 1287 00:52:14,680 --> 00:52:16,200 MORE RED BLOOD CELLS BUT IT'S A 1288 00:52:16,200 --> 00:52:16,640 FUTILE ATTEMPT. 1289 00:52:16,640 --> 00:52:19,000 SO THE PRECURSORS ARE EXPANDED 1290 00:52:19,000 --> 00:52:22,920 WITH THE VERY CELLS THAT PRODUCE 1291 00:52:22,920 --> 00:52:23,680 ERYTHROFERRONE. 1292 00:52:23,680 --> 00:52:26,520 IN ADDITION TO THAT, THOSE CELLS 1293 00:52:26,520 --> 00:52:29,480 ARE STIMULATED BY EWO, AND EWO 1294 00:52:29,480 --> 00:52:33,040 IS HIGH, BECAUSE THE PATIENTS 1295 00:52:33,040 --> 00:52:34,080 ARE -- PLUS LARGER NUMBER OF 1296 00:52:34,080 --> 00:52:39,720 CELLS THAT PRODUCE ERFE BOTH 1297 00:52:39,720 --> 00:52:45,360 CONTRIBUTE TO HIGH LEVELS IN 1298 00:52:45,360 --> 00:52:45,880 INEFFECTIVE -- 1299 00:52:45,880 --> 00:52:47,000 >> THANK YOU. 1300 00:52:47,000 --> 00:52:48,760 DR. EPSTEIN ASKED, IS THERE ANY 1301 00:52:48,760 --> 00:52:52,240 EVIDENCE THAT -- LESIONS IN 1302 00:52:52,240 --> 00:52:53,720 TUBERCULOSIS OR SARCOIDOSIS ARE 1303 00:52:53,720 --> 00:52:57,880 RELATED TO IERP LEVELS IN IRON LEVELS IN THE 1304 00:52:57,880 --> 00:52:59,560 MACROPHAGES OR OTHER 1305 00:52:59,560 --> 00:53:00,240 INFLAMMATORY CELLS? 1306 00:53:00,240 --> 00:53:01,480 HAS THAT BEEN STUDIED? 1307 00:53:01,480 --> 00:53:03,280 >> THERE HAS BEEN A SPECULATION 1308 00:53:03,280 --> 00:53:03,920 THAT INTRACELLULAR IRON WILL 1309 00:53:03,920 --> 00:53:05,440 PLAY A ROLE. 1310 00:53:05,440 --> 00:53:09,080 HOWEVER, WHEN WE MANIPULATED 1311 00:53:09,080 --> 00:53:11,920 IRON, EITHER MADE HIGHER IERNL 1312 00:53:11,920 --> 00:53:12,960 IN MACROPHAGES OR MADE LOWER 1313 00:53:12,960 --> 00:53:14,960 IRON IN MACROPHAGES, 1314 00:53:14,960 --> 00:53:16,280 MANIPULATING IRON LEVELS IN 1315 00:53:16,280 --> 00:53:17,920 MACROPHAGES DID NOT AFFECT IN 1316 00:53:17,920 --> 00:53:20,640 ANY WAY THE GROWTH OF MTB, AND 1317 00:53:20,640 --> 00:53:23,360 IT WAS NOT DONE JUST BY US, 1318 00:53:23,360 --> 00:53:24,920 ANOTHER LAB AT OXFORD DID THE 1319 00:53:24,920 --> 00:53:25,880 SAME THING. 1320 00:53:25,880 --> 00:53:27,800 SO MANIPULATING MACROPHAGE IRON 1321 00:53:27,800 --> 00:53:28,920 LEVELS DID NOT CHANGE THE GROWTH 1322 00:53:28,920 --> 00:53:31,920 RATE OF MTB, BUT MTB DOES NEED 1323 00:53:31,920 --> 00:53:32,440 IRON. 1324 00:53:32,440 --> 00:53:34,440 IT'S JUST THAT BECAUSE IT'S SO 1325 00:53:34,440 --> 00:53:39,120 SLOW GROWING, IT CAN OBTAIN 1326 00:53:39,120 --> 00:53:40,960 WHATEVER RNA NEEDS INITY SLOW 1327 00:53:40,960 --> 00:53:42,640 MANNER, SO CHANGING -- LEVELNOT 1328 00:53:42,640 --> 00:53:43,400 HAVE AN EFFECT. 1329 00:53:43,400 --> 00:53:45,480 BUT A LITTLE BIT OF IRON IS 1330 00:53:45,480 --> 00:53:47,200 NECESSARY AND IT SEEMS THAT THE 1331 00:53:47,200 --> 00:53:48,640 PATHOGEN IS ABLE TO OBTAIN IT 1332 00:53:48,640 --> 00:53:50,960 AND BECAUSE IT'S GROWING SO 1333 00:53:50,960 --> 00:53:52,400 SLOWLY, IT JUST DOESN'T NEED AS 1334 00:53:52,400 --> 00:53:53,360 MUCH AS ONCE. 1335 00:53:53,360 --> 00:53:54,560 >> THANK YOU. 1336 00:53:54,560 --> 00:53:56,560 BEFORE I CONTINUE WITH THE 1337 00:53:56,560 --> 00:53:58,240 QUESTIONS, LET ME -- ONE 1338 00:53:58,240 --> 00:54:01,280 LISTENER ASKED FOR THE CME 1339 00:54:01,280 --> 00:54:01,520 NUMBER. 1340 00:54:01,520 --> 00:54:04,320 LET ME JUST GIVE THAT AGAIN. 1341 00:54:04,320 --> 00:54:06,720 36712, FOR THOSE WHO NEED THAT 1342 00:54:06,720 --> 00:54:12,480 NUMBER. 1343 00:54:12,480 --> 00:54:13,840 DR. THIEN ASKS IF YOU COULD 1344 00:54:13,840 --> 00:54:20,320 DESCRIBE HOW THE MUTATIONS IN 1345 00:54:20,320 --> 00:54:22,480 PIEZ01 AFFECTS IRON LEVELS IN 1346 00:54:22,480 --> 00:54:23,000 MACROPHAGES. 1347 00:54:23,000 --> 00:54:24,440 I'M NOT QUITE SURE WHY FOCUSING 1348 00:54:24,440 --> 00:54:28,160 ON THAT, BUT SHE ASKED ABOUT 1349 00:54:28,160 --> 00:54:29,560 THAT RELATIONSHIP. 1350 00:54:29,560 --> 00:54:34,080 >> SO PIEZ01 WAS ACTUALLY THE 1351 00:54:34,080 --> 00:54:35,520 MOLECULE MOST RECENTLY THE 1352 00:54:35,520 --> 00:54:42,800 FEATURE OF -- IT'S DN IT HAPPEN 1353 00:54:42,800 --> 00:54:44,720 TO BE -- GAIN OF FUNCTION 1354 00:54:44,720 --> 00:54:47,920 MUTATION END UP WITH HIGHER IRON 1355 00:54:47,920 --> 00:54:48,360 LEVELS. 1356 00:54:48,360 --> 00:54:51,120 WE'RE NOT QUITE SURE WHAT THE 1357 00:54:51,120 --> 00:54:54,240 ACTUAL ROLE OF PIEZ01 IS, BUT IT 1358 00:54:54,240 --> 00:54:55,920 VERY POSSIBLE THAT FOR CELLS 1359 00:54:55,920 --> 00:54:57,320 SUCH AT MACROPHAGES THAT HAVE A 1360 00:54:57,320 --> 00:54:58,680 LOT OF MECHANICAL DISTORTION, 1361 00:54:58,680 --> 00:55:01,560 FOR EXAMPLE, RELATED TODAY 1362 00:55:01,560 --> 00:55:02,760 ERYTHROPHAGOCYTOSIS, THERE IS A 1363 00:55:02,760 --> 00:55:05,600 LOT OF CHANGING IN MECHANICAL 1364 00:55:05,600 --> 00:55:06,680 TENSION, THAT SOMEHOW IT SENSES 1365 00:55:06,680 --> 00:55:07,320 THAT. 1366 00:55:07,320 --> 00:55:09,960 AND THERE'S AN ALTERATION OF 1367 00:55:09,960 --> 00:55:11,280 IRON HOMEOSTASIS, THERE IS MORE 1368 00:55:11,280 --> 00:55:14,120 IRON BEING RETAINED WITHIN 1369 00:55:14,120 --> 00:55:14,680 MACROPHAGES. 1370 00:55:14,680 --> 00:55:17,080 WHAT IS INTERESTING ABOUT THAT, 1371 00:55:17,080 --> 00:55:18,720 ONE IS THERE IS A DISEASE THAT 1372 00:55:18,720 --> 00:55:20,120 RESULTS FROM GAIN OF FUNCTION 1373 00:55:20,120 --> 00:55:27,520 MUTATIONS IN PIEZ01, ALSO 1374 00:55:27,520 --> 00:55:30,280 ASSOCIATED WITH IRON OVERLOAD, 1375 00:55:30,280 --> 00:55:32,280 BUT ALSO THERE IS A HIGH 1376 00:55:32,280 --> 00:55:35,840 PREVALENCE OF POLYMORPHISM IN 1377 00:55:35,840 --> 00:55:39,800 AFRICAN POPULATION IN PIEZ01, 1378 00:55:39,800 --> 00:55:41,640 THAT SEEMS LIKELY SOMEWHAT 1379 00:55:41,640 --> 00:55:46,920 PROTECTIVE AGAINST MALARIA BUT 1380 00:55:46,920 --> 00:55:48,200 UNFORTUNATELY RESULTS IN HIGHER 1381 00:55:48,200 --> 00:55:49,240 IRON LOAD IN THESE PATIENTS. 1382 00:55:49,240 --> 00:55:50,480 >> THANK YOU. 1383 00:55:50,480 --> 00:55:53,400 DR. CARRINGTON ASKS, COULD 1384 00:55:53,400 --> 00:55:58,120 DYSREGULATION OF HEPCIDIN IMPACT 1385 00:55:58,120 --> 00:55:59,960 THE RESPONSE TO IMMUNE 1386 00:55:59,960 --> 00:56:01,200 CHECKPOINT THERAPY OF CANCER? 1387 00:56:01,200 --> 00:56:04,280 >> I DON'T KNOW EXACTLY YET, BUT 1388 00:56:04,280 --> 00:56:07,680 WHAT WE DO KNOW IS THAT IRON 1389 00:56:07,680 --> 00:56:10,920 RESTRICTION DOES AFFECT B AND 1390 00:56:10,920 --> 00:56:13,680 T-CELL CLONAL EXPANSION AND 1391 00:56:13,680 --> 00:56:14,840 ADAPTIVE IMMUNE RESPONSE. 1392 00:56:14,840 --> 00:56:19,760 SO WHEN CELLS HAVE TO BE RAPIDLY 1393 00:56:19,760 --> 00:56:27,880 EXPAND, SUCH AND B AND T-CELLS, 1394 00:56:27,880 --> 00:56:29,120 THEY ABSOLUTELY NEED A LOT OF 1395 00:56:29,120 --> 00:56:33,560 IRON IN ORDER TO EXPAND. 1396 00:56:33,560 --> 00:56:34,960 IT HAS BEEN SHOWN THAT WHEN 1397 00:56:34,960 --> 00:56:39,120 HEPCIDIN IS ELEVATED AND CAUSES 1398 00:56:39,120 --> 00:56:41,440 IRON RESTRICTION, THAT WILL 1399 00:56:41,440 --> 00:56:46,320 IMPAIR THE T AND B CELL CLONAL 1400 00:56:46,320 --> 00:56:46,800 INFECTION. 1401 00:56:46,800 --> 00:56:51,240 SO ADAPTIVE IMMUNITY, BUT 1402 00:56:51,240 --> 00:56:52,880 NOTHING HAS BEEN STUDIED 1403 00:56:52,880 --> 00:56:59,720 YESTERDAY . 1404 00:56:59,720 --> 00:57:01,400 >> DR. THIEN, THE REASON FOR HER 1405 00:57:01,400 --> 00:57:04,720 QUESTION, THE PIEZ01 MUTATION IS 1406 00:57:04,720 --> 00:57:06,880 APPARENTLY FOUND IN ABOUT 30% OF 1407 00:57:06,880 --> 00:57:07,880 SICKLE CELL PATIENTS. 1408 00:57:07,880 --> 00:57:10,120 WHICH I DID NOT KNOW. 1409 00:57:10,120 --> 00:57:13,320 >> THAT COULD BE BECAUSE OF THE 1410 00:57:13,320 --> 00:57:14,520 CONNECTION TO AFRICA. 1411 00:57:14,520 --> 00:57:20,240 SO PROBABLY EVOLUTIONARILY, IT 1412 00:57:20,240 --> 00:57:23,840 WAS FOR PROTECTION OF MALARIA. 1413 00:57:23,840 --> 00:57:30,800 INTERESTINGLY, PIEZO1 -- HOLE 1414 00:57:30,800 --> 00:57:32,440 THE WHOLE PATHOLOGY NEEDS TO 1415 00:57:32,440 --> 00:57:33,120 COME TOGETHER STILL WILL BE 1416 00:57:33,120 --> 00:57:34,120 EXPLORED IN MORE DETAIL. 1417 00:57:34,120 --> 00:57:35,880 >> I THINK WE HAVE TIME FOR 1418 00:57:35,880 --> 00:57:39,720 PERHAPS ONE MORE QUESTION. 1419 00:57:39,720 --> 00:57:40,960 DR. PORCHENKO ASKS WHAT IS THE 1420 00:57:40,960 --> 00:57:44,160 ROLE OF HEPCIDIN PRODUCED BY 1421 00:57:44,160 --> 00:57:46,280 NON-HEPATIC CELLS LIKE 1422 00:57:46,280 --> 00:57:46,720 MACROPHAGES? 1423 00:57:46,720 --> 00:57:54,720 >> THERE ARE LOCAL CELLS THAT. 1424 00:57:54,720 --> 00:57:56,280 IT'S NOW BECOMING APPARENT THAT 1425 00:57:56,280 --> 00:57:57,720 THEY DO CONTRIBUTE TO SOME 1426 00:57:57,720 --> 00:58:01,320 IMPORTANT FUNCTIONS LOCALLY. 1427 00:58:01,320 --> 00:58:03,280 SO FOR EXAMPLE, THE BEST 1428 00:58:03,280 --> 00:58:05,120 DESCRIBED ONE IS PRODUCTION OF 1429 00:58:05,120 --> 00:58:06,880 HEPCIDIN BY CARDIOMYOCYTES IN 1430 00:58:06,880 --> 00:58:09,720 THE HEART, WHERE IT CAN CONTROL 1431 00:58:09,720 --> 00:58:11,560 LOCAL CARDIOMYOSIDE IRON LEVELS, 1432 00:58:11,560 --> 00:58:13,240 AND IF YOU KNOCK OUT EITHER THAT 1433 00:58:13,240 --> 00:58:16,720 OR HEPCIDIN RECEPTOR IN THE 1434 00:58:16,720 --> 00:58:19,720 HEART, IT COMPLETELY IMPAIRED 1435 00:58:19,720 --> 00:58:22,920 MAINTENANCE OF CARDIAC 1436 00:58:22,920 --> 00:58:24,160 HOMEOSTASIS AND ACTUALLY CAN 1437 00:58:24,160 --> 00:58:28,440 CAUSE LETHALITY IN MICE. 1438 00:58:28,440 --> 00:58:30,480 HEPCIDIN IS ALSO EXPRESSED IN 1439 00:58:30,480 --> 00:58:30,760 MACROPHAGES. 1440 00:58:30,760 --> 00:58:34,240 JUST TO WHICH EXTENT THAT 1441 00:58:34,240 --> 00:58:35,440 CONTRIBUTES TO LET'S SAY CONTROL 1442 00:58:35,440 --> 00:58:38,160 THE INFECTION HAS NOT BEEN QUITE 1443 00:58:38,160 --> 00:58:40,840 CLARIFIED. 1444 00:58:40,840 --> 00:58:44,040 SYSTEMATIC DECEPTION OF HIGH -- 1445 00:58:44,040 --> 00:58:45,400 NEEDS TO BE DONE TO COMPLETELY 1446 00:58:45,400 --> 00:58:46,400 UNDERSTAND THE CONTRIBUTION, BUT 1447 00:58:46,400 --> 00:58:47,920 I'M PRETTY SURE THAT SOME LOCAL 1448 00:58:47,920 --> 00:58:49,280 CONTROL WILL BE NECESSARY. 1449 00:58:49,280 --> 00:58:51,640 THERE IS ALSO PRODUCTION OF 1450 00:58:51,640 --> 00:58:54,040 LOCAL HEPCIDIN BY DENDRITIC 1451 00:58:54,040 --> 00:58:58,720 CELLS IN THE GUT, AND THAT WAS 1452 00:58:58,720 --> 00:59:03,960 JUST -- THE SUSCEPTIBILITY TO 1453 00:59:03,960 --> 00:59:07,400 INFLAMMATORY BOWEL DESEIZE, 1454 00:59:07,400 --> 00:59:10,400 WHETHER OR NOT IT'S PRESENT IN 1455 00:59:10,400 --> 00:59:10,600 CELLS. 1456 00:59:10,600 --> 00:59:13,520 >> THANK YOU INVESTMENT THE 1:00 HOUR HAS JUST STRUCK AND I, 1457 00:59:13,520 --> 00:59:16,320 AT LEAST IN THE EAST, A LITTLE 1458 00:59:16,320 --> 00:59:18,840 EARLIER FOR YOU. 1459 00:59:18,840 --> 00:59:20,080 BUT ON BEHALF OF THE COMMITTEE 1460 00:59:20,080 --> 00:59:21,560 AND OF NIH AS A WHOLE, I'D LIKE 1461 00:59:21,560 --> 00:59:24,880 TO THANK YOU VERY MUCH FOR THIS 1462 00:59:24,880 --> 00:59:26,400 SUPERB TALK AND CLARIFYING AT 1463 00:59:26,400 --> 00:59:28,400 LEAST FOR SEVERAL HOURS IN MY 1464 00:59:28,400 --> 00:59:30,960 MIND THE COMPLEX INTERACTIONS 1465 00:59:30,960 --> 00:59:33,080 BETWEEN THESE FACTORS, I HOPE 1466 00:59:33,080 --> 00:59:37,640 THERE ARE NO MORE FACTORS 1467 00:59:37,640 --> 00:59:38,720 DISCOVERED, BUT IT DELIGHTFUL AS 1468 00:59:38,720 --> 00:59:42,320 MY WIFE INDICATED TO UNDERSTAND 1469 00:59:42,320 --> 00:59:45,200 SO MUCH NOW COMPARED TO THE 1470 00:59:45,200 --> 00:59:47,360 UNCERTAINTY THAT PERMEATED ALL 1471 00:59:47,360 --> 00:59:49,240 OF SO-CALLED BENIGN HEMATOLOGY 1472 00:59:49,240 --> 00:59:50,720 FOR THE PREVIOUS 50 YEARS. 1473 00:59:50,720 --> 00:59:51,480 THANK YOU VERY MUCH. 1474 00:59:51,480 --> 00:59:52,040 >> THANK YOU VERY MUCH. 1475 00:59:52,040 --> 00:59:53,680 IT WAS A PLEASURE TO 1476 00:59:53,680 --> 00:59:54,480 PARTICIPATE, AND THANK YOU FOR 1477 00:59:54,480 --> 00:59:55,480 INVITING ME. 1478 00:59:55,480 --> 00:59:57,120 >> GOOD DAY. 1479 00:59:57,120 --> 01:01:49,080 >> BYE.