THE MODULATION OF CELL SURVIVAL DURING HEPATOCYTE LINEAGE PLASTICITY IN CHRONIC LIVER DISEASE - PROJECT SUMMARY/ABSTRACT CHRONIC LIVER DISEASE (CLD) IS A HETEROGENEOUS AND PREVALENT CONDITION THAT AFFECTS NEARLY 1 IN 5 INDIVIDUALS WORLDWIDE. IT IS RESPONSIBLE FOR MILLIONS OF DEATHS IN THE UNITED STATES ANNUALLY AND CURRENTLY HAS NO THERAPEUTIC INTERVENTIONS THAT DELAY OR SLOW THE PROGRESSION OF DECLINING LIVER FUNCTION AND CIRRHOSIS. TO ADDRESS THIS CONCERN, OUR LAB HAS AIMED TO CHARACTERIZE THE DYNAMIC LANDSCAPE OF HEPATOCYTES DURING LIVER INJURY. IN MOST FORMS OF CLD, BETWEEN 15% AND 80% OF HEPATOCYTES DISPLAY A PLASTIC, INTERMEDIATE PHENOTYPE, EXPRESSING BOTH HEPATOCYTE- AND BILIARY EPITHELIAL CELL (BEC)-SPECIFIC PROTEIN MARKERS. NOTCH SIGNALING WAS FOUND TO BE REQUIRED AND SUFFICIENT TO INDUCE REPROGRAMMING IN HEPATOCYTES, AND OUR LAB DEVELOPED A TRANSPOSON-BASED SYSTEM TO STUDY THESE PLASTIC HEPATOCYTES IN MOUSE MODELS. WE FOUND THAT THESE CELLS EXHIBIT A CYTOSTATIC CELL STATE AND ARE HIGHLY RESISTANT TO ONCOGENIC STIMULATION. THESE CHARACTERISTICS MAY PROTECT AGAINST CELLULAR TRANSFORMATION DURING A CHRONIC INSULT. HOWEVER, IT REMAINS ELUSIVE IF THESE CELLS ALSO PLAY A ROLE IN REGULATING DISEASE PROGRESSION SINCE PLASTIC HEPATOCYTES ARE UBIQUITOUSLY PRESENT THROUGHOUT THE DISEASE COURSE. GIVEN THIS, WE HYPOTHESIZE THAT PLASTIC HEPATOCYTES MODULATE CELL SURVIVAL RESPONSES TO REGULATE HEPATIC FUNCTION DURING A LIVER INJURY. WE AIM TO STUDY HOW THESE CELLS RESPOND TO HEPATOTOXIC TRIGGERS AND WHAT THEIR ROLES ARE IN REGULATING THE CHRONICITY AND PROGRESSION OF LIVER DISEASE. USING NOVEL GENETICALLY ENGINEERED MOUSE MODELS THAT MODULATE HEPATOCYTE REPROGRAMMING STATUS, WE WILL STUDY HOW PLASTIC CELLS INFLUENCE INTRINSIC AND EXTRINSIC INFLAMMATORY RESPONSES AND DETERMINE WHICH MOLECULAR PATHWAYS REGULATE THIS RESPONSE. WE WILL APPLY THIS SYSTEM TO TEST HOW THESE CELLS RESPOND TO CLINICALLY RELEVANT LIVER DAMAGE MODELS. THE RESULTS FROM THIS EXPERIMENT WILL GUIDE FUTURE THERAPEUTIC TREATMENTS, AND WE AIM TO DESCRIBE PARTIAL REPROGRAMMING AS A VIABLE STRATEGY FOR CLINICAL USE FOR A VARIETY OF LIVER DISEASES. AS A RESULT, PATIENTS WHO SUFFER FROM CLD WILL GAIN VALUABLE TIME TO EXPLORE CONCURRENT THERAPIES AND GAIN A HIGHER QUALITY OF LIFE. THIS PROPOSAL WILL ALSO SERVE AS A TRAINING OPPORTUNITY FOR ME TO EXPAND MY KNOWLEDGE IN TRANSLATIONAL RESEARCH BY WORKING WITH CLINICALLY RELEVANT IN VIVO MOUSE MODELS, WORKING WITH HIGHLY IMPACTFUL RESEARCHERS AND PHYSICIANS, AND DEVELOPING THE NECESSARY SCIENTIFIC COMMUNICATION SKILLS NEEDED TO CONVEY MY RESEARCH. BY WORKING CLOSELY WITH DRS. JOAN FONT-BURGADA AND SIDDHARTH BALACHANDRAN AS MY SPONSOR AND CO-SPONSOR, RESPECTIVELY, A TRAINING PLAN HAS BEEN DEVISED TO HELP ACHIEVE THESE GOALS. FURTHERMORE, UNDER THE CLINICAL GUIDANCE OF DRS. JOSHUA MEYER, ZACHARY REICHENBACH AND YEDIDYA SAIMAN, I WILL LEVERAGE CLINICAL OPPORTUNITIES AT FOX CHASE CANCER CENTER AND THE LEWIS KATZ SCHOOL OF MEDICINE TO GAIN VALUABLE OPPORTUNITIES TO INTERACT WITH PATIENTS TO DEVELOP MY CLINICAL SKILLS AND GAIN EXPOSURE ON HOW RESEARCH INTEGRATES INTO PATIENT CARE AND MEDICAL ADVANCEMENTS. BY COMPLETING THIS PROPOSAL, I WILL BECOME A MORE COMPETENT AND WELL-ROUNDED PHYSICIAN-SCIENTIST WHO CAN APPLY IMPACTFUL IN VIVO MODELS TO REAL-WORLD CLINICAL SCENARIOS.