Project Grant K38HL175027

THE LIPOFIBROBLAST TO MYOFIBROBLAST TRANSITION IN SYSTEMIC SCLEROSIS - PROJECT SUMMARY/ABSTRACT SYSTEMIC SCLEROSIS (SSC) IS A RARE AUTOIMMUNE FIBROSING DISEASE THAT AFFECTS 24.4/100,000 PEOPLE IN THE UNITED STATES. WHILE RARE, SSC HAS THE HIGHEST MORTALITY OF ALL RHEUMATOLOGIC DISEASES. THE COMPLICATION MOST ASSOCIATED WITH THIS HIGH MORTALITY IS INTERSTITIAL LUNG DISEASE (ILD). DESPITE THIS, THERE REMAIN LIMITED TREATMENTS FOR SYSTEMIC SCLEROSIS ASSOCIATED INTERSTITIAL LUNG DISEASE (SSC-ILD), AND THE TREATMENTS THAT DO EXIST ONLY SLOW BUT DO NOT REVERSE ILD. TO CREATE NEW AND BETTER TREATMENTS FOR SSC-ILD, WE NEED TO BETTER UNDERSTAND THE MECHANISMS THAT DRIVE FIBROSIS. A PREVIOUS STUDY SHOWED THAT MYOFIBROBLASTS (THE CELLS THAT DRIVE FIBROSIS THROUGH THE PRODUCTION OF EXTRACELLULAR MATRIX) ARE DERIVED FROM LIPOFIBROBLASTS IN A MOUSE MODEL OF INTERSTITIAL LUNG DISEASE. THUS, THE LIPOFIBROBLAST TO MYOFIBROBLAST TRANSITION IN SYSTEMIC SCLEROSIS MAY REPRESENT A NOVEL TARGET FOR TREATMENT. TO DATE, HOWEVER, THE MECHANISMS INVOLVED IN THIS TRANSITION ARE NOT WELL UNDERSTOOD. ONE KNOWN PLAYER IN THE LIPOFIBROBLAST TO MYOFIBROBLAST TRANSITION IS PPARG (PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA), A MASTER REGULATOR OF LIPID METABOLISM AND ADIPOGENESIS. PPARG HAS BEEN SHOWN TO BE DOWNREGULATED DURING THE LIPOFIBROBLAST TO MYOFIBROBLAST TRANSITION AND PPARG AGONISTS REDUCE FIBROSIS IN MOUSE MODELS OF ILD. IN THIS PROPOSAL, WE AIM TO DEFINE THE MECHANISMS THROUGH WHICH PPARG IS ITSELF REGULATED ALLOWING FOR THE LIPOFIBROBLAST TO MYOFIBROBLAST TRANSITION TO OCCUR. WE WILL DO THIS BY USING A MULTIOMICS APPROACH TO EXAMINE THE EXPRESSION AND CHROMATIN ACCESSIBILITY OF TWO GENES, PER3 (PERIOD CIRCADIAN PROTEIN HOMOLOG 3) AND CD36 (CLUSTER OF DIFFERENTIATION 36), THAT WE BELIEVE FUNCTION UPSTREAM AND DOWNSTREAM OF PPARG RESPECTIVELY. IN AIM 1 OF THIS PROPOSAL, WE WILL IDENTIFY THE TRANSITIONAL CELL STAGE DURING WHICH LIPOFIBROBLASTS ARE TRANSITIONING TO MYOFIBROBLASTS AND IN AIM 2, WE WILL CHARACTERIZE THE ROLE OF PER3 AND CD36 IN THE LIPOFIBROBLAST TO MYOFIBROBLAST TRANSITION. BASED ON PREVIOUS STUDIES THAT HAVE DEFINED THEIR ROLES IN ADIPOGENESIS (PER3) AND FIBROSIS (CD36), WE HYPOTHESIZE THAT PER3 INHIBITS PPARG TRANSCRIPTIONAL FUNCTION DURING THE LIPOFIBROBLAST TO MYOFIBROBLAST TRANSITION AND THAT DOWNREGULATION OF PPARG DURING THIS TRANSITION LEADS TO DECREASED CD36 EXPRESSION. IMPORTANTLY, THE USE OF MULTIOMICS ALLOWS FOR AN UNBIASED APPROACH SO THAT WE ARE NOT LIMITED TO EXPLORING CHANGES IN GENE EXPRESSION AND CHROMATIN ACCESSIBILITY DURING THIS TRANSITION IN ONE CANDIDATE AT A TIME. THE PROPOSED RESEARCH BUILDS UPON MY BACKGROUND IN LIPID METABOLISM RESEARCH DURING MY TIME ON THE R38. THE EXPERIMENTS OUTLINED IN THIS PROPOSAL WILL TAKE PLACE AT UCLA WHERE I WILL HAVE ACCESS TO NECESSARY EQUIPMENT AND CORE FACILITIES SUCH AS THE UCLA TISSUE PATHOLOGY CORE LABORATORY AND THE UCLA TECHNOLOGY CENTER FOR GENOMICS AND BIOINFORMATICS TO SUPPORT THE SUCCESSFUL COMPLETION OF MY PROPOSED RESEARCH. IN ADDITION, THROUGH MY CAREER DEVELOPMENT AND TRAINING PLAN, I WILL DEVELOP NEW SKILLS IN ANALYZING SINGLE-CELL RNA-SEQUENCING AND ATAC-SEQUENCING DATA. I WILL ALSO BE ABLE TO USE THE RESULTS OF THIS STUDY AS A BASIS FOR MY FUTURE K08 APPLICATION, WHICH I PLAN TO SUBMIT IN THE FALL OF 2025.