Project Grant R00AR079554

ELUCIDATING MICROBIAL AND HOST MECHANISMS SUPPORTING EARLY LIFE IMMUNE IMPRINTING BY SKIN MONOCYTES - PROJECT SUMMARY/ABSTRACT: EARLY LIFE INTERACTIONS BETWEEN COMMENSAL MICROBES AND THE DEVELOPING IMMUNE SYSTEM HAVE FORMATIVE EFFECTS ON HUMAN HEALTH AND SUSCEPTIBILITY TO CHRONIC INFLAMMATORY DISEASE. PREVIOUS STUDIES FROM THE HOST LAB AND OTHER GROUPS HAVE DEMONSTRATED THAT OUR MICROBIAL SYMBIONTS CAN TUNE SKIN-RESIDENT T CELL FUNCTION, ESPECIALLY DURING THE NEONATAL WINDOW. HOWEVER, COMPARATIVELY LITTLE IS KNOWN ABOUT HOW COMMENSALS INFLUENCE CUTANEOUS MYELOID IMMUNITY IN EARLY LIFE. DR. DHARIWALA HAS FOUND THAT COMMENSAL MICROBES INFLUENCE THE COMPOSITION AND FUNCTION OF THE MYELOID COMPARTMENT IN NEONATAL SKIN. SPECIFICALLY, COMMENSAL MICROBES DRIVE THE ACCUMULATION OF A POPULATION OF LY6CHIMHC-IILO INFLAMMATORY MONOCYTES IN NEONATAL SKIN. THESE CELLS HAVE TRADITIONALLY BEEN STUDIED AS PRIMARY MEDIATORS OF INFLAMMATION IN RESPONSE TO INFECTION OR FOR THEIR ABILITY TO FILL VACANT TISSUE MYELOID NICHES. HOWEVER, DR. DHARIWALA'S PRELIMINARY STUDIES DEMONSTRATE A PREVIOUSLY UNEXPLORED REGULATORY IMMUNE IMPRINTING ROLE FOR NEONATAL SKIN MONOCYTES. TO DISSECT THE MOLECULAR MECHANISMS THAT UNDERPIN THIS PHENOMENON, WE WILL EMPLOY A COMBINATION OF TRANSGENIC MOUSE MODELS, HIGH THROUGHPUT ASSAYS LIKE MASS CYTOMETRY AND SINGLE CELL RNA SEQUENCING ALONG WITH NOVEL EX VIVO TRANSLATIONAL TOOLS. STUDIES PROPOSED IN THIS APPLICATION WILL (AIM 1) DISSECT THE MECHANISM(S) BY WHICH COMMENSAL MICROBES INFLUENCE MONOCYTE RECRUITMENT AND FUNCTION IN NEONATAL SKIN, (AIM 2) ELUCIDATE THE MECHANISM(S) BY WHICH NEONATAL MONOCYTES CONTRIBUTE TO SKIN IMMUNE HOMEOSTASIS AND (AIM 3) FUNCTIONALLY ELUCIDATE THE ROLE OF NEONATAL MONOCYTES IN HUMAN SKIN. RESULTS FROM THIS CROSS-DISCIPLINARY APPROACH WILL BENEFIT OUR UNDERSTANDING OF EARLY IMMUNE DEVELOPMENT AND LAY THE GROUNDWORK FOR NEXT GENERATION THERAPIES FOR CHRONIC INFLAMMATORY DISEASES. THE PROPOSED RESEARCH AND TRAINING PLAN WILL BUILD ON DR. DHARIWALA'S STRENGTHS IN THE FIELDS OF MICROBIOLOGY, IMMUNOLOGY AND TRANSLATIONAL SCIENCE. LEVERAGING TOOLS HE HAS ESTABLISHED IN THE HOST LAB, SUCH AS MASS CYTOMETRY, EX VIVO FUNCTIONAL ASSAYS IN HUMAN SKIN AND MANIPULATION OF SKIN-RESIDENT MYELOID CELL POPULATIONS IN MURINE MODELS, ALONG WITH STUDIES LIKE METABOLOMICS PROPOSED IN THIS APPLICATION WILL NOT ONLY ELEVATE THE PROJECT BUT ALSO ADVANCE HIS TRAINING. HIS SCIENTIFIC AND CAREER PROGRESS WILL BE WELL SUPPORTED BY A STRONG MENTORSHIP TEAM INCLUDING DRS. TIFFANY SCHARSCHMIDT, CLIFFORD LOWELL, MICHAEL ROSENBLUM AND PETER TURNBAUGH. ADDITIONALLY, THROUGH PRESENTATIONS AT LOCAL AND INTERNATIONAL CONFERENCES ALONG WITH FORMAL AND INFORMAL TRAINING AT UCSF DR. DHARIWALA WILL ADVANCE HIS TRANSITION TO INDEPENDENCE. PROMISING PRELIMINARY DATA, A STRONG TRAINING PLAN AND AN EXCELLENT TRAINING ENVIRONMENT WILL ALLOW DR. DHARIWALA TO CARVE OUT A NICHE FOR HIMSELF AND ESTABLISH AN INDEPENDENT RESEARCH PROGRAM STUDYING THE INFLUENCE OF COMMENSAL MICROBES ON MYELOID IMMUNE DEVELOPMENT IN NEONATAL BARRIER TISSUES.