Project Grant K08AI182489

MECHANISMS OF REGULATORY T CELL ADAPTATION TO INFLAMMATION - PROJECT SUMMARY/ ABSTRACT THIS IS AN APPLICATION FOR A K08 AWARD FOR DR. NIKOLAOS SKARTSIS, AN ASSISTANT PROFESSOR OF MEDICINE AT MAYO CLINIC COLLEGE OF MEDICINE AND SCIENCE, ROCHESTER, MN. DR. SKARTSIS IS ESTABLISHING HIMSELF AS A YOUNG INVESTIGATOR IN CLINICAL SCIENCE RESEARCH WITH A TRANSLATIONAL FOCUS ON THE IMPACT OF INFLAMMATION ON REGULATORY T CELLS (TREGS) WITH AN OVERARCHING GOAL TO DESIGN THE NEXT GENERATION TREG-ENHANCING THERAPIES FOR TRANSPLANTATION. THIS K08 AWARD WILL PROVIDE DR. SKARTSIS WITH THE SUPPORT NECESSARY TO ACCOMPLISH THE FOLLOWING GOALS: (1) TO BECOME AN EXPERT TRANSLATIONAL RESEARCHER IN TREG BIOLOGY AS IT RELATES TO INFLAMMATION; (2) TO DEVELOP ALL THE TOOLS NECESSARY TO HAVE AN INDEPENDENT TRANSLATIONAL RESEARCH CAREER. TO ACHIEVE THESE GOALS, DR. SKARTSIS HAS ASSEMBLED A MULTIDISCIPLINARY MENTORING TEAM OF EXPERTS COMPRISED OF HIS PRIMARY MENTOR, DR. WILLIAM FAUBION, EXPERT IN BASIC AND TRANSLATIONAL RESEARCH IN TREG BIOLOGY AND EPIGENETICS; CO-MENTORS ARE: DR. CORNELIA WEYAND, EXPERT IN IMMUNOMETABOLISM; DR. VIRGINIA SHAPIRO, EXPERT IN T CELL ACTIVATION AND MATURATION; DR. MARK STEGALL, EXPERT IN CLINICAL TRIALS IN KIDNEY TRANSPLANTATION, AND DR. VESNA GAROVIC, EXPERT IN IMMUNOLOGICAL MECHANISMS OF PREECLAMPSIA. HE HAS ESTABLISHED COLLABORATIONS WITH DR. SUN, EXPERT IN BIOINFORMATICS, AND DR. WANGENSTEEN, EXPERT IN CRISPR SCREENS. THE IMPACT OF INFLAMMATORY SIGNALS ON TREGS IS NOT WELL UNDERSTOOD DESPITE THE PIVOTAL CONTRIBUTION OF TREGS TO TERMINATE IMMUNE RESPONSES AND MAINTAIN IMMUNE SYSTEM HOMEOSTASIS. THE CENTRAL HYPOTHESIS FOR THIS PROPOSAL IS THAT HUMAN TREGS CAN POSITIVELY RESPONSE TO PROINFLAMMATORY CYTOKINES BY STABILIZING THEIR CELL LINEAGE, WHILE CLONALLY EXPAND TO SCALE TO INFLAMMATION. MOLECULAR MECHANISMS THAT CONTROL HUMAN TREG LINEAGE STABILITY AND PROLIFERATION IN INFLAMMATION ARE NOT FULLY UNDERSTOOD, WHICH WILL BE THE FOCUS OF HIS RESEARCH IN THE NEXT 5 YEARS. IN AIM 1, DR. SKARTSIS WILL STUDY THE TRANSCRIPTIONAL AND EPIGENETIC CHANGES INDUCED BY TNFR2 THAT PROMOTE FOXP3 EXPRESSION IN TREGS. IN AIM 2, HE WILL ANALYZE THE TRANSCRIPTIONAL AND METABOLOMIC CONTROL OF TREG PROLIFERATIVE FITNESS UNDER INFLAMMATORY CONDITIONS. THIS PROPOSAL REPRESENTS AN INNOVATIVE APPROACH TO STUDYING TREG BIOLOGY BECAUSE IT INCORPORATES CRISPR GENE EDITING, FUNCTIONAL GENOMICS, AND IN-VIVO DISEASE MODELING IN HUMANIZED NSG MICE TO DISSECT THE IMPACT OF INFLAMMATORY SIGNALS ON TREG HOMEOSTASIS THAT HAVE NOT PREVIOUSLY APPLIED TOGETHER IN TREG STUDIES IN TRANSPLANTATION OR AUTOIMMUNE DISEASES. THIS PROJECT ADDRESSES A MAJOR GAP IN OUR KNOWLEDGE OF THE IMPACT OF INFLAMMATION ON TREGS, AND THE TRAINING PLAN IT REQUIRES WILL FORM THE BASIS FOR A COMPELLING R01 GRANT APPLICATION TO HARNESS THE MOLECULAR PATHWAYS THAT PROMOTE TREG SURVIVAL AND FUNCTION UNDER INFLAMMATORY CONDITIONS TO DESIGN THE NEXT GENERATION OF TREG ENHANCING THERAPIES IN TRANSPLANTATION AND AUTOIMMUNE DISEASES.