Project Grant F31HL189139

TEMPORAL EFFECTS OF CD8+ T-CELLS ON WOUND HEALING AFTER ACUTE MYOCARDIAL INFARCTION - PROJECT SUMMARY OVER 800,000 PEOPLE EACH YEAR IN THE UNITED STATES HAVE A MYOCARDIAL INFARCTION (MI). FOLLOWING AN MI, IMMUNE CELLS INFILTRATE THE NECROTIC AREA OF THE HEART AND BEGIN THE PROCESS OF SCAR DEVELOPMENT AND REMODELING. MYOCARDIAL AND CELLULAR REMODELING RESULTS IN VENTRICULAR DILATION AND ECCENTRIC HYPERTROPHY TO COMPENSATE FOR DECREASED SYSTOLIC FUNCTION BY MAINTAINING STROKE VOLUME AND SYSTEMIC PERFUSION. HOWEVER, PROGRESSIVE REMODELING CAN LEAD TO FURTHER MYOCYTE LOSS AND DECOMPENSATION. THUS, LV REMODELING AND SUBSEQUENT CONSTITUTIVE PROPERTIES OF THE FOCAL SCAR ARE IMPORTANT FOR HEART HEALTH. IMPROVING THE PROCESS OF SCAR FORMATION AND REMODELING TOWARDS CREATING A STIFFER, STRONGER FOCAL SCAR MAY HELP DECREASE THE RISK OF HEART FAILURE AND OTHER COMPLICATIONS FOR MI PATIENTS. WHILE STUDIES HAVE INDICATED INJURED CARDIOMYOCYTES CAN BE DESTROYED IN THE INFARCT BY CD8+ T-CELLS. THIS STUDY SEEKS TO UNDERSTAND HOW THE TEMPORAL REGULATION OF CD8+ T-CELLS AFFECTS THE PROLIFERATIVE AND MATURATION STAGES OF POST-MI CARDIAC REMODELING. ACCORDINGLY, I HYPOTHESIZE THAT CD8+ T-CELLS IMPAIR POST-MI SCAR FORMATION BY UNDERGOING TEMPORAL CHANGES THAT MODULATE FIBROBLAST ACTIVATION. I WILL TEST THIS HYPOTHESIS BY USING A NOVEL INDUCIBLE MOUSE MODEL TO DEPLETE CD8+ T-CELLS AT DIFFERENT TIMEPOINTS AFTER MI. PRELIMINARY DATA SHOW THAT CD8+ T-CELLS EXHIBIT VARYING TEMPORAL PHENOTYPES OVER THE POST-MI TIME COURSE. I SEEK TO FURTHER CHARACTERIZE THESE TEMPORAL CHANGES AND DETERMINE THEIR EFFECTS ON CARDIAC FUNCTION, SCAR BIOMECHANICS, AND INTERACTIONS WITH CARDIAC FIBROBLASTS BY USING A COMBINATION OF METHODS INCLUDING SERIAL ECHOCARDIOGRAPHY, SINGLE CELL SEQUENCING OF T-CELLS POST-MI, EX VIVO SCAR BIOMECHANICAL TESTING, AND IN VITRO ASSAYS. OVERALL, THE GOAL OF THIS PROJECT IS TO IDENTIFY IDEAL TIMEPOINTS FOR DEPLETING CD8+ T-CELLS POST-MI TO ENSURE OPTIMAL SCAR FORMATION AND IMPROVED CARDIAC FUNCTION IN MI PATIENTS, WHICH WILL BE CRUCIAL FOR IMMUNOTHERAPY DEVELOPMENT.