Project Grant DP2HL173948

PROBING SEX DIFFERENCES IN MYOCARDIAL FIBROSIS AT MULTIPLE LENGTH SCALES USING BIOMATERIALS - PROJECT SUMMARY MY PROPOSED RESEARCH FOR THE NIH DIRECTOR'S NEW INNOVATOR AWARD SEEKS TO DETERMINE HOW BIOLOGICAL SEX MODULATES MYOCARDIAL FIBROSIS AND DEVELOP INNOVATIVE MODELS OF SEX-SPECIFIC TISSUE REMODELING USING ADVANCED BIOMATERIAL TECHNOLOGIES. MYOCARDIAL FIBROSIS, OR THE ABERRANT REMODELING OF EXTRACELLULAR MATRIX IN THE HEART, IS A COMMON OUTCOME OF SEVERAL CARDIAC PATHOLOGIES, INCLUDING VENTRICULAR PRESSURE OVERLOAD, MYOCARDIAL INFARCT, HYPERTENSION, CARDIAC INFLAMMATION, AND/OR GENETIC CARDIOMYOPATHIES, ALL OF WHICH CAN LEAD TO HEART FAILURE. EVEN THOUGH STANDARD-OF-CARE MEDICATIONS HAVE BEEN USEFUL TO HELP RELIEVE HEART FAILURE SYMPTOMS, CLINICALLY EFFECTIVE THERAPEUTICS TO HALT AND REVERSE MYOCARDIAL FIBROSIS PROGRESSION ARE NOT AVAILABLE. BIOLOGICAL SEX IS A POTENT MODULATOR OF MYOCARDIAL FIBROSIS. FOR EXAMPLE, CLINICAL STUDIES HAVE ESTABLISHED THAT PATIENTS EXPERIENCING DIASTOLIC DYSFUNCTION AND DEVELOP HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF) ARE 2.84-FOLD MORE LIKELY TO BE FEMALE. UNFORTUNATELY, THE HISTORICAL DEPENDENCE ON MALE-BIASED DISEASE MODELS FOR UNDERSTANDING MYOCARDIAL FIBROSIS HAS LEFT A SIGNIFICANT GAP IN UNDERSTANDING FEMALE-SPECIFIC HEART FAILURE MECHANISMS, CAUSING SIGNIFICANT HEALTH DISPARITIES IN TREATMENT OUTCOMES FOR FEMALE PATIENTS. TO CHANGE COURSE, OUR LABORATORY WILL DEVELOP SEX-SPECIFIC CARDIAC FIBROSIS MODELS AND DETERMINE PATHS TOWARD SEX-SPECIFIC THERAPIES TO HALT DISEASE PROGRESSION AND MOVE TOWARD EQUITABLE TREATMENT OUTCOMES. MY PROPOSAL OUTLINES AN INNOVATIVE RESEARCH PROGRAM TO IDENTIFY HOW X-CHROMOSOME DOSAGE IN CARDIAC MYOFIBROBLASTS GIVES RISE TO SEX DIFFERENCES IN MYOCARDIAL FIBROSIS AFTER INJURY. OUR THREE PROJECT THRUSTS CENTRALIZE AROUND THE HYPOTHESIS THAT X-CHROMOSOME DOSAGE REGULATES (1) MYOFIBROBLAST ACTIVATION SIGNALING NETWORKS IN CARDIAC FIBROBLASTS, (2) EXTRACELLULAR MATRIX REMODELING AFTER MYOCARDIAL INJURY, AND (3) INFLAMMATION DURING MYOCARDIAL FIBROSIS IN FEMALES. UNDERSTANDING SEX-SPECIFIC MECHANISMS OF MYOCARDIAL FIBROSIS MAY INFORM PATHS TOWARD SEX-SPECIFIC TREATMENT PROTOCOLS AND SIGNIFICANTLY IMPACT CLINICAL PRACTICE. IF SUCCESSFUL, THE PROPOSED RESEARCH WILL SIGNIFICANTLY AND BROADLY ADVANCE OUR FUNDAMENTAL UNDERSTANDING OF SEX-SPECIFIC BIOLOGY IN MYOCARDIAL FIBROSIS AND OTHER CARDIOVASCULAR DISEASES.