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.

PROJECT NARRATIVE The proposed research is relevant to public health because we aim to develop new bioengineered technologies to determine the biological mechanisms that regulate sex differences in heart failure and identify paths to sex-specific treatment options. This project is relevant to the mission of the NIH, as the development of sex-specific treatment options would impact 6.2 million individuals in the United States currently living with heart failure and help move toward resolving sex and gender health disparities in cardiovascular medicine.