Probing sex differences in myocardial fibrosis at multiple length scales using biomaterials

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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.