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.

Grant Number: 1DP2HL173948-01
NIH Institute/Center: NIH
Principal Investigator: Brian Aguado