# Decoupling sex chromosome and sex hormone regulation of cardiac myofibroblast activation

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $42,132

## Abstract

PROJECT SUMMARY
Heart failure is a result of aberrant matrix remodeling in the left ventricle; male patients experience ventricular
wall thinning, whereas females experience ventricular wall thickening. While current pharmacologic agents
palliate symptoms associated with heart failure, the morbidity of the disease remains high as these treatments
do not provide a universal cure, necessitating a sex-specific understanding of heart failure. Mechanical cues and
gonadal hormones regulate the sex-specific cardiac remodeling observed during heart failure through changes
in the extracellular matrix (ECM). Resident cardiac fibroblasts that reside in the ventricular wall largely regulate
aberrant ECM remodeling during heart failure, but the sex-specific regulation of cell-mediated ECM remodeling
remains poorly understood. Both sex hormones and sex chromosomes have been implicated in regulating sex
differences in cardiac ECM remodeling, but current methods do not decouple their synergistic effects. My
proposal seeks to decouple the effects of sex chromosomes and sex hormones using gonadectomized animal
models and biomaterials-based cell culture tools that recapitulate the cardiac ECM during fibrotic stiffening. Our
laboratory tools enable our central hypothesis: sex chromosome combination and gonadal hormones
synergistically regulate myofibroblast phenotypes, and X-chromosome linked genes and estrogen
dosage will promote myofibroblast matrix remodeling. The hypothesis will be investigated through the
following aims: Aim 1 will improve our understanding of myofibroblast populations that drive sex-specific matrix
remodeling independent of gonadal hormones; Aim 2 will use engineered hydrogels to mimic sex-specific
myofibroblast phenotypes in vitro; Aim 3 will investigate the role of estrogen and estrogen receptor expression
on mediating the myofibroblast phenotype independent of sex chromosome combination. By leveraging animal
models and biomaterial technologies, this study will unveil a robust understanding of the myofibroblast phenotype
by decoupling the effects of sex chromosomes and sex hormones. If successful, the proposed research will
significantly advance the understanding of sex-specific biology in myocardial fibrosis.

## Key facts

- **NIH application ID:** 10998141
- **Project number:** 1F31HL176153-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Rayyan Gorashi
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,132
- **Award type:** 1
- **Project period:** 2024-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998141

## Citation

> US National Institutes of Health, RePORTER application 10998141, Decoupling sex chromosome and sex hormone regulation of cardiac myofibroblast activation (1F31HL176153-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10998141. Licensed CC0.

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