# Investigating sex differences in persistent valvular myofibroblast activation using hydrogel culture substrates

> **NIH NIH R00** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $82,453

## Abstract

PROJECT SUMMARY
Aortic valve stenosis (AVS) is a progressive disease where fibroblast-like valvular interstitial cells (VICs) become
persistently activated myofibroblasts, which contribute to pathologic aortic valve leaflet stiffening. AVS is treated
with valve replacement surgeries, which may be avoided if small molecule drug combinations could be identified
to inhibit persistent myofibroblast activation. However, the molecular mechanisms regulating persistent
myofibroblast activation are unknown and may vary from patient-to-patient and/or by sex. My proposed R00
research seeks to continue characterizing the sex- and patient-specific differences that lead to persistent
myofibroblast activation during AVS and optimize drug combinations to inhibit myofibroblast activation as a
function of patient-specific cues. We hypothesize (i) sex-linked differences in how male and female VICs respond
to mechanical cues and (ii) patient-specific biochemical cues found in AVS patient sera contribute to persistent
activation and subsequent myofibroblast response to small molecule drugs. In Aim 1 (completed), we have
characterized genes that escape X-chromosome inactivation that regulate myofibroblast activation uniquely in
female VICs seeded on PEG hydrogels. In Aim 2 (in progress), we will generate persistently activated
myofibroblasts in human AVS patient sera and determine alterations (e.g. open chromatin regions) in the VIC
epigenome due to patient-specific serum factors using Assay for Transposase-Accessible Chromatin with
sequencing (ATAC-seq). In Aim 3 (proposed), we will identify optimal combinations of small molecule drugs to
inhibit persistent myofibroblast activation in the presence of AVS patient serum using a differential evolution
algorithm. In sum, the proposed research will address an urgent, unmet need for sex-specific and precision
medicine approaches for identifying molecular mechanisms of myofibroblast persistence, which may provide a
bridge toward non-surgical AVS therapies.

## Key facts

- **NIH application ID:** 10631477
- **Project number:** 3R00HL148542-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Brian Alberto Aguado
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $82,453
- **Award type:** 3
- **Project period:** 2021-09-05 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10631477

## Citation

> US National Institutes of Health, RePORTER application 10631477, Investigating sex differences in persistent valvular myofibroblast activation using hydrogel culture substrates (3R00HL148542-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10631477. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*