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

> **NIH NIH R00** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $248,997

## Abstract

PROJECT SUMMARY / ABSTRACT
 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 current
research has revealed that persistent myofibroblasts can be obtained on stiff poly(ethylene glycol) (PEG)
hydrogels that recapitulate fibrotic valve stiffness, and our preliminary data suggest sex-specific differences in
how male and female VICs obtain persistence over time. My research also suggests serum factors from
individual AVS patients variably impact myofibroblast activation on engineered hydrogels. My proposed research
seeks to characterize the sex- and patient-specific differences that lead to persistent myofibroblast activation
during AVS in the mentored K99 phase and optimize drug combinations to inhibit myofibroblast activation as a
function of patient-specific cues in the independent R00 phase. 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, we will characterize sex-linked epigenetic modifiers that regulate myofibroblast persistence pathways in male
and female VICs seeded on PEG hydrogels using chromatin characterization assays and transcriptomics
analyses. In Aim 2, 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, 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 that correlates myofibroblast inhibition with a
personalized combinatorial drug dose. In the K99 phase of the award, Prof. Kristi Anseth will serve as my main
mentor, who is a pioneer in using PEG hydrogel materials for manipulating cellular phenotypes. I will consult my
mentoring team, including Prof. Leslie Leinwand (sex-specific cardiac diseases), Prof. Tim McKinsey
(epigenetics during fibrosis), Dr. Mary Allen (short-read sequencing), and Prof. Dean Ho (computational
algorithms for optimizing drug treatments). My K99 training will consist of learning key short-read sequencing
and epigenetic characterization techniques to propel me toward developing precision medicine-based treatments
for AVS using biomaterials durin...

## Key facts

- **NIH application ID:** 10480909
- **Project number:** 5R00HL148542-04
- **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:** $248,997
- **Award type:** 5
- **Project period:** 2021-09-05 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480909

## Citation

> US National Institutes of Health, RePORTER application 10480909, Investigating sex differences in persistent valvular myofibroblast activation using hydrogel culture substrates (5R00HL148542-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10480909. Licensed CC0.

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