# Understanding valvular fibroblast mechanical memory using photo-tunable PEG hydrogels

> **NIH NIH F31** · UNIVERSITY OF COLORADO · 2020 · $31,251

## Abstract

PROJECT SUMMARY
Aortic valve stenosis (AVS) is a progressive disease characterized by excessive deposition of the extracellular
matrix (ECM) components in the aortic valve, leading to increased valve stiffness and eventual heart failure.
Unfortunately, the only current treatment is invasive surgical valve replacement or repair. A non-surgical
alternative for treating AVS would reduce complications related to surgery, however, developing a
pharmacological treatment has been limited by an incomplete understanding of disease progression. The clinical
consensus is that early stages of AVS are characterized by persistent activation of resident fibroblasts (VICs).
In healthy tissue, VICs transiently activate to myofibroblasts to repair injured tissue. In disease, chronic exposure
to increased tissue stiffness prevents reversal of myofibroblast to quiescent VICs, resulting in persistently
activated myofibroblasts. This time-dependent myofibroblast persistence implies VICs possess a mechanical
memory of their past environments. Mesenchymal stem cells also possess a mechanical memory which is
maintained through chromatin remodeling. In this proposal, we seek to understand the regulatory mechanisms
responsible for myofibroblast persistence that will provide insights into AVS progression and identify potential
therapy targets. We hypothesize that chromatin remodeling plays a role in myofibroblast persistence. In Aim I,
we will determine the role of epigenetics in myofibroblast persistence. First, we will identify the mechanical cues
that lead to transiently or persistently activated myofibroblasts. We will use photo-tunable PEG hydrogels where
the hydrogel modulus may be tuned via UV light exposure to achieve moduli that mimic the stiffness of healthy
and fibrotic tissues. We will initially culture VICs for varying times on stiff hydrogels, followed by an in situ modulus
reduction to a softer hydrogel stiffness to mimic native tissue. After recovery at specified time points, VICs will
be analyzed for persistence using established myofibroblast markers. To identify if mechanical cues play a role
in chromatin remodeling, we will identify chromatin architecture differences between transient and persistent
myofibroblasts by 1) immunofluorescence of methylation and acetylation, 2) RT-qPCR to measure the gene
expression of common chromatin modifiers, 3) MATLAB algorithm to measure chromatin condensation. Finally,
we will use chromatin remodeling inhibitors to determine if epigenetics plays a role in persistence. We will culture
VICs under conditions to induce myofibroblast persistence, with and without the inhibitor, to determine if
persistence is altered measured by the established myofibroblast markers. In Aim II, we will characterize
molecular differences between the transient and persistently activated myofibroblasts by examining the RNA
transcriptome of each myofibroblast population and identifying differentially expressed genes and signaling
pathways betwee...

## Key facts

- **NIH application ID:** 9984515
- **Project number:** 5F31HL142223-03
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Cierra Walker
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,251
- **Award type:** 5
- **Project period:** 2018-08-15 → 2021-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984515

## Citation

> US National Institutes of Health, RePORTER application 9984515, Understanding valvular fibroblast mechanical memory using photo-tunable PEG hydrogels (5F31HL142223-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9984515. Licensed CC0.

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