# Hydrogels to Study Synergistic Effects of Signaling Factors and Matrix Mechanics on Valve Disease Progression

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2020 · $360,945

## Abstract

Myofibroblast activation of Valvular Interstitial Cells (VICs) is considered to be a primary driver of
valvular fibrosis and stenosis. For this reason, the external cues that act to control the
myofibroblast phenotype of VICs have been topics of considerable attention in the field.
Increasing evidence suggests that beyond receptor-mediated activation of VICs by soluble growth
factors, physical cues from the matrix play a critical role in this process. Unfortunately, traditional
methods used to culture VICs inherently leads to their myofibroblast activation, such that it
becomes difficult to determine the effects of environmental stiffness on activation and especially
de-activation. To address this issue, our group has demonstrated that unique hydrogel materials
can be used to create soft, non-activating substrates for VIC culture that allow VICs to maintain a
phenotype that more closely resembles that of freshly isolated cells. Now, we aim to examine how
matrix stiffness in combination with pro-inflammatory cytokines influence the VIC fibroblast-to-
myofibroblast transition, the epigenetic changes that may occur to these cells over time, and the
pathways in matrix signaling that might be useful in reversing the pathogenic myofibroblast
phenotype. Specifically, we propose to: 1) Use a combinatorial approach to study the effect of
pro-inflammatory cytokines on VIC phenotypes as a function of microenvironmental stiffness 2)
Identify the effects of mechanical and inflammatory cues on the fibroblast-to-myofibroblast
transition and its reversal using hydrogels with dynamically tunable mechanical properties, and 3)
Discover new molecular targets for therapeutics to temper pathogenic VIC myofibroblast
activation under inflammatory conditions. Together, work completed within each of these Aims
will provide unique insight into the progression of fibrotic aortic valvular stenosis. The creation of
tunable cell culture platforms will allow us to answer questions about differences between
reversible (transient, wound healing state) and irreversible (persistent, pathogenic state) VIC
myofibroblasts that cannot be adequately addressed with traditional methods. Subsequent
analysis of the signaling pathways and genes will be used to identify new targets with therapeutic
potential to reverse VIC activation and treat valve disease. Moreover, successful completion of
these Aims should be of general interest to the field of medicine, as mechanisms of fibrosis are
likely shared among most fibrosis-related diseases.

## Key facts

- **NIH application ID:** 9838810
- **Project number:** 5R01HL132353-04
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** KRISTI S. ANSETH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,945
- **Award type:** 5
- **Project period:** 2016-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838810

## Citation

> US National Institutes of Health, RePORTER application 9838810, Hydrogels to Study Synergistic Effects of Signaling Factors and Matrix Mechanics on Valve Disease Progression (5R01HL132353-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9838810. Licensed CC0.

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