# Hypertrophic cardiomyopathy-induced paracrine signaling and stromal activation

> **NIH NIH F31** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2021 · $46,036

## Abstract

PROJECT SUMMARY/ABSTRACT
Hypertrophic cardiomyopathy (HCM) affects 1:500 of the population and is the leading cause of sudden cardiac
death in young people. Clinical presentation of HCM includes thickening of the left ventricular wall, diastolic
dysfunction, and fibrosis. Tissue remodeling from fibrosis replaces 30 to 50% of the myocardium in end-stage
HCM and is a key determinant in patient outcome. Mutations in numerous sarcomeric proteins that regulate
cardiac contractility have been identified as causes of HCM, about 30% of which are in located β-myosin heavy
chain (MYH7), but it remains unclear how the intrinsic changes in contractility of cardiomyocytes lead to fibrotic
remodeling. While previous studies have provided important insight into fibrosis, limitations in experimental
models, such as limited patient samples, limited ability to study human cardiomyocytes ex vivo, and species
variances in cardiovascular biology, have made it difficult to determine a mechanism of fibrosis preceding stromal
activation. Advancements in human induced pluripotent stem cell (hiPSC) and CRISPR/Cas9 technology have
allowed investigators to model and study inherited cardiac diseases compared to a healthy isogenic background
in vitro. While hiPSC-CMs have provided important insight into functional changes in diseased cardiomyocytes,
a multicellular 3D model is needed to study the pathological remodeling in fibrosis. Cardiac microtissue (CMT)
platforms offer a unique tool to study the effects of cardiomyocytes on stromal cells and the microenvironment.
The overall hypothesis of this proposal is that MYH7-variant hiPSC-CMs pathogenically activate stromal
cells through paracrine signaling, leading to a fibrotic phenotype. This proposal will determine targets to
attenuate a fibrotic phenotype in the following Specific Aims. Aim 1. To model stromal activation in MYH7-variant
hiPSC-CM in vitro models of HCM. Aim 2. To determine key paracrine factor signaling from pathogenic MYH7
variants that leads to a fibrotic response in stromal cells. Aim 3. To target paracrine factor receptors in stromal
cells to decrease fibrotic development in MYH7-variant CMTs. The in vitro model of stromal activation will be
characterized and validated with the quantification of collagen deposition, stiffness, gene expression, and
contractility. The paracrine signaling from MYH7-variant hiPSC-CM leading to these changes will be identified
using a combination of conditioned media experiments, phosphoproteomics, and RNA-sequencing. Key
signaling pathways will be targeted with small-molecule inhibitors, and the attenuation of stromal activation will
be confirmed through the quantification of collagen deposition, stiffness, gene expression, and contractility. The
results of this study will provide new insights into the disease pathology of HCM and will provide potential
therapeutic targets to attenuate this pathology, and thus improve clinical outcomes.

## Key facts

- **NIH application ID:** 10234370
- **Project number:** 1F31HL158195-01
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** Jourdan Ewoldt
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10234370

## Citation

> US National Institutes of Health, RePORTER application 10234370, Hypertrophic cardiomyopathy-induced paracrine signaling and stromal activation (1F31HL158195-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10234370. Licensed CC0.

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