# Characterization of Pathological Pathways of Hypertrophic Cardiomyopathy at Single Cell Resolution

> **NIH NIH F32** · TUFTS MEDICAL CENTER · 2020 · $31,772

## Abstract

Project Summary
 Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular
disease, but the molecular mechanisms driving the disease remain poorly understood. HCM
displays a vast phenotypic heterogeneity, but is characterized by left ventricular hypertrophy
unexplained by secondary causes, asymmetric, and typically accompanied by a preserved or
increased ejection fraction. In addition, the cardiomyocytes often display hypertrophy and
disarray in HCM. The clinical presentation can run the gamut from a relatively benign course to
sudden cardiac death. HCM has primarily been thought of as a disease of the sarcomere with
mutations in more than a dozen sarcomere-associated proteins correlated with HCM. However,
up to about 70% of HCM cases do not have disease causing sarcomere mutations.
Furthermore, the pleiotropic effects that are observed in both myocyte and non-myocyte
populations in HCM are not easily explained by these mutations.
 To understand the underlying cause of HCM, we have chosen an unbiased approach to
determine the pathogenic alterations at single cell resolution. At Tufts Medical Center, we have
one of the largest HCM referral centers, performing approximately 100 septal myectomy
surgeries per year to alleviate symptoms of obstructive HCM, a severe form of the disease. We
propose to identify pathological pathways activated in human myectomy samples at single cell
resolution. Our specific aims are: 1. Identify genes that are differentially expressed in different
cardiomyocyte populations in human myectomy samples using single nuclei RNA-Seq 2.
Develop a mouse model that recapitulates the human HCM phenotype 3. Characterize the role
of RARRES1, a top candidate from our preliminary data, plays in hypertrophy, fatty acid
metabolism, and autophagy in HCM. We will generate nuclei suspensions from myectomy
tissue and use commercial systems to isolate thousands of individual nuclei for RNA-Seq. We
will use CRISPR/Cas9 to target MYBPC3 to generate a mouse model that phenocopies human
HCM to study drug targets and therapies of HCM. Top candidates from these studies will be
further analyzed using mouse neonatal cardiomyocytes. The goal of these studies is to gain a
better understanding of the underlying pathogenesis of HCM. This approach is innovative in
that it uses an advanced single cell transcriptomics approach on a unique clinical resource
available at our center. To the best of our knowledge, this approach has not been done before.
The results from this study will not only lead to a better understanding of the pathology of this
disease, but will uncover new potential therapeutic targets and treatments for patients.

## Key facts

- **NIH application ID:** 9908805
- **Project number:** 1F32HL147492-01A1
- **Recipient organization:** TUFTS MEDICAL CENTER
- **Principal Investigator:** Amy Larson Gordon
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,772
- **Award type:** 1
- **Project period:** 2020-03-01 → 2020-08-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908805

## Citation

> US National Institutes of Health, RePORTER application 9908805, Characterization of Pathological Pathways of Hypertrophic Cardiomyopathy at Single Cell Resolution (1F32HL147492-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9908805. Licensed CC0.

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