# Comprehensive Analysis of Allelic, Cellular and Molecular Heterogeneity in Human 3-Dimensional Cardiac Microtissues with MYH7 Mutations

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $539,937

## Abstract

PROJECT SUMMARY/ABSTRACT
 Hypertrophic cardiomyopathy (HCM) patients are at risk for sudden cardiac death and progressive heart
failure (HF), and there are no effective therapeutics, due in part to our limited genetic understanding of HCM
pathogenesis. There are critical gaps in our current knowledge of the molecular mechanisms that link specific
mutations in the beta myosin heavy chain gene (MYH7) to pathological thickening of the heart muscle that is
associated with HCM. Our long-term goals are to utilize genomic tools combined with 3-dimensional cardiac
microtissues derived from human induced pluripotent stem cells to interrogate mechanisms of HCM secondary
to specific MYH7 variants, and to utilize these insights to identify new disease biomarkers and therapeutic targets
for specific HCM patients.
 Our previous studies identified that two HCM-associated MYH7 variants, arginine 403 to glutamine and
valine 606 to methionine that are located in the actin-binding domain of beta myosin heavy chain protein (MHC-
β), generate increased microtissue contraction force with associated abnormalities in contraction kinetics.
Studies by others have indicated that MYH7 variants located in distinct structural domains of MHC-β cause
distinct phenotypes. These results lead to our central hypothesis that HCM is a heterogeneous disorder, in which
patient symptoms and therapeutic responses are dependent on the location of the causative MYH7 variant(s)
within the gene and on cell-type specific transcriptional and epigenetic programs, which initiate from
abnormalities in contractile function. Guided by our comprehensive preliminary data, we propose to pursue three
Specific Aims to determine multi-scale insights into HCM pathogenesis: (1) to characterize functional
consequences of MYH7 variants localized to the actin-binding, ATP-binding and converter domains of MHC-
β, (2) to identify cell type-specific transcriptional and epigenetic mechanisms of HCM in microtissues using paired
single-cell RNA-seq and ATAC-seq and (3) to interrogate the function of C1ORF105, a nuclear-encoded
mitochondrial protein that is associated with HCM and is specifically expressed in human cardiomyocytes.
 In summary, the execution of these aims will provide a more precise understanding of the functional role
of MYH7 variant localization, generate novel cell-type specific and molecular mechanisms of HCM and identify
critical molecular linkages between sarcomere and mitochondrial function that will broadly impact the field of
HCM and heart failure.

## Key facts

- **NIH application ID:** 9983170
- **Project number:** 5R01HL142787-03
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** John Travis Hinson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $539,937
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983170

## Citation

> US National Institutes of Health, RePORTER application 9983170, Comprehensive Analysis of Allelic, Cellular and Molecular Heterogeneity in Human 3-Dimensional Cardiac Microtissues with MYH7 Mutations (5R01HL142787-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9983170. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*