# MTSS1 in Myocardial Disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $795,028

## Abstract

PROJECT SUMMARY
Heart failure is a complex and heterogeneous syndrome that imposes a substantial burden on public health.
Despite decades of investment in basic research in cardiomyocyte biology, pharmacotherapy exclusively
targets the neurohormonal response to heart failure and does not directly target myocyte dysfunction. The
substantial investment in understanding myocyte biology thus remains untranslated to patient benefit.
Approaches that have appeared promising in animal models have frequently proven ineffective in human
subjects, casting doubt on the relevance of such models alone to identify the most compelling targets.
Genome science in very large population samples has now matured to the point where targets of in vivo
relevance in humans can be identified directly through genetic association alone. Human genomics thus
provides a roadmap for target selection and a focus for experiments in model systems and drug development.
Using a combination of population genomic, transcriptomic, and epigenomic approaches, we have uncovered
compelling evidence supporting MTSS1 as a therapeutic target for human myocardial disease. In our
preliminary studies, we have found that genetic variants within a cardiac-specific enhancer reduce expression
of MTSS1 specifically in the left ventricle and associate with multiple cardioprotective phenotypes in human
populations, including reduced left ventricular (LV) mass, reduced LV diameter, increased fractional
shortening, and reduced risk of dilated cardiomyopathy. Further, we have found that Mtss1 knockout mice
have a baseline cardiac phenotype that parallels findings in humans (reduced LV mass, LV dimension, and
increased ejection fraction). These findings motivate our central hypothesis that reduction of MTSS1 will be
cardioprotective for myocardial diseases. The overall goals of this proposal are to (1) refine the patient
subgroup(s) that might benefit the most from MTSS1 reduction, (2) establish causality of the association
between reduced MTSS1 and cardioprotection, and (3) modulate cardiac MTSS1 expression in vivo to assess
therapeutic effects and protein biology.

## Key facts

- **NIH application ID:** 10219827
- **Project number:** 5R01HL141232-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** THOMAS P. CAPPOLA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $795,028
- **Award type:** 5
- **Project period:** 2019-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219827

## Citation

> US National Institutes of Health, RePORTER application 10219827, MTSS1 in Myocardial Disease (5R01HL141232-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10219827. Licensed CC0.

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