# Uncovering The Mechanogenomic Basis For Cardiac Plasticity

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $441,250

## Abstract

PROJECT SUMMARY
Heart disease has been the leading cause of death in this country for over eighty years. Two fundamental
drivers of heart failure are architectural remodeling and matrix deposition (fibrosis). Both of which lack targeted
interventions for their prevention or reversal underscoring the need to decipher the molecular basis for this
maladaptive structural remodeling. Mechanical forces influence cellular architecture throughout the body,
especially in blood vessels, muscle and bone. In accordance with these findings we recently demonstrated that
myocyte biomechanics is a primary driver of the nature and severity of cardiac structural remodeling. These
data led to the development of a computational description of a cardiac myocyte's mechanical state called the
tension index, which trumped all other molecular-genetic metrics as a predictor of the heart's architectural
phenotype and disease state in mice and inherited cardiomyopathy patients. This new mechanical paradigm
holds promise for early prevention and customized mechanical interventions that could reprogram maladaptive
growth and geometry back to normal provided the following key questions are resolved: (1) How do the
collective actions of fibroblasts and myocytes that regulate mechanical homeostatic feedback mechanisms
guide cardiac plasticity; (2) How is mechanical disequilibrium that is associated with cardiac remodeling
sensed by fibroblasts and myocytes; and (3) how do mechanical imbalances alter myocyte epigenetic and
transcriptional patterns. Using a newly engineered mouse genetics approach that permits the tactical tuning of
the heart's mechanical properties, this application will address these questions by testing the central
hypothesis that the magnitude and direction of mechanical disequilibrium initiates predictable architectural
remodeling that is reversible by balancing intra and extracellular mechanics. This approach overcomes the
field's inability to study mechanical relationships in vivo, which will reveal for the first time how coordinated
actions and integration of mechanical sources directs cardiac plasticity. Here these mechanical homeostatic
feedback mechanisms will be coopted to discover biomarkers of the heart's mechanical state and hence
structural remodeling. We anticipate these findings will fulfill the clinically unmet need for a predictive
diagnostic tool and preventive strategy for maladaptive fibrotic and architectural remodeling of the heart.

## Key facts

- **NIH application ID:** 10186474
- **Project number:** 5R01HL142624-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Jennifer Michelle Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $441,250
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186474

## Citation

> US National Institutes of Health, RePORTER application 10186474, Uncovering The Mechanogenomic Basis For Cardiac Plasticity (5R01HL142624-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10186474. Licensed CC0.

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