# Uncovering The Mechanogenomic Basis For Cardiac Plasticity

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $732,762

## Abstract

PROJECT SUMMARY / ABSTRACT
Inherited mutations in sarcomeric genes, which decrease cardiac myocyte tension generation, are principal
drivers of dilated cardiomyopathy (DCM)– the leading cause of heart failure. Progress towards developing
precision therapeutics for and defining the underlying determinants of DCM has been entirely cardiac myocyte
centric with negligible attention directed towards fibroblasts despite their role in regulating the best predictor of
DCM severity, cardiac fibrosis. Our recent findings in a mouse model of inherited DCM demonstrated that prior
to the onset of fibrosis and dilated myocyte remodeling both the myocardium and extracellular matrix (ECM)
stiffen from enhanced collagen fiber alignment and expansion of the cardiac fibroblast population, which was
reversed by blocking cardiac fibroblast function with targeted genetic silencing of p38. This cardiac fibroblast-
targeted intervention unexpectedly improved the primary cardiac myocyte defects in contractile function and
reversed ECM and dilated myocardial remodeling. Together these findings challenge the long-standing paradigm
that ECM remodeling is a secondary complication to inherited defects in myocyte contractile function and instead
demonstrate cardiac fibroblasts play an unequivocal role in DCM outcomes. As an extension of this work we
propose the overarching hypothesis that atypical p38-mediated fibroblast adaptations to DCM-linked sarcomere
mutations are irreversible with myocyte-centric approaches, owing to the disproportionate expansion of
sensitized and hyperresponsive Periostin+ fibroblasts during postnatal development that when left functionally
enabled by myocyte-targeted therapies leave inherited DCM hearts vulnerable to heightened fibrosis. This
hypothesis will be tested with the following aims: [Aim 1] Examine the developmental & molecular basis for
adaptive cardiac fibroblast expansion in an inherited DCM mouse model; [Aim 2] Examine the effectiveness of
myocyte versus fibroblast-targeted genetic interventions at various stages of DCM disease progression; and
[Aim 3] Examine the generalizability of p38-dependent cardiac fibroblast response to inherited & acquired DCM.
Outcomes from this work will start to resolve unknown fibroblast-based mechanisms that link primary myocyte
defects with the DCM disease process and identify whether therapeutic interventions for DCM may require
fibroblast-specific strategies to be effective.

## Key facts

- **NIH application ID:** 10977913
- **Project number:** 2R01HL142624-05A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Jennifer Michelle Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $732,762
- **Award type:** 2
- **Project period:** 2018-07-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977913

## Citation

> US National Institutes of Health, RePORTER application 10977913, Uncovering The Mechanogenomic Basis For Cardiac Plasticity (2R01HL142624-05A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10977913. Licensed CC0.

---

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