# Regulators of Myofibroblast State Stability & Fibrotic Responsiveness of the Heart

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $621,846

## Abstract

PROJECT SUMMARY
Cardiac fibrosis is the pathologic development of scar tissue around the muscle cells of the heart. It
occurs with nearly every form of heart disease and rapidly progresses the heart to failure. A fundamental
cellular determinant of fibrosis is the transition of fibroblasts into myofibroblasts, which are the primary
producers of fibrotic matrix. Notably, myofibroblast revert to quiescence as organs including the heart
recover from some injuries and fibrosis resolves. New evidence from liver and skin suggests these
deactivated myofibroblasts are primed to reactivate with enhanced fibrotic responsiveness and wound
healing capabilities as a protective adaptation to future injury. This has never been examined in the heart,
but our preliminary data suggests cardiac fibrosis more than doubles when recovered hearts experience
a second bout of pathologic stress. Given heart disease develops from cumulative rounds of stress and
recovery, cardiac myofibroblasts likely undergo multiple cycles of deactivation and reactivation providing
impetus for delineating these processes and determining how they are regulated. Our previous work
suggests that p38 MAPK regulates the stability of the myofibroblast phenotype and the heart's fibrotic
response. Moreover, recent findings suggest p38 inhibition appears to deactivate myofibroblasts
reverting them to quiescence. This finding suggests that we can use experimental p38 perturbations of
the myofibroblast state to study its impact on the heart's fibrotic response. Hence two comprehensive
specific aims will be used to examine the overarching hypothesis that p38 regulation of myofibroblast
state stability and the kinetics and fate trajectory of deactivation underlies long-term fibrotic
responsiveness of the heart. Here single cell RNA sequencing in combination with myofibroblast lineage
reporter mice engineered with targeted gain or loss of p38 function will be used to determine: (Aim 1) the
role of p38 in regulating myofibroblast deactivation and resolving cardiac fibrosis, and (Aim 2) the effects
of p38 activity on deactivated cardiac myofibroblast reactivation, fibrotic responsiveness, and fibrotic
memory. Together these aims will attempt (A) to define the process and regulation of cardiac
myofibroblast deactivation and reactivation, (B) to identify compensatory responses to perturbations in
myofibroblast activity, and (C) to identify the function of deactivated myofibroblasts, their epigenetic
memories of injury, and their role in enhancing the heart's fibrotic responsiveness.

## Key facts

- **NIH application ID:** 10852861
- **Project number:** 5R01HL162229-03
- **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:** $621,846
- **Award type:** 5
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852861

## Citation

> US National Institutes of Health, RePORTER application 10852861, Regulators of Myofibroblast State Stability & Fibrotic Responsiveness of the Heart (5R01HL162229-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10852861. Licensed CC0.

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