# Role of ROCK isoform-mediated actin cytoskeleton modification in the pathogenesis of heart disease

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $436,060

## Abstract

PROJECT ABSTRACT
 The prevention and treatment of heart disease remain challenging. Rho kinase (also named ROCK)
has recently emerged as a potential therapeutic target for various cardiovascular diseases. A long-term goal of
our past twenty years of research on ROCK pathophysiology is to define the roles and underlying mechanisms
of ROCK-mediated signal pathway in regulating cardiac remodeling. The two members of the ROCK family,
ROCK1 and ROCK2, have both shared and distinct cellular functions and can compensate each other in
numerous single isoform knockout conditions. The majority of our knowledge on the cellular and molecular
function of ROCKs comes from research on proliferative cell types in which ROCKs modulate actin
cytoskeleton organization through promoting actomyocin contraction and F-actin stabilization. Cardiomyocytes
stand apart from other cell types because they contain both sarcomeric and non-sarcomeric cytoskeleton.
There is a gap in our knowledge on how ROCKs regulate sarcomeric and non-sarcomeric F-actin in
cardiomyocytes and how these processes contribute to overall heart function. Recently, for the first time to use
inducible approach to delete both ROCK isoforms in cardiomyocytes, we have discovered that although
ROCKs are not required for maintaining sarcomeric cytoskeleton in adult hearts, they do participate in the
regulation of non-sarcomeric F-actin organization, inhibit autophagy by promoting mammalian target of
rapamycin (mTOR) activity and contribute to age-related cardiac fibrosis. In contrast, the non-sarcomeric F-
actin dynamics are able to be maintained with the presence of either isoform in the cardiomyocytes where the
other isoform has been deleted; this might be attributed to compensatory over-activation of the remaining
isoform in cardiomyocytes having single ROCK isoform deletion. The proposed research aims to further
elucidate the pathophysiological roles and downstream pathways of ROCK-mediated actin cytoskeleton
changes in cardiomyocytes and fibroblasts under pathological stress sceneries. Aim 1 will determine if deletion
of both ROCK1 and ROCK2 from adult cardiomyocytes limits the progression of heart failure in pathological
hypertrophy and myocardial ischemic injury through activating autophagy and facilitating autophagic flux by
inhibiting mTOR signaling. Aim 2 will determine if deletion of both ROCK1 and ROCK2 from adult fibroblasts
limits the activation of myofibroblasts and fibrotic response through inhibition of F-actin regulated transcription
factor activation including the serum response factor (SRF) and myocardin-related transcription factors
(MRTFs); the direct contribution of ROCKs/F-actin/MRTFs/SRF axis in fibroblasts to cardiac fibrosis has never
been demonstrated in vivo, and our preliminary results indicate that the inducible approach is required for
double ROCK knockout in fibroblasts. The biomedical significance of this work is to provide the cutting-edge
concepts for understanding patho...

## Key facts

- **NIH application ID:** 10762336
- **Project number:** 5R01HL151480-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Jianjian Shi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $436,060
- **Award type:** 5
- **Project period:** 2021-01-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10762336

## Citation

> US National Institutes of Health, RePORTER application 10762336, Role of ROCK isoform-mediated actin cytoskeleton modification in the pathogenesis of heart disease (5R01HL151480-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10762336. Licensed CC0.

---

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