# The fibrogenic role of Hippo-Yap signaling following ischemic injury

> **NIH NIH F32** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $70,082

## Abstract

PROJECT SUMMARY/ABSTRACT
End stage heart failure is a common outcome of cardiac injury such as myocardial infarction (MI). Following
ischemic injury, prolonged myofibroblast activation can lead to exacerbated extracellular matrix production,
decreased cardiac compliance, myocyte uncoupling, and progressive heart failure. However, an emerging role
for myofibroblasts regarding cardiac regenerative healing has been underappreciated and underexplored.
Thus, there is great interest in assessing myofibroblast's role in the adult heart following ischemic injury and
molecular pathways that can be targeted to control myofibroblast activation and inactivation. In recently
published studies we found that genetic deletion of Yap in the regenerative zebrafish model exacerbated scar
formation, modulated immune cell infiltration, and delayed cardiac regeneration following cardiac cryoinjury.
Yap is a transcriptional activator that promotes cell survival and proliferation that is inhibited by the Hippo
signaling pathway through Lats mediated phosphorylation. It was recently reported that either forced
expression of Yap, or the deletion of core Hippo kinases extend the regenerative window of cardiomyocytes in
neonatal rodent hearts, thus, therapeutically targeting the Hippo-Yap pathway is a promising approach for
remuscularization of the heart. However, understanding the role of Yap activity in non-myocytes during cardiac
regeneration is critical prior to implementing therapeutic regenerative approaches targeting this pathway. Here,
our preliminary data show that Yap is essential for scar formation and resolution in the regenerating zebrafish
heart and depletion of Yap in mammalian cardiac fibroblasts modulates fibrotic and inflammatory
cyto/chemokine gene programs. Our central theory is that precisely modulating the myofibroblast response by
targeting the Hippo-Yap pathway will facilitate critical wound healing and pro-regenerative responses while
preventing excessive ECM production and fibrosis in the heart following ischemic injury. Thus, this proposal
aims to define the role of Hippo-Yap signaling in myofibroblasts following cardiac injury in adult mice.

## Key facts

- **NIH application ID:** 10379059
- **Project number:** 5F32HL150958-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Michael A Flinn
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $70,082
- **Award type:** 5
- **Project period:** 2021-02-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10379059

## Citation

> US National Institutes of Health, RePORTER application 10379059, The fibrogenic role of Hippo-Yap signaling following ischemic injury (5F32HL150958-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10379059. Licensed CC0.

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