# Functional and mechanistic delineation of HuR-Wisp1 signaling on myofibroblast activity

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $650,453

## Abstract

PROJECT SUMMARY:
 Cardiac fibrosis is regulated by the activation and phenotypic switching of quiescent cardiac fibroblasts
(CFs) to active myofibroblasts (MFs) which have extracellular matrix (ECM) remodeling and contractile
functions which play a central role in cardiac remodeling in response to injury. As such, there is consensus
effort in the field to manipulate fibroblast activity for therapeutic gain. However, a more complete understanding
of the signaling pathways and mechanisms that regulate MF activity in cardiac remodeling remains an unmet
need.
We previously demonstrated that the RNA binding protein Human antigen R (HuR) directly mediates
hypertrophic signaling in cardiac myocytes (CMs), and that CM-specific genetic deletion or pharmacological
inhibition of HuR reduces pathological remodeling and preserves cardiac function following transverse aortic
constriction (TAC)-induced pressure overload in part through a reduction in pro-fibrotic gene expression. New
preliminary data suggests that HuR activity in cardiac fibroblasts may play an equally important role in cardiac
remodeling. Our new data demonstrates a necessary role for HuR in MF activation and the ECM-remodeling
capacity of cardiac fibroblasts. Furthermore, we have identified Wisp1 (Ccn4) as a downstream HuR-
dependent mediator of MF activation, and show that exogenous addition of recombinant Wisp1 partially
restores MF activity upon HuR inhibition.
 The primary goal of this proposal is to determine the functional role that HuR-Wisp1 signaling plays on MF
activity and whether functional inhibition of these pathways in fibroblasts will provide therapeutic benefit during
pathological cardiac remodeling. Our central hypothesis is that HuR-Wisp1 signaling in cardiac
fibroblasts is necessary for myofibroblast activity and promotes pathological cardiac remodeling. The
specific Aims of this proposal are to:
 (1) Determine the functional role of HuR in CFs in vivo and define its pleiotropic role across cell types
 during pathological cardiac remodeling.
 (2) Identify the functional and mechanistic role of HuR-dependent control of Wisp1 expression on MF
 activity and pathological cardiac remodeling.
 The expected results of this proposal will provide a deeper understanding of the functional impact of the
HuR-Wisp1 signaling axis across cardiac cell types during pathological cardiac remodeling that is necessary
for potential therapeutic manipulation of HuR or HuR-dependent gene expression in cardiac remodeling as
suggested by our previous work.

## Key facts

- **NIH application ID:** 11046830
- **Project number:** 7R01HL166326-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Onur Kanisicak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $650,453
- **Award type:** 7
- **Project period:** 2023-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11046830

## Citation

> US National Institutes of Health, RePORTER application 11046830, Functional and mechanistic delineation of HuR-Wisp1 signaling on myofibroblast activity (7R01HL166326-02). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/11046830. Licensed CC0.

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