# Signaling Mechanisms Governing Myocardial Fibrosis in Diseased Heart

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $562,534

## Abstract

Virtually every form of progressive heart failure (HF) is associated with increased fibrosis. However, currently,
there is no approved therapy to specifically target myocardial fibrosis in the diseased heart. Until recently, HF
studies were largely limited to cardiomyocytes (CMs), primarily due to unavailability of fibroblast (FB)-specific
mouse models. The foundation of the current proposal is primarily based on our reports on the role of the GSK-
3 family of kinases in myocardial fibrosis. Recently, we used novel FB-specific mouse models to demonstrate
the opposing function of the GSK-3 family of kinases in myocardial fibrosis. Specifically, GSK-3α mediates;
however, GSK-3β inhibits myocardial fibrosis. Mechanistically, we identified that GSK-3α promotes fibrosis via
the RAF-MEK-ERK pathway in a TGF-β1-SMAD-3 independent manner. In contrast, GSK-3β directly interacts
with SMAD-3 to limit the profibrotic TGF-β1/SMAD-3 signaling. Herein, we are proposing translational studies
with newly created conditional global GSK-3α KO mouse and recently developed GSK-3α-specific
pharmacological inhibitor to determine if GSK-3α could be a viable therapeutic target for the diseased heart
(Aim 1). Furthermore, we will delineate the mechanism of GSK-3β mediated myocardial fibrosis regulation by
employing multiple conditional FB-specific KO models (Aim 2). We believe the proposed PeriostinMCM and
TCF21MCM are currently the strongest tools available for FB-specific gene targeting in vivo. The proposed
research is highly significant since it proposes novel strategies to prevent cardiac dysfunction and adverse
remodeling in the diseased heart. The long-term goal of the proposed studies is to identify new therapeutic
targets for the treatment of cardiac dysfunction, myocardial fibrosis, and subsequent HF.

## Key facts

- **NIH application ID:** 10878070
- **Project number:** 2R01HL133290-06A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Hind Lal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $562,534
- **Award type:** 2
- **Project period:** 2017-02-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878070

## Citation

> US National Institutes of Health, RePORTER application 10878070, Signaling Mechanisms Governing Myocardial Fibrosis in Diseased Heart (2R01HL133290-06A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10878070. Licensed CC0.

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