# Signaling Mechanisms Governing Myocardial Fibrosis in Diseased Heart

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $371,250

## Abstract

Virtually every form of progressive heart failure (HF) is associated with increased fibrosis. Currently there is no
approved therapy to specifically target myocardial fibrosis in the diseased heart. Until very recently, HF studies
have been largely limited to cardiomyocytes, primarily due to unavailability of cardiac fibroblast (CF)-specific
mouse models. Recently, we used novel CF-specific mouse models to demonstrate that deletion of CF-GSK-
3β is detrimental in the ischemic heart. This successful utilization of CF-specific gene targeting provides a
unique opportunity to further employ these newly optimized models to understand the role of CFs and their
activation in myocardial disease process in vivo. The long-term goal of the proposed studies is to identify new
therapeutic targets for the treatment of myocardial fibrosis and subsequent HF. Three specific aims are
designed to identify the key signaling pathways and underlying primary mechanisms responsible for regulation
of myocardial fibrosis. Aim 1: To elucidate the molecular mechanism by which CF-GSK-3α regulates fibrotic
remodeling in the ischemic heart. The GSK-3 family consists of two isoforms, α and β. In stark contrast to our
recent report with GSK-3β, our preliminary studies suggest that CF-specific deletion of GSK-3α is protective,
post-MI. Based on this observation we hypothesize that CF-GSK-3α is deleterious in the process of post MI
fibrotic remodeling. This hypothesis will be tested by employing CF-GSK-3α KO (periostin-cre) and tamoxifen-
inducible fibroblast specific GSK-3α KO (TCF21-cre) mouse models. Aim 2: To define the molecular
mechanisms by which CF-specific deletion of GSK-3β leads to adverse myocardial fibrosis. We hypothesize
that GSK-3β, SMAD-3 and β-catenin function as an integrated central profibrotic signaling cascade. We will
cross our GSK-3βfl/fl mice with SMAD-3fl/fl and β-cateninfl/fl mice to determine whether inhibition of the SMAD-3
and β-catenin axis is sufficient to abolish myocardial fibrosis in GSK-3βKO mice. Aim 3: Determine the
mechanisms by which Integrin α1β1 (ITGα1β1) cross-talks with the profibrotic SMAD-3 and p38 pathways and
identify the role of this interaction in regulation of myocardial fibrosis. Our preliminary data suggest that
mechanical stretch couples to SMAD-3 activation even in the absence of TGF-β1 treatment. The predominant
integrin expressed in CFs is ITGα1β1. In this aim, we will test the hypothesis that ITGα1β1 negatively
regulates the TGF-β1/SMAD-3 and p38 pathways and thus exerts a critical break on myocardial fibrotic
remodeling. The proposed approach is innovative, because it departs from status quo by utilizing novel CF-
specific loss of function mouse models and isolated cells from them to understand the molecular mechanism of
myocardial fibrosis in diseased heart. New research horizons are expected to become attainable as a result.
The proposed research is highly significant, since it proposes novel strategies to prevent fibrot...

## Key facts

- **NIH application ID:** 10075771
- **Project number:** 7R01HL133290-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Hind Lal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,250
- **Award type:** 7
- **Project period:** 2017-02-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075771

## Citation

> US National Institutes of Health, RePORTER application 10075771, Signaling Mechanisms Governing Myocardial Fibrosis in Diseased Heart (7R01HL133290-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10075771. Licensed CC0.

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