# Molecular control of ischemia-induced tissue fibrosis

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $539,142

## Abstract

Abstract
 Chronic ischemia induced tissue fibrosis contributes to numerous end-stage diseases. It is
well accepted that macrophages play a major role in the generation of fibrotic tissues whereby
dysregulated macrophage accumulation, activation, polarization and functions contribute to
uncontrolled production of matrix metalloproteinases and extracellular matrix remodeling. Under
pathological conditions, macrophages, along with fibroblasts and other cell types, serve as an
initial and/or additional source of TGF-β1 and significantly contribute to the fibrosis. Moreover,
endomyocardial biopsy specimens from patients with atherosclerotic coronary disease-induced
ischemic cardiomyopathy demonstrated 45% of replacement fibrosis. Thus, identifying the
signaling cascades in macrophage that regulates fibrosis in chronic ischemic diseases will have
significant clinical benefit. MKP-5 has been implicated in innate immune responses,
regenerative myogenesis and vascular inflammation. Our exciting preliminary data show that
MKP-5 is upregulated in the fibrogenic zone of the heart. Genetic deletion of MKP-5 protects
against early atherogenesis that leads to coronary artery insufficiency, decreases cardiac
fibrosis and ameliorates ischemia-induced cardiac dysfunction in vivo. In vitro mechanistic
studies and RNA-seq analysis suggested that loss of MKP-5 downregulated arrays of
profibrogenic pathway genes including TGF-β signaling in macrophages and circulating
monocytes. The central goal of this study is to identify the signaling cascades regulated
by MKP-5 in macrophage that lead to tissue fibrosis. By using a novel chronic ischemia-
induced cardiomyopathy model, we aim to: (1) interrogate the role of macrophage MKP-5 in
ischemia-induced tissue fibrosis, (2) uncover the molecular mechanisms of macrophage
MKP-5 in regulation of pro- and anti-fibrogenic signaling cascade, and (3) test the
therapeutic potential of a newly developed MKP-5 allosteric inhibitor against fibrosis in
vivo. We hypothesize that MKP-5 exacerbates tissue fibrosis through macrophage infiltration,
polarization and TGF-β signaling. The success of proposed study will define the role of MKP-5
in regulating chronic ischemia-induced tissue fibrosis; provide proof-of-concept for applying
MKP-5 inhibition for the management of this deadly disease.

## Key facts

- **NIH application ID:** 10034005
- **Project number:** 1R01HL153599-01
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Jun Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $539,142
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10034005

## Citation

> US National Institutes of Health, RePORTER application 10034005, Molecular control of ischemia-induced tissue fibrosis (1R01HL153599-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10034005. Licensed CC0.

---

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