# Myocardin in the pathogenesis of pleural remodeling

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH CTR AT TYLER · 2021 · $475,566

## Abstract

Pleural injury often leads to extensive remodeling of the pleural surfaces, which in severe cases leads to
pleural fibrosis (PF). PF can occur as a result of bacterial pneumonia, trauma, radiation exposure and
asbestos-related pleural injury. When severe, PF can cause restrictive lung disease or fibrothorax. PF with
lung restriction is often seen in medical practice but current treatment is unsatisfactory and effective
pharmacotherapy is not available. PF is characterized by proliferation of alpha-smooth muscle actin (α-SMA)
expressing myofibroblasts. These myofibroblasts contribute to the thickening of the pleura via increased
extracellular matrix deposition. The expansion of myofibroblasts is largely due to mesenchymal transition (MT)
of resident pleural mesothelial cells, termed MesoMT. Our preliminary data show that TGF-β induces
myocardin expression and activity. Further, myocardin and its effector proteins, smooth muscle myosin,
calponin, and KIF5A are upregulated in our mouse models of pleural injury. Conversely, myocardin down-
regulation attenuates TGF-β mediated induction of MesoMT marker, α-SMA, secretion of collagen and
fibronectin and pleural fibrosis. We also reported that KIF5A is upregulated in TGF-β induced PF and critical
for collagen secretion. Based on these observations and strong preliminary data, we strongly infer that
myocardin expression and activation substantively contribute to the progression of PF. In this project, we will
test the central hypothesis that the activation and upregulation of myocardin and its effector proteins are critical
determinants in the acquisition of the activated PMC phenotypes and the progression of PF. Our objective is to
test this postulate using state of the art cellular, biochemical, molecular, physiologic and imaging techniques.
Primary human (H) and mouse (M) PMCs will be used to define mechanisms by which MesoMT is regulated.
Three murine models will be used to assess the role of myocardin and KIF5 signaling in PF: carbon
black/bleomycin (CBB) induced PF, Streptococcus pneumoniae-induced empyema/PF and TGF-β induced PF.
Our specific aims are: 1) To define the mechanism of myocardin-induced MesoMT of HPMCs, 2) to define the
mechanism of KIF5 activation in MesoMT and ECM deposition by HPMCs and 3) to define the contribution of
myocardin and related effector proteins to neo-matrix deposition in the progression of PF in vivo. We will use
new murine models of fibrosing pleural injury, including mice with mesothelial labelling to enable fate-mapping
analyses, molecular, biochemical and immunohistochemical techniques with which we have expertise and
state of the art CT imaging and pulmonary function analyses to accomplish these aims. The mechanism(s) by
which TGF-β and myocardin regulate MesoMT and PF are currently unclear, representing potentially important
gaps in our understanding of the pathogenesis of pleural organization and our ability to identify new therapeutic
targets. This proposal a...

## Key facts

- **NIH application ID:** 10200133
- **Project number:** 5R01HL142853-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH CTR AT TYLER
- **Principal Investigator:** Steven Idell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $475,566
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200133

## Citation

> US National Institutes of Health, RePORTER application 10200133, Myocardin in the pathogenesis of pleural remodeling (5R01HL142853-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10200133. Licensed CC0.

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