# Defining and targeting mechanisms of smoke-mediated fibrosis progression

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $392,500

## Abstract

Several environmental exposures, especially tobacco smoking, have been associated with increased risk for
idiopathic pulmonary fibrosis (IPF), a progressive and incurable interstitial lung disease. This disease has a
median survival time of 3 to 5 years, worse than many cancers. With 41%-83% of IPF patients being current or
former smokers, cigarette smoking plays a crucial role in IPF development and progression. Unfortunately, the
mechanisms by which smoking promotes fibrosis are poorly understood. Of great concern, there are no reliable
biomarkers and/or specific therapies available for smoking-associated IPF. To discover the regulators of IPF
fibroblast activation, we compared and integrated the gene profiles of IPF fibroblasts from two different
microarray platforms. Among the genes identified, myristoylated alanine-rich C-kinase substrate (MARCKS) was
found to be highly correlated with the expression of the myofibroblast marker alpha smooth muscle actin (α-SMA)
and was notably elevated in IPF fibroblasts. We previously identified the membrane-associated protein MARCKS
as a smoke-responsive molecule associated with lung cancer progression. Our preliminary data have
demonstrated that up-regulation of phospho-MARCKS concomitant with an increase of protein tyrosine
phosphorylation level in smoke-exposed cells. Using a phospho-kinase antibody array screen, we found the AXL
receptor tyrosine kinase (RTK) as a top-one RTK active in response to smoke. In addition, our LC-MS/MS data
have revealed AXL is a putative binding partner of phospho-MARCKS. Co-expression of phospho-MARCKS and
phospho-AXL were observed in lung tissues with exposure to both mainstream and sidestream cigarette smoke.
Surprisingly, the inhibition of phospho-MARCKS resulted in downregulation of AXL autophosphorylation and its
downstream signaling. Given these observations, we hypothesize that cigarette smoke through MARCKS-AXL
signaling stimulates fibroblast activation, thereby contributing to lung fibrosis progression. To test this hypothesis,
three specific aims are proposed: 1) characterize the role of cigarette smoke-activated MARCKS-AXL axis in
fibroblast cell proliferation, migration, and/or differentiation in vitro; 2) to determine that MARCKS inhibition
effectively suppresses smoke-mediated lung fibrosis in vivo; 3) to evaluate the clinical relevance of phospho-
MARCKS and phospho-AXL in smoking-related IPF tissues. Achievement of these specific aims will characterize
novel molecular mechanisms underlying smoke-mediated fibrosis progression, thereby providing novel
therapeutic targets such as phospho-MARCKS and phospho-AXL for combating pulmonary fibrosis.

## Key facts

- **NIH application ID:** 9898452
- **Project number:** 5R01HL146802-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Ching-Hsien Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,500
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898452

## Citation

> US National Institutes of Health, RePORTER application 9898452, Defining and targeting mechanisms of smoke-mediated fibrosis progression (5R01HL146802-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9898452. Licensed CC0.

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