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Therapeutic targeting to inhibit lung fibrosis progression

Institution: University of California, Davis
Investigator(s): Ching-Hsien Chen,
Award Cycle: 2019 (Cycle 28) Grant #: 28IR-0061 Award: $925,286
Subject Area: Pulmonary Disease
Award Type: High Impact Research Project Award

Initial Award Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with a median survival time of only 3 to 5 years. Of great concern, there are no reliable biomarkers and specific therapies available to measure progression or treat the disease. Cigarette smoking is one of the most recognized factors associated with the development and progression of IPF. However, the mechanism by which smoking contributes to IPF pathogenesis is largely unknown. Through integration and analysis of detailed molecular data, we have identified the protein “myristoylated alanine-rich C kinase substrates” (MARCKS) as a putative smoke-responsive molecule involved in the abnormal activation of cells called fibroblasts in the lungs of IPF patients. Our preliminary data have shown that high production of a specific form of this protein, phospho-MARCKS, occurs in cells exposed to cigarette smoke and that another protein, AXL, is active in response to smoke. Given these and other observations, we hypothesize that smoke-triggered elevation of phospho-MARCKS cooperates with AXL to activate fibroblasts in response to smoke, contributing to lung fibrosis progression. To study this hypothesis, we will first confirm whether MARCKS and AXL are dysregulated in smoke-related IPF fibroblast cells and tissues. Next, we will characterize the role of AXL signaling in activating lung fibroblasts and conversion to a cell type that promotes fibrosis. Lastly, we will determine if blockade of AXL activity suppresses lung fibrosis and enhances drug efficacy. 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 AXL for combating pulmonary fibrosis.