Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating, and ultimately fatal disease for which no effective therapy exists. Recent research has focused on mechanisms that regulate activation of fibroblasts, the cell responsible for excessive matrix protein secretion and fibrosis. Interestingly, a cellular isoform of the matrix protein fibronectin (cellular fibronectin;cFn), termed EIIIA cFn, is deposited prior to the development of fibrosis and is essential for fibroblast activation through integrin receptor signaling. Fibroblast activation also relies on decreased levels and/or activity of an intracellular phosphatase called PTEN, which induces EIIIA cFn production. Thus, this proposal will focus on the hypothesis that decreased levels and/or activity of PTEN induces EIIIA cFn production which promotes and amplifies fibroblast activation. Experiments outlined in this application will define the mechanism by which PTEN regulates fibroblast activation in vitro and in vivo. Among the questions to be addressed are: 1) How does PTEN regulate EIIIA cFn expression? (i.e. what intracellular mechanisms regulate EIIIA cFn production when PTEN is inhibited?) 2) How does EIIIA cFn influence fibroblast behavior, and which integrin receptors are involved? 3) Can fibroblast activation, and subsequent pulmonary fibrosis, be attenuated when EIIIA cFn binding by fibroblasts is blocked in vivo? 4) Can fibroblast activation and fibrosis be made to occur when adding EIIIA cFn back to an in vivo system lacking EIIIA fibronectin? The relevance of this research is to define, in a mechanistic fashion, the series of events that leads to inappropriate scar tissue formation (fibrosis) in the lungs. The studies outlined in this proposal will specifically address how lung injury progresses to fibrosis and whether experimental lung fibrosis can be prevented or reversed. Successful completion of these experiments may also identify novel, potentially therapeutic, agents to combat lung fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085083-05
Application #
8081836
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
2007-07-15
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$372,200
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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