Activated fibroblasts determine the extent of pulmonary fibrosis by their production of collagen and other matrix components. Fibroblast specific protein 1 (FSP1) is a member of the S100 protein superfamily and appears to play an early role in establishing the fibroblast phenotype. Although the origin of activated fibroblasts in pulmonary fibrosis is uncertain, recent studies in the kidney have shown that fibroblasts may arise from epithelium through a phenomenon called epithelial- mesenchymal transformation. Transforming growth factor-beta and other phenotypic modulators appear to regulate this process through up- regulation of FSP1 and other proteins that control fibroblast phenotype. In this project, we propose to investigate the following hypothesis. In lung fibrosis, activated lung fibroblasts are derived from airway epithelial cells as well as from resident interstitial fibroblasts. FSP1 is both a marker and important determinant of this cellular phenotype. The appearance and persistence of FSP1 expressing cells are crucial for determining the extent of lung fibrosis. We propose three specific aims: 1) to identify the role of FSP1+ cells in experimental lung fibrosis, 2) to determine whether epithelial-mesenchymal transformation occurs in the lungs and contributes to lung fibrosis in the mouse, 3) to modulate FSP1 expression and determine the effects on epithelial-mesenchymal transformation and induction of lung fibrosis. Identification of a more useful fibroblast marker in the lungs would allow identification and monitoring of this cell population after fibrogenic stimuli and could foster targeted treatments that alter the accumulation or function of cells exhibiting the fibroblast phenotype. In addition, we plan to explore the origins of lung fibroblasts in experimental lung fibrosis with the hope that determining the presence and extent of epithelial-mesenchymal transformation in the lungs in these models will lead to innovative interventions to inhibit or reverse this transformation, thus limiting fibrosis and lung dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068121-03
Application #
6603974
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Reynolds, Herbert Y
Project Start
2001-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
3
Fiscal Year
2003
Total Cost
$339,750
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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