application): This revised proposal will focus on a central hypothesis: monocyte and macrophage accumulation and activation in the lung induce inflammation and initiate fibrosis. The goal of this proposal is to dissect the mechanisms underlying the lung injury and fibrosis seen in idiopathic pulmonary fibrosis (IPF). IPF is a progressive, fatal lung disease of unknown cause and precious few therapeutic options to effectively treat patients. There is firm agreement in academic pulmonary medicine that studies are needed to define the etiology of the disease and to dissect the mechanisms underlying the fibrosis and lung injury. Mice deficient in either the tyrosine phosphatase SHP-1 or the inositol 5-phosphatase SHIP suffer unregulated accumulations of macrophages in their lungs and die of a pulmonary fibrosis-like state. In comparison, bleomycin-treated animals also suffer pulmonary fibrosis that appears to be dependent on macrophage accumulation in the lung. Since macrophage colony-stimulating factor appears to be the primary survival factor for monocytes, including monocytes that are precursors to tissue macrophages, the applicant will investigate the hypothesis that these phosphatases suppress M-CSF-induced cellular activation and survival, and that the lack of these phosphatases leads to macrophage accumulation and possibly fibrosis.
The specific aims of the proposal are: 1) to determine the molecular targets of the phosphatases SHP-1 and SHIP in M-CSF activated human monocytes; 2) to determine the functional outcome of SHP-1 and SHIP deficiency in M-CSF-induced monocyte survival and determine how M-CSF suppresses phosphatase activity; and 3) to define the role of monocytes and M-CSF in lung injury and fibrosis induced by bleomycin or found in SHP-1-/- and SHIP-/- mice. They will perform both in vitro and in vivo studies to dissect these aims, using human monocytes, murine macrophages and animals that develop pulmonary fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063800-02
Application #
6390561
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Musson, Robert
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2001-07-23
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$286,010
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
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