Intestinal fibrosis is a common sequela of chronic intestinal inflammation in patients with Crohn's disease. Data suggest that smooth muscle cells, fibroblasts and myofibroblasts are the major sites of intestinal collagen synthesis leading to stricture formation. Insulin-like growth factor I (IGF-I) is a potent fibrogenic peptide that is increased in fibrotic intestine of patients with Crohn's disease. IGF binding protein 5 (IGFBP-5) is a unique protein that associates with the extracellular matrix (ECM) and increases the actions of IGF-I on its target cell. IGF-I has a mitogenic effect on intestinal smooth muscle and increases collagen synthesis and synthesis of IGFBP-5 by rat intestinal smooth muscle cells (RISM) in vitro. IGF-I acts through the type I IGF receptor to activate multiple signal transduction pathways including the phosphatidylinositol 3-kinase (Pl3K) and the mitogen-activated protein kinase (MAPK) pathways. IGF-I regulates IGFBP-5 synthesis by transcriptional and posttranscriptional mechanisms and increases IGFBP-5 mRNA stability by factors that may act through newly recognized regions of the 3' UTR that modulate mRNA stability. PI's hypothesis is that IGF-I is increased in inflamed intestine and acts on intestinal smooth muscle cells to increase synthesis of collagen and IGFBP-5. IGFBP-5, in turn, associates with the ECM near the target cell and enhances the fibrogenic actions of IGF-I on smooth muscle. Factors that mediate IGF-I signal transduction and that modulate IGFBP-5 expression are key to the actions of IGF-I in the gut. This grant application will study basic mechanisms of IGF-I mediated effects on smooth muscle cells.
Our specific aims are 1) to define the relative contributions of the Pl3K and the MAPK pathways to IGF-I signaling in smooth muscle cells, 2) to define the mechanism(s) that regulate IGFBP-5 mRNA stability, 3) to modulate IGFBP-5 in vivo and determine the effect on intestinal inflammation and fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056750-02
Application #
6517679
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
2
Fiscal Year
2002
Total Cost
$295,981
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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