The overall hypotheses underlying this work are that IGF-I system, ?V?3 integrin and the ?V?3 integrin-binding ligands, vitronectin and fibronectin, regulate the smooth muscle hyperplasia, excess collagen production and fibrosis in the intestine that is central to stricture formation in Crohn's disease, and that selective IGF-I and ?V?3 inhibitors can be used to diminish muscle hyperplasia, fibrosis and stricture formation. Our studies during the current funding period have identified the mechanisms by which endogenous IGF-I, IGFBP-5, IGFBP-3 and ?V?3 integrin act jointly to regulate smooth muscle growth and collagen II production in normal intestinal muscle and excess muscle growth, collagen II production and fibrosis in Crohn's disease and in TNBS-induced colitis in mice. Occupancy of ?V?3 integrin by its ligands, vitronectin and fibronectin, regulates the intensity and duration of IGF-I-stimulated, IGF-I receptor activation and effects. Our recent work and preliminary results show that, like smooth muscle in stricturing Crohn's disease, smooth muscle of mice with TNBS-induced colitis have increased endogenous ?V?3 integrin ligands. The resulting activation of ?V?3 integrin jointly with upregulated endogenous IGF-I and IGF binding proteins are central mediators of smooth muscle cell hyperplasia, increased collagen II production and resulting fibrosis. Muscle hyperplasia, collagen II production, ?V?3 integrin-dependent effects and fibrosis can be decreased by pharmacologic blockade of ?V?3 integrin activation or of IGF-I receptor activation. The first specific aim is to identify the mechanisms regulating increased IGF-I and IGFBP-5 expression and their roles in the development of muscle hyperplasia, collagen production and fibrosis in stricturing Crohn's disease and chronic TNBS-induced colitis. The second specific aim is to characterize the mechanisms regulating ?V?3 integrin binding vitronectin and fibronectin expression and their function in ?V?3 integrin activation and development of muscle hyperplasia, collagen production and fibrosis in stricturing Crohn's disease and chronic TNBS- induced colitis. The third specific aim is to characterize the mechanisms regulating ?V and ?3 integrin subunit expression and the role of ?V?3 integrin activation in muscle hyperplasia, collagen production and fibrosis in stricturing Crohn's disease and chronic TNBS-induced colitis. Their completion will advance our understanding of the unique pathophysiology of intestinal smooth muscle hyperplasia, collagen production, fibrosis and stricture formation in the inflamed intestine and identify potential therapeutic strategies, via ?V?3 integrin and IGF-I receptor inhibition, to decrease stricture formation in patients with stricturing Crohn's disease.

Public Health Relevance

The objective of this proposal is to characterize the endogenous factors and the interdependent signaling pathways that mediate smooth muscle hyperplasia, collagen production and fibrosis leading to stricture formation in Crohn's disease. The project involves analysis of the molecular mechanisms by which the ?V?3 integrin, and its ligands regulate IGF-I-dependent and IGF binding protein-dependent muscle hyperplasia, collagen production and fibrosis in the initiation and progression of stricture formation during inflammation and to determine the suitability of ?V?3 and IGF-I inhibitors to diminish fibrosis and stricture formation in Crohn's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK049691-16
Application #
8496756
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Carrington, Jill L
Project Start
1995-09-25
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
16
Fiscal Year
2013
Total Cost
$313,783
Indirect Cost
$103,895
Name
Virginia Commonwealth University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Li, Chao; Kuemmerle, John F (2014) Mechanisms that mediate the development of fibrosis in patients with Crohn's disease. Inflamm Bowel Dis 20:1250-8
Li, Chao; Flynn, Robert S; Grider, John R et al. (2013) Increased activation of latent TGF-?1 by ?V?3 in human Crohn's disease and fibrosis in TNBS colitis can be prevented by cilengitide. Inflamm Bowel Dis 19:2829-39
Mahavadi, Sunila; Flynn, Robert S; Grider, John R et al. (2011) Amelioration of excess collagen I?I, fibrosis, and smooth muscle growth in TNBS-induced colitis in IGF-I(+/-) mice. Inflamm Bowel Dis 17:711-9
Flynn, Robert S; Murthy, Karnam S; Grider, John R et al. (2010) Endogenous IGF-I and alphaVbeta3 integrin ligands regulate increased smooth muscle hyperplasia in stricturing Crohn's disease. Gastroenterology 138:285-93