Scientific Abstract
Proposal No. IBD-0002
Principal Investigator: Matthew B. Grisham, Ph.D.
Applicant Organization: Louisiana State University (Shreveport, U.S.A.)
Project Title: Role of the collagen-binding integrin alpha 1, beta 1 in an immune-based model of chronic colitis
Period of Award: January 1, 2002 - February 29, 2004
The inflammatory bowel diseases (IBD - Crohn’s disease, ulcerative colitis) are chronic idiopathic inflammatory disorders of the intestinal tract. IBD is characterized by the infiltration of large numbers of monocytes, lymphocytes, and neutrophils into the intestinal and/or colonic interstitium. Leukocyte infiltration is accompanied by extensive mucosal and/or transmural injury suggesting that the inflammatory infiltrate plays an important role in the pathophysiology of IBD. Recent evidence suggests that interactions between collagen-binding integrins (e.g., α1β1) localized on certain leukocytes and the extracellular matrix promote migration and activation of interstitial leukocytes in different models of inflammation. However, relatively little information is available describing the importance of leukocyte-interstitial matrix interactions in chronic gut inflammation.
Therefore, the overall objective of this study is to better understand the role of the α1β1 collagen-binding integrin in the pathophysiology of chronic gut inflammation in an immune-based murine model of chronic colitis. Hypothesis: We propose that T-cell and/or granulocyte-associated integrin α1β1 interacts with interstitial collagen in the colonic interstitium resulting in the activation of these cells with the upregulation of certain pro-inflammatory cytokines that may initiate and/or perpetuate chronic gut inflammation. In order to test this hypothesis we propose the following specific aims: 1) Evaluate the importance of T-lymphocyte α1β1 surface expression on the promotion of chronic gut inflammation using donor T-cells from a1-deficient (α1-/-) mice. 2) Determine the importance of granulocyte (e.g., monocyte/macrophage, PMNs) α1β1 surface expression on the initiation and/or perpetuation of chronic gut inflammation using RAG-2-/- ´ α1-/- double-deficient recipient animals. Understanding the importance of this integrin in an immune-based model of IBD may provide new insight into the pathogenesis of chronic gut inflammation and could provide new avenues for drug design and treatment of human IBD.