This proposal is aimed at the investigation of the extracellular matrix (ECM) in inflammatory bowel disease (IBD). Both forms of IBD, Crohn's disease (CD) and ulcerative colitis (UC) are characterized by a chronic inflammatory process that leads to functional and structural abnormalities, including prominent fibrosis and stricture formation. These are the result of altered ECM deposition and remodeling, but knowledge of the composition of the ECM in each form and stage of IBD is quite limited. In addition, little is known about the upstream regulatory events responsible for fibroblast activation and ECM production in IBD intestine. Thus, the central hypothesis is that changes in the ECM of CD and UC patients are specific for each type of IBD and are regulated by the interaction of mesenchymal cells with immune cells. This hypothesis will be tested by two specific aims.
Aim 1 will define the composition of basement membrane ECM, interstitial ECM, and ECM remodeling enzymes in normal intestinal tissue, and the quantitative and qualitative changes present in tissues from CD and UC patients.
Aim 2 will investigate whether the synthesis of ECM components and remodeling enzymes is differentially regulated in intestinal fibroblasts from control, CD and UC tissues, and how synthesis is regulated by cytokines and T-cell interaction. The results of these studies will expand knowledge of the mechanisms of intestinal inflammation and may lead to novel approaches to prevention or treatment of stricture formation.
| Vogel, Jon D; West, Gail A; Danese, Silvio et al. (2004) CD40-mediated immune-nonimmune cell interactions induce mucosal fibroblast chemokines leading to T-cell transmigration. Gastroenterology 126:63-80 |
