Grant: Fellowship - Priority Announcement - Inflammatory Bowel Disease

Intestinal inflammation causes changes in the structure and function of the intestinal wall, affecting how it contracts and relaxes appropriately to processes food ("motility"). In both humans and in animal models, intestinal inflammation results in the thickening of the intestinal wall, which will affect intestinal movement. Multiplication of generally dormant intestinal smooth muscle cells (ISMC) will contribute to these pathological symptoms, which are characteristic of inflammatory bowel disease (IBD). In particular, ISMC growth will contribute to the life-threatening complication of stricture formation in Crohn's disease. Since inflammation-induced ISMC multiplication leads to both long term (wall thickening) and short term compromise of intestinal function, basic research into the cause of ISMC growth is an important approach to the design of new interventional strategies. Our earlier work showed that the appearance of a receptor for a growth factor (PDGF-R beta) is the single key event that leads to ISMC proliferation, in the animal as well as in tissue culture. In this project, we ask how the events of inflammation might cause this, proposing that pro-inflammatory cytokines (factors that are released early in inflammation, which in turn lead to subsequent events) might cause either the expression or activation of PDGF-beta receptor, and how this then affects ISMC proliferation. Initially, we will be using isolated intestinal smooth muscle cells from rats and then progressing to human intestinal cells and ultimately, testing our hypothesis in vivo using a rat model of Crohn's disease.