Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD). Both diseases involve cycles of mucosal damage requiring mucosal restitution or regeneration to restore bowel function. In contrast to UC, CD is associated with transmural inflammation and fibrogenic complications, typified by submucosal granulomas altered mesenchymal cell proliferation and increased collagen deposition. Insulin- like growth factor I (IGF-I) expression is elevated in areas of fibrosis in bowel of animal models of chronic IBD. Expression of IGF-I and the related IGF-II is increased in involved bowel of patients with CD. IGFs prone proliferation of intestinal mesenchymal cells in vitro and intestinal epithelial cells in vitro and in vivo. Proposed studies will test the following hypotheses: 1. Phenotypically modified smooth muscle (SM) cells and/or fibroblasts (myofibroblasts) underlie fibrogenic complications of CD. 2. IGFs play an integral role in phenotypic modification or clonal expansion of the modified intestinal mesenchymal cells during development of fibrosis in CD. 3. Cytokines and/or extracellular matrix components within inflamed/fibrotic bowel of patients with CD induce IGF expression by intestinal mesenchymal cells or modulate IGF responsiveness by effects on IGF receptors or IGF binding proteins (IGFBPs). To test these hypotheses:
Aim 1 will elucidate the precise mesenchymal cell types that express IGF-I and IGF-II and show increased collagen deposition in inflamed or fibrotic regions of bowel from patients with CD.
Aim 2 will analyze cultured human intestinal smooth muscle cells and fibroblasts/myofibroblasts: a) to test IGF effects on proliferation, collagen deposition and phenotype in normal cells, b) to test effects of cytokines or extracellular matrix from inflamed/fibrotic bowel on IGF expression, phenotype and IGF responsiveness of normal cells and c) to examine whether cells from patients with CD show altered IGF expression or responsiveness compared with cells from patients with UC or noninflammatory bowel disease.
Aim 3 will use GH, IGF-I and IGFBP 1 transgenic mice (mice with inducible overexpression of IGFBP 1 a natural inhibitor of IGF-l action) to define in vivo effects of altered IGF-I production or action on susceptibility, course, severity and histopathology of experimental bowel inflammation and fibrosis.
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