Inflammatory bowel disease (IBD) is a progressive multi-step disease, with initiating and perpetuating events associated with immunoregulatory abnormalities, tissue damage and eventually clinical symptoms. Multiple factors, from genetic, environmental, microbial, immunologic, as well as non-immune elements of the mucosa are cited as involved in IBD pathogenesis. While the immunology of IBD has been the focus of intense studies, how the intestinal extracellular matrix (ECM) changes and contributes to progression of intestinal inflammation remains largely unknown. Our central hypothesis is that specific alterations in the intestinal basement membrane contribute crucially to early inflammation, while altered synthesis and modulation of interstitial ECM are important in progression of disease from early to chronic stages of disease. Furthermore, clinical evidence suggests that beyond certain common features, Crohn's disease (CD) and ulcerative colitis (UC), the two IBD subtypes, are diverse entities, with possibly fundamental differences in their ECM makeover. The current proposal will investigate this by elucidating ECM changes underlying early and chronic stages of IBD in pediatric and adult patients with CD and UC.
Aim 1 will elucidate ECM gene expression profiles in early and late stages of UC and CD in pediatric and adult patients by state-of-the-art DNA microarray techniques.
Aim 2 will elucidate changes of selected basement membrane and interstitial ECM proteins in bowel tissues from pediatric and adult IBD patients.
Aim 3 will elucidate changes in the same set of ECM components in induced and genetic murine models of colitis. Gene expression profiling of UC and CD tissue by DNA microarray will allow an unprecedented viewing of the entire repertoire of transcripts that differentiate UC from CD, as well as early from chronic stages of inflammation and fibrosis. In-depth studies of selected ECM components will provide a basic understanding of alterations that occur at the protein level. A newly developed animal model of intestinal fibrosis will offer the flexibility of following ECM changes from the onset to established to fibrosis stages of inflammation. Ultimately, the gene expression studies will provide the technology for a comprehensive comparison of animal models with human IBD and identify possible targets for new and better therapeutic approaches.
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