The intestinal epithelium is a highly dynamic cell compartment in which rapid proliferation must be closely balanced by the rate of subsequent cellular differentiation and cell loss. Maintenance of this balance must require complex interaction of those factors which control cell proliferation and those which lead to functional maturation. In the studies encompassed by this proposal, the role of previously recognized growth factors (including TGF beta, EGF, PDGF and peptide hormones) on intestinal cell proliferation and differentiation will be defined using organ culture, primary isolated cell culture and established cell lines. Binding of peptide growth factors to epithelial cell populations in proximal and distal small intestinal as well as colonic epithelium will be characterized. The effects of these factors singly and in combination, on thymidine incorporation, glycoprotein structure and enzlymatic and molecular markers of differentation will be determined. A second major thrust of this proposal will be the isolation of additional peptide growth factors which may specifically regulate intestinal proliferation and differentiation. Preliminary studies have identified a peptide in the intestinal villus distinct from known growth factors which specifically inhibits intestinal cell proliferation and may promote commitment to functional differentiation. This factor will be isolated, characterized and its mechanism of action defined using molecular biologic approaches to characterize cellular transcripts following exposure to this factor. A second previously unrecognized growth factor(s) which stimulates cellular proliferation in the intestinal and colonic crypt has been found as a product of human colonic carcinoma cells. This proliferation promoting substance will be purified and its mechanism of action examined. The interaction of these different factors may provide the regulation essential to these complex and dynamic epithelial cell populations.
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