ROLE OF TRANSFORMING GROWTH FACTORS IN THE INTESTINE

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Autocrine growth regulatory peptides are molecules that are synthesized and secreted by cells that are also responsive to the growth inhibitory or stimulatory effects of the same molecules. When first described, autocrine growth factors were primarily considered important in the genesis of neoplasia, however recent work strongly supports a fundamental role in the regulation of normal cell growth as well. These recent advances in the biology of cell growth control have opened exciting new opportunities for understanding the process of proliferation and differentiation of the normal gastrointestinal tract epithelium. A more basic comprehension of the mechanisms responsible for the control of normal gastrointestinal growth and differentiation will provide valuable insight into the abnormalities and adaptive phenomena seen in the gastrointestinal epithelium following small intestinal resection, in streptozotocin-induced diabetes, during early infancy, during malnutrition and in a host of other pathophysiological circumstances. The current proposal is designed to investigate the hypothesis that both growth stimulatory (TGFa) and growth inhibitory (TGFB) autocrine polypeptide growth factors play an integral role in the control of growth and differentiation of the normal gastrointestinal tract. It is postulated that autocrine stimulatory factors predominate in the intestinal crypt and that autocrine inhibitory factors predominate near the villus tip. Adaptation of normal autocrine growth control mechanisms may occur following small bowel resection and chemical induction of diabetes, events that are characterized by mucosal hyperplasia. The following three complementary experimental approaches will be utilized in these studies: 1) cell culture of IEC-6, a nontransformed rat jejunal crypt epithelial cell line, that will differentiate in response to TGFB and extracellular matrix proteins; 2) elution and fractionation of small intestinal epithelial cells from the intestinal crypt-villus axis of normal rats, streptozotocin diabetic rats and rats that have undergone distal small intestinal resection and 3) immunocytochemical and in situ hybridization studies of histologic sections of rat intestinal mucosa. These experimental approaches will be used to examine: 1) TGFa and TGFB gene expression and regulation of gene expression; 2) TGFa and TGFB protein production and secretion; 3) TGFa and TGFB receptor distribution, characterization and cell membrane localization; 4) the effect of TGFa and TGFB on cell proliferation and competence gene expression and 5) the effects of TGFB on differentiation of the enterocyte.