ROLE OF TRANSFORMING GROWTH FACTORS IN THE INTESTINE

自分泌生长调节肽是一种分子 合成和分泌的细胞也对 相同分子的生长抑制或刺激作用。 当第一次描述时，自分泌生长因子主要是 被认为在肿瘤的发生中很重要，尽管是最近的 Work强烈支持在监管中发挥基础性作用 细胞生长也是正常的。生物学上的这些最新进展 对细胞生长控制的研究为 了解细胞增殖和分化的过程 正常胃肠道上皮。一个更基本的 对负责控制的机制的理解 正常的胃肠道生长和分化将提供 对所见异常和适应现象的有价值的见解 在小肠后的胃肠上皮中 链脲佐菌素诱导的糖尿病患者早期行手术切除 婴儿期、营养不良期间和许多其他 病理生理环境。 目前的提案旨在调查这样一种假设 生长促进(TGFa)和生长抑制(TGFb) 自分泌多肽生长因子在血管生成中起着不可或缺的作用 正常人生长和分化的调控 胃肠道。据推测，自分泌 刺激因素在肠隐窝中占主导地位， 绒毛顶端附近以自分泌抑制因子为主。 正常的自分泌生长控制机制可能发生适应 在小肠切除和化学诱导糖尿病之后， 以粘膜增生为特征的事件。这个 以下三种互补的实验方法将是 用于这些研究：1)IEC-6细胞培养，a 未转化的大鼠空肠隐窝上皮细胞系 对TGFb和细胞外基质的反应诱导分化 蛋白质；2)小肠的洗脱和分离 正常肠隐窝-绒毛轴上皮细胞 大鼠，链脲佐菌素糖尿病大鼠和 远端小肠切除和3)免疫细胞化学和原位 大鼠肠道组织切片的原位杂交研究 粘膜。这些实验方法将用于检查： 1)TGFa、TGFb基因表达及基因表达调控； 2)TGFa和TGFb蛋白的产生和分泌；3)TGFa和TGFb 受体的分布、特性和细胞膜 4)TGFa和TGFb对细胞增殖的影响 和感受态基因的表达以及5)转化生长因子b对细胞周期的影响。 肠细胞的分化。

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.