ROLE OF TRANSFORMING GROWTH FACTORS IN THE INTESTINE

自分泌生长调节肽是一种分子， 由细胞合成和分泌， 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 被认为在瘤形成的发生中很重要，但最近 工作有力地支持了在监管方面的基本作用， 正常的细胞生长。 这些生物学上的最新进展 细胞生长控制的发展为人类 了解细胞的增殖和分化过程， 正常胃肠道上皮。 一个更基本 了解负责控制的机制， 正常的胃肠道生长和分化将提供 有价值的洞察异常和适应性现象， 在小肠后的胃肠上皮中 在链脲佐菌素诱导的糖尿病中， 婴儿期、营养不良期间和其他许多时期， 病理生理环境。 目前的建议旨在调查以下假设， 生长刺激（TGF α）和生长抑制（TGF β） 自分泌多肽生长因子在肿瘤生长中起着不可或缺的作用。 正常细胞的生长和分化 胃肠道 据推测， 刺激因子在肠隐窝中占主导地位， 自分泌抑制因子在绒毛尖端附近占优势。 可能发生正常自分泌生长控制机制的适应 在小肠切除术和糖尿病的化学诱导之后， 以粘膜增生为特征的事件。 的 以下三个互补的实验方法将是 在这些研究中使用：1）IEC-6的细胞培养， 非转化大鼠空肠隐窝上皮细胞系，这将 对TGFB和细胞外基质的反应分化 蛋白质; 2）小肠的洗脱和分级 正常人肠腺-绒毛轴上皮细胞 大鼠、链脲佐菌素糖尿病大鼠和已经经历 远端小肠切除术和3）免疫细胞化学， 大鼠小肠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)TGF α和TGF β B基因表达及基因表达调控; 2)TGF α和TGF β B蛋白的产生和分泌; 3）TGF α和TGF β B 受体分布、表征和细胞膜 TGF α和TGF β B对细胞增殖的影响 和感受态基因表达的影响; 5）TGFB对 肠上皮细胞的分化。

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.