SURGICAL STUDIES OF GI PEPTIDES--MECHANISMS OF ACTION

胃泌素是人体正常粘膜的一种营养激素。 胃肠道(GI)。我们发现胃泌素能刺激 啮齿动物和人胃肠道肿瘤在体内和体外的生长。然而， 胃泌素调节细胞增殖的机制尚未得到证实 已确认身份。我们的长期目标是了解信号的机制 从细胞表面到细胞核的转导，允许胃泌素 调节胃肠道细胞增殖。需要检验的假设包括： 胃泌素通过细胞类型特异性胃泌素调节胃肠道细胞生长 受体；介导胃泌素营养作用的胃泌素受体 与特定细胞类型的细胞内信号转导有关 胃泌素通过胃泌素调节某些肿瘤的体内生长 受体，而在其他受体中，胃泌素与其他肽相互作用， 调节体内生长的生长因子。在这方面的研究中 我们计划通过胃泌素受体来表征胃泌素受体 调节细胞增殖。初步数据显示， 有多个受体能够结合胃泌素；我们的研究将 明确哪些受体介导胃泌素对胃肠道的营养作用 上皮细胞。我们将描述与受体相连的细胞内 胃泌素调节细胞的信号转导途径 扩散。初步研究表明，特定类型的细胞 细胞内信号转导途径，包括环磷酸腺苷， 磷脂酰肌醇的水解和细胞内钙的动员 被胃泌素以一种细胞类型特异性的方式激活以调节细胞 扩散。我们将定义涉及的细胞和分子事件 胃泌素刺激的信号转导。我们将研究其影响 胃泌素对自然表达胃泌素的人细胞生长的影响 受体和在组织培养中生长和作为异种移植的 裸鼠或裸鼠。我们将确定结果是否 的体外研究准确地预测了外源性和 内源性胃泌素对体内细胞增殖的影响。我们还将检查 胃泌素的类似物以及胃泌素家族的其他成员 (缩胆囊素)和结构无关的多肽(血管活性 肠多肽[VIP])，单独和与胃泌素联合使用。这个 这些研究的长期目标是准确地确定 胃泌素与其特异性相互作用后的信号转导 胃肠道上皮细胞的转录活性和基因表达。我们的 在未来，研究可以为开发新的 基于胃泌素作用的治疗策略 恢复肠道粘膜肿块，调节肠癌生长 以类似于目前内分泌策略的方式 乳腺癌和前列腺癌的治疗。

Gastrin is a trophic hormone for the normal mucosa of the gastrointestinal tract (GI). We have found that gastrin stimulates the growth of rodent and human GI cancers in vivo and in vitro. However, the mechanisms by which gastrin regulates cell proliferation have not been identified. Our long-term goal is to understand the mechanism of signal transduction from the cell surface to the nucleus that allows gastrin to regulate GI cell proliferation. The hypotheses to be tested include: gastrin regulates growth of GI cells by cell type-specific gastrin receptors; gastrin receptors that mediate the trophic action of gastrin are linked to cell type-specific intracellular signal-transduction pathways; gastrin regulates in vivo growth of some tumors through gastrin receptors, while in others gastrin interacts with other peptides and growth factors to regulate in vivo growth. In the studies in this proposal, we plan to characterize gastrin receptors through which gastrin regulates cell proliferation. The preliminary data suggest that there are multiple receptors capable of binding gastrin; our studies will define which receptors mediate the trophic actions of gastrin on GI epithelial cells. We will characterize the receptor-linked intracellular signal-transduction pathways through which gastrin regulates cell proliferation. Preliminary studies have shown that cell type-specific intracellular signal-transduction pathways, including cyclic AMP, phosphatidylinositol hydrolysis, and mobilization of intracellular Ca2+ are activated by gastrin in a cell type-specific manner to regulate cell proliferation. We will define cellular and molecular events involved in signal transduction stimulated by gastrin. We will examine the effects of gastrin on growth of human cells that naturally express gastrin receptors and that grow both in tissue culture and as xenografts in athymic nude mice or nude rats. We will determine whether the results of in vitro studies accurately predict the effects of exogenous and endogenous gastrin on cell proliferation in vivo. We will also examine analogs of gastrin as well as other members of the gastrin family (cholecystokinin) and structurally unrelated peptides (vasoactive intestinal polypeptide [VIP]), alone and combined with gastrin. The long-term goal of these studies is to precisely identify the steps in signal transduction after gastrin interacts with its specific transcriptional activity and gene expression in GI epithelial cells. Our studies could, in the future, provide the basis for development for new therapeutic strategies based upon manipulation of gastrin's action to restore gut mucosal mass and to regulate the growth of cancers of the gut in a manner similar to current strategies employed for endocrine treatment of breast and prostate cancers.