GASTROINTESTINAL ENDOCRINOLOGY

该计划的长期目标是提供有用的新信息 胃肠激素(GIH)和钙的作用机制 调节性多肽影响人体功能。我们将研究基因 其表达、合成、储存、释放、转运及其机制 对靶细胞的作用，激素-激素的相互关系，靶 细胞反应，以及受这些因子调控的基因表达。这个 汤普森博士的项目将研究 GIH在肠道的老化过程中发挥作用。我们计划定义一些 年龄相关生长、分泌和基因变化的机制 胃肠道的表达。我们将研究胃肠激素在 调节肠粘膜细胞凋亡。我们计划研究 慢性卡路里限制作为一种抗衰老策略。该项目由 Greeley博士将研究嗜铬粒蛋白A(CGA)和 环丙沙星在肠道内分泌中被加工成胰抑素的机制 细胞。我们将研究CGA动态平衡和共居的调节 多肽。我们将研究前激素转换酶的作用，以及 确定CGA是否与胃泌素肽和甲状旁腺共存 胰腺、结肠、卵巢和肝脏中的激素相关肽 癌细胞以及CGA和共存肽是否显示出特性 受调节的分泌。汤森博士的这个项目将研究 蛙皮素(BBS)对多肽基因表达和释放的影响 神经降压素。我们将研究特定的受体和信号转导 BBS影响多肽基因表达、多肽释放的途径 GI细胞的生长、释放和生长。我们将确定是否 特定的受体和受体连接的信号转导通路是 这些功能中的每一项都不同。我们将检查这两个细胞 表达BBS受体以及转GRP或GRP基因的人细胞 神经介素B受体和受体突变体来剖析这些通路。 我们已经发现，同样的GIH可能会刺激或抑制生长 癌细胞的数量。这些研究将使我们能够准确地确定 GIH影响人类肿瘤生长的细胞特异性机制 细胞。库珀博士的这项研究将检验这一假设 钙调节多肽，特别是PTHrP，发挥着重要作用 肠道中的调节作用。我们将确定通过哪些机制 PTHrP调节上皮细胞的生长和分化。我们会 确定甲状旁腺激素受体是否为自分泌/旁分泌调节剂 检测甲状旁腺素rP对肠道细胞凋亡的影响，以及甲状旁腺激素在其中的作用 PTHrP在再生肝中的表达。我们将研究细胞内的机制 血管活性肠肽(VIP)和甲状旁腺素受体激动剂(PTHrP) 环磷酸腺苷和鸟氨酸脱羧酶的mR-NA活性 对人结肠癌细胞生长的相反影响。自上个月以来 竞争性审查我们已经证明了我们的 我们出版物的合作努力：许多出版物涉及 不止一个项目。在这笔赠款的支持下，我们的研究 从整个动物进化到细胞、亚细胞和分子 胃肠激素的作用机制，以满足长期 我们计划的目标。

The long-term goal of this program is to provide useful new information on the mechanisms by which gastrointestinal hormones (GIH) and calcium- regulatory peptides influence body function. We will study gene expression, synthesis, storage, release, transport and mechanisms of action on target cells, hormone-hormone interrelationships, the target cell responses, and gene expression as regulated by these agents. The project by Dr. Thompson will study the role (both cause and effect) that GIH play in the aging of the gut. We plan to define some of the mechanisms involved in age-related changes in growth, secretion and gene expression of the GI tract. We will examine the role of GI hormones in regulating apoptosis in gut mucosa. We plan to study the effects of chronic caloric restriction as an anti-aging strategy. The project by Dr. Greeley will examine the role of chromogranin A (CGA) and the mechanisms by which CGA is processed to pancreastatin in enteroendocrine cells. We will study the regulation of CGA homeostasis and co-resident peptides. We will examine the role of prohormone convertases, and determine whether CGA co-resides with gastrin peptides and parathyroid hormone-related peptide (PTHrP) in pancreatic, colon, ovarian and liver cancer cells and whether CGA and co-resident peptides exhibit properties of regulated secretion. The project by Dr. Townsend will examine the effects of bombesin (BBS) on gene expression and release of the peptide, neurotensin. We will examine specific receptor and signal transduction pathways by which BBS affects peptide gene expression, peptide release and growth release and growth of GI cells. We will determine whether specific receptors and receptor-linked signal transduction pathways are different for each of these functions. We will examine both cells that express BBS receptors as well as human cells transfected with GRP or neuromedin B receptors and receptor mutants to dissect these pathways. We have found that the same GIH may either stimulate or inhibit growth of cancer cells. These studies will allow us to determine precisely the cell-specific mechanisms by which GIH affect growth of human cancer cells. The project by Dr. Cooper will examine the hypothesis that calcium-regulatory peptides, specifically PTHrP, play important regulatory roles in the gut. We will identify the mechanisms by which PTHrP regulates growth and differentiation of epithelial cells. We will determine whether PTHrP is an autocrine/paracrine regulatory agent and examine the effects of PTHrP on apoptosis in gut cells, and the role of PTHrP in regenerating liver. We will examine intracellular mechanisms by which vasoactive intestinal peptide (VIP) and PTHrP both stimulate cyclic AMP and ornithine decarboxylase mRNA activity and yet have opposite effects on growth of human colon cancer cells. Since the last competitive review we have demonstrated the productivity of our collaborating efforts by our publications: many publications relate to more than one project. With the support of this grant, our studies have evolved from whole animals to cellular, subcellular and molecular mechanisms of actions of GI hormones in order to meet the long-term objectives of our program.