GASTROINTESTINAL ENDOCRINOLOGY

胃肠内分泌学

• 批准号: 2693154
• 负责人: Courtney M Townsend
• 金额: $ 0.3万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-22 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2693154
• 关键词: GASTROINTESTINAL; ENDOCRINOLOGY

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.

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 调节肽影响身体功能。 我们将研究基因 的表达、合成、储存、释放、运输和机制 对靶细胞的作用、激素-激素相互关系、靶标 这些试剂调节细胞反应和基因表达。 这 汤普森博士的项目将研究的作用（因果） GIH 在肠道衰老中发挥作用。 我们计划定义一些 与年龄相关的生长、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。 我们计划研究影响 长期热量限制作为抗衰老策略。 该项目由 Greeley 博士将研究嗜铬粒蛋白 A (CGA) 的作用以及 CGA 在肠内分泌中加工成胰酶的机制 细胞。 我们将研究CGA稳态和共存的调节 肽。 我们将研究激素原转化酶的作用，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 (PTHrP) 癌细胞以及 CGA 和共存肽是否表现出特性 的调节分泌。 汤森博士的项目将检查 铃蟾肽 (BBS) 对基因表达和肽释放的影响， 神经降压素。 我们将检查特定受体和信号转导 BBS 影响肽基因表达、肽释放的途径 以及胃肠道细胞的生长释放和生长。 我们将确定是否 特定受体和受体相关信号转导途径是 这些功能中的每一个都不同。 我们将检查这两个细胞 表达 BBS 受体以及用 GRP 或转染的人类细胞 神经调节素 B 受体和受体突变体来剖析这些途径。 我们发现相同的 GIH 可能会刺激或抑制生长 癌细胞。这些研究将使我们能够准确地确定 GIH 影响人类癌症生长的细胞特异性机制 细胞。 库珀博士的项目将检验以下假设： 钙调节肽，特别是 PTHrP，发挥着重要作用 在肠道中的调节作用。 我们将确定机制 PTHrP 调节上皮细胞的生长和分化。 我们将 确定 PTHrP 是否是一种自分泌/旁分泌调节剂，以及 检查 PTHrP 对肠道细胞凋亡的影响，以及 PTHrP 在肝脏再生中的作用。 我们将检查细胞内机制 血管活性肠肽 (VIP) 和 PTHrP 均能刺激 环 AMP 和鸟氨酸脱羧酶 mRNA 活性，但具有 对人类结肠癌细胞的生长有相反的影响。 自从上次 竞争性审查我们已经证明了我们的生产力 我们出版物的合作：许多出版物涉及 不止一个项目。 在这笔资助的支持下，我们的研究取得了进展 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需求 我们计划的目标。