EFFECT OF AGING ON GASTROINTESTINAL HORMONES

衰老对胃肠激素的影响

• 批准号: 6217565
• 负责人: JAMES C THOMPSON
• 金额: $ 11.71万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6217565
• 关键词: aging; animal age group; antioxidants; apoptosis; bombesin; caloric dietary content; cell growth regulation; cholecystokinin; diet; electron microscopy; fasting; gastrins; gastrointestinal hormones; gene expression; hormone metabolism; hormone receptor; hormone regulation /control mechanism; immunocytochemistry; intestinal mucosa; laboratory rat; neurotensin; nutrition related tag; radioimmunoassay; secretion

The overall hypothesis of this research proposal is that gastrointestinal (GI) hormones are related in both cause and effect to the changes that occur in the GI tract with aging. These age-related alterations include 1) an increased proliferative activity of the GI mucosa, and 2) a decreased secretory function in the GI tract. The long-term objective of this project is to define at least some of the mechanisms involved in the pathophysiology of the age-related derangements in growth and secretion of the GI tract. To establish the progression of GI organismal aging, Fischer 344 rats of three age groups (4-mo, 12-mo, and 24-mo old) will be used. Associations of causality with GI hormones will be established by giving GI hormones either as an exogenous administration or as an increased endogenous release, with or without the administration of highly selective GI hormone receptor antagonists. One specific aim will test the hypothesis that apoptosis in GI mucosa is regulated by GI hormones, and that loss of regulation of apoptosis by GI hormones is responsible for an exaggerated mucosal cell proliferation. Apoptosis in the stomach, duodenum, ileum and colon will be induced by causing mucosal atrophy, which will be accomplished either by fasting or by feeding an elemental diet. The ability of trophic GI hormones (eg, gastrin, cholecystokinin [CCK], neurotensin [NT], bombesin [BBS]) to inhibit apoptosis will be determined, and correlated with changes in GI mucosal cell proliferation. Apoptosis will be monitored histologically by in situ immunostaining of nuclear DNA fragmentation. Cell proliferation will be monitored by BrdU nuclear labelling. Patterns of gene expression associated with apoptosis in the GI tract will be established by measuring changes in mRNA and protein levels of GI hormones and their receptors, and of apoptosis-associated genes (eg, TGF-Beta1, p53 and bcl- 2). A second specific aim will test the hypothesis that the anti-aging actions of caloric restriction (CR) operate through the regulation of GI hormone metabolism which, in turn, determines the expression of cytoprotective mechanisms, namely antioxidant scavenging enzymes (catalase and superoxide dismutase [SOD]) and heat-shock proteins (hsp). CR will be accomplished by feeding CR-restricted rats 60% (wt/wt) the amount of food ingested by ad lib fed rats. CR-induced changes in GI hormone metabolism will be investigated at the levels GI hormone gene expression (tissue mRNA and peptide levels) and release, and at the responsiveness of the GI hormone targets (GI hormone receptor gene expression). The relationships between changes in GI hormone metabolism with changes in gastric acid secretion, pancreatic exocrine and endocrine secretions, and expression of catalase, SOD and hsp70 in GI hormone targets, will be established. Understanding of the mechanisms involved in dysregulation of growth and secretion of the GI tract in rats may help to devise strategies for the treatment of age-related diseases with similar derangements in humans.

本研究提案的总体假设是胃肠道 （GI）激素与以下变化有因果关系： occur in the GI tract with aging. These age-related alterations include 1) 胃肠道粘膜增殖活性增加，2) decreased secretory function in the GI tract.长期目标 该项目旨在至少定义一些涉及的机制 与年龄相关的生长和分泌紊乱的病理生理学 胃肠道。为了确定胃肠道有机衰老的进展， 三个年龄组（4 个月、12 个月和 24 个月大）的 Fischer 344 只大鼠将 被使用。将建立与胃肠道激素的因果关系 通过给予胃肠道激素作为外源性给药或作为 增加内源性释放，无论是否给予 高选择性胃肠激素受体拮抗剂。一个具体的目标将 检验胃肠道粘膜细胞凋亡受胃肠道调节的假设 激素，并且胃肠道激素对细胞凋亡的调节丧失 导致粘膜细胞过度增殖。细胞凋亡 胃、十二指肠、回肠和结肠会因引起粘膜炎症而诱发 萎缩，可以通过禁食或喂食来实现 基本饮食。 The ability of trophic GI hormones (eg, gastrin, 胆囊收缩素 [CCK]、神经降压素 [NT]、铃蟾肽 [BBS]) 抑制 细胞凋亡将被确定，并与胃肠道粘膜的变化相关 细胞增殖。细胞凋亡将通过原位组织学监测 immunostaining of nuclear DNA fragmentation. Cell proliferation will be monitored by BrdU nuclear labelling. Patterns of gene expression 与胃肠道细胞凋亡相关的 测量胃肠道激素的 mRNA 和蛋白质水平的变化及其 受体和凋亡相关基因（例如 TGF-Beta1、p53 和 bcl-） 2）。第二个具体目标将检验抗衰老的假设 热量限制 (CR) 的作用是通过调节 GI 来实现的 激素代谢反过来又决定了 细胞保护机制，即抗氧化剂清除酶 （过氧化氢酶和超氧化物歧化酶 [SOD]）和热休克蛋白 (hsp)。 CR 将通过喂食 CR 限制的大鼠 60%（wt/wt）来实现 amount of food ingested by ad lib fed rats. CR 引起的 GI 变化 将在胃肠道激素基因水平上研究激素代谢 表达（组织 mRNA 和肽水平）和释放，以及 胃肠道激素目标的反应性（胃肠道激素受体基因 表达）。胃肠道激素代谢变化之间的关系 随着胃酸分泌、胰腺外分泌和内分泌的变化 胃肠道激素中过氧化氢酶、SOD、hsp70的分泌及表达 targets, will be established. Understanding of the mechanisms involved 大鼠胃肠道生长和分泌失调可能有助于 制定治疗与年龄相关的疾病的策略 similar derangements in humans.