EFFECT OF AGING ON GASTROINTESTINAL HORMONES

衰老对胃肠激素的影响

• 批准号: 6314065
• 负责人: JAMES C THOMPSON
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6314065
• 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.

这项研究建议的总体假设是， (GI)激素在原因和效果上都与这些变化有关， 随着年龄的增长发生在胃肠道。这些与年龄有关的变化包括 1)GI粘膜的增殖活性增加，和2） 胃肠道分泌功能下降。的长期目标 本项目将至少确定其中一些机制， 与年龄相关的生长和分泌紊乱的病理生理学 的胃肠道。为了确定GI器官老化的进展， Fischer 344只三个年龄组（4月龄、12月龄和24月龄）的大鼠将 被利用将确定与GI激素的因果关系 通过给予胃肠激素作为外源性给药或作为 增加的内源性释放，有或没有给予 高选择性胃肠道激素受体拮抗剂。一个具体目标是 检验胃肠道粘膜细胞凋亡受胃肠道调节的假设， 激素，并且GI激素对细胞凋亡的调节丧失， 导致粘膜细胞过度增殖凋亡 胃、十二指肠、回肠和结肠将通过引起粘膜 萎缩，这将是通过禁食或喂养一个 基本饮食胃肠道营养激素（如胃泌素， 胆囊收缩素[CCK]、神经降压素[NT]、蛙皮素[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杂交进行组织学监测。 核DNA片段化的免疫染色。细胞增殖将是 通过BrdU核标记进行监测。的基因表达模式 与胃肠道细胞凋亡相关的基因将通过以下方法建立： 测量胃肠道激素的mRNA和蛋白质水平的变化， 受体，以及糖尿病相关基因（例如，TGF-β 1，p53和bcl-2）， 2）。第二个具体目标将测试的假设，即抗衰老 热量限制（CR）的作用是通过调节GI 激素代谢，这反过来又决定了 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）。 通过给CR限制大鼠喂食60%（wt/wt）的 自由进食大鼠摄入的食物量。CR诱导的GI变化 将在GI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，并在 GI激素靶点的反应性（GI激素受体基因 表达式）。胃肠道激素代谢变化的关系 伴有胃酸分泌、胰腺外分泌和内分泌的变化 胃肠道激素过氧化氢酶、超氧化物歧化酶和热休克蛋白70的表达 目标，将建立。了解所涉机制 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， 类似的精神错乱