Mammalian Sir2 Function in Pancreatic Beta Cells

哺乳动物 Sir2 在胰腺 β 细胞中的功能

• 批准号: 6943505
• 负责人: SHIN-ICHIRO IMAI
• 金额: $ 30.98万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6943505
• 关键词: aging; amidohydrolases; biological signal transduction; enzyme activity; gene expression; genetic transcription; genetically modified animals; glucose metabolism; glucose tolerance test; immunoprecipitation; insulin; insulinlike growth factor; laboratory mouse; longevity; nicotinamide adenine dinucleotide; pancreatic islet function; polymerase chain reaction; protein protein interaction; radioimmunoassay; small interfering RNA; tissue /cell culture; transcription factor; western blottings

DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to understand the function of mammalian Sir2 in the endocrine control of aging and longevity by the insulin/IGF-I system in mammals. Recent studies have demonstrated that insulin/IGF-I signaling pathways play critical roles in regulating the pace of aging and longevity in worms, flies and mice. Additionally, caloric restriction, which extends life span in a wide variety of organisms, reduces blood insulin and IGF-I levels in mammals. The Sir2 (silent information regulator 2) nicotinamide adenine dinucleotide (NAD)-dependent deacetylases have been demonstrated to link glucose metabolism to the mechanism of aging and longevity in yeast and C. elegans. We have found evidence that mammalian Sir2 plays an important role in regulating transcription in pancreatic beta cells. Based on our preliminary findings presented in this proposal, it is hypothesized that mammalian Sir2 controls glucose metabolism, aging and longevity by regulating transcription of specific genes required for the insulin-producing function of pancreatic b cells through its NAD-dependent deacetylase activity. This hypothesis will be addressed by the following specific aims: 1) examine insulin gene expression and insulin secretion in mouse primary islets infected with recombinant adenovirus carrying Sir2 cDNA or siRNA, 2) elucidate the molecular mechanism of mammalian Sir2-mediated transcriptional regulation by examining expression and modification of important transcriptional regulators in beta cells, and 3) examine the in vivo function of mammalian Sir2 in b cells by measuring multiple physiological parameters for glucose homeostasis in beta cell-specific Sir2 transgenic mice. These studies should provide a molecular framework to understand the function of mammalian Sir2 in beta cells, glucose metabolism and longevity control in mammals.

描述（由申请方提供）：本提案的长期目标是了解哺乳动物Sir 2在哺乳动物中通过胰岛素/IGF-I系统对衰老和长寿进行内分泌控制的功能。最近的研究表明，胰岛素/IGF-I信号通路在调节蠕虫、苍蝇和小鼠的衰老和长寿的速度中起着关键作用。此外，热量限制延长了各种生物体的寿命，降低了哺乳动物的血液胰岛素和IGF-I水平。Sir 2（沉默信息调节因子2）依赖的烟酰胺腺嘌呤二核苷酸（NAD）脱乙酰酶已被证明将葡萄糖代谢与酵母和C.优雅的我们已经发现哺乳动物Sir 2在调节胰腺β细胞转录中起重要作用的证据。基于我们在该提案中提出的初步发现，假设哺乳动物Sir 2通过其NAD依赖性脱乙酰酶活性调节胰腺B细胞产生胰岛素功能所需的特定基因的转录来控制葡萄糖代谢、衰老和寿命。 这一假设将通过以下具体目标加以解决：1）检测用携带Sir 2 cDNA或siRNA的重组腺病毒感染的小鼠原代胰岛中的胰岛素基因表达和胰岛素分泌，2）通过检测β细胞中重要转录调节因子的表达和修饰来阐明哺乳动物Sir 2介导的转录调节的分子机制，和3）通过测量β细胞特异性Sir 2转基因小鼠中葡萄糖稳态的多个生理参数来检查哺乳动物Sir 2在B细胞中的体内功能。这些研究将为理解哺乳动物Sir 2在β细胞、葡萄糖代谢和哺乳动物寿命控制中的功能提供一个分子框架。