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（由申请人提供）：该提案的长期目标是了解哺乳动物SIR2在哺乳动物中胰岛素/IGF-I系统对内分泌和长寿的内分泌控制中的功能。最近的研究表明，胰岛素/IGF-I信号通路在调节蠕虫，苍蝇和小鼠中衰老和寿命的速度方面起着关键作用。此外，在各种生物体中延伸寿命的热量限制会降低哺乳动物的血液胰岛素和IGF-I水平。 SIR2（无声信息调节剂2）烟酰胺腺嘌呤二核苷酸（NAD）依赖性脱乙酰基酶已被证明可以将葡萄糖代谢与酵母和秀丽隐杆线虫的衰老和寿命机理联系起来。我们发现证据表明哺乳动物SIR2在调节胰腺β细胞的转录中起重要作用。基于我们在该提案中提出的初步发现，据推测，哺乳动物SIR2通过调节胰腺B细胞通过其NAD依赖性deacetylase活性的胰岛素产生功能所需的特定基因来控制葡萄糖代谢，衰老和寿命。 该假设将通过以下具体目的来解决：1）检查携带siR2 cDNA或siRNA的重组腺病毒感染的小鼠原发胰岛中的胰岛素基因表达和胰岛素分泌，2）阐明通过检查重要的转录和修饰的哺乳动物SIRMALIAN SIRMALIAIN SIRCRICT介导的转录和修饰的分子机制。通过测量β细胞特异性SIR2转基因小鼠中葡萄糖稳态的多个生理参数，通过测量B细胞中的哺乳动物siR2。这些研究应提供一个分子框架，以了解哺乳动物siR2在β细胞，葡萄糖代谢和哺乳动物的寿命控制中的功能。