Mammalian Sir2 Function in Pancreatic Beta Cells

描述（由申请人提供）：本提案的长期目标是了解哺乳动物Sir2在哺乳动物胰岛素/IGF-I系统对衰老和长寿的内分泌控制中的功能。最近的研究表明，胰岛素/ igf - 1信号通路在调节蠕虫、苍蝇和小鼠的衰老和寿命方面发挥着关键作用。此外，热量限制可以延长多种生物的寿命，降低哺乳动物血液中的胰岛素和igf - 1水平。在酵母和秀丽隐杆线虫中，Sir2（沉默信息调节因子2）烟酰胺腺嘌呤二核苷酸（NAD）依赖的去乙酰化酶已被证明将葡萄糖代谢与衰老和长寿机制联系起来。我们已经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。基于我们在本提案中提出的初步发现，我们假设哺乳动物Sir2通过其nad依赖性去乙酰化酶活性调节胰腺b细胞胰岛素生成功能所需的特定基因的转录，从而控制葡萄糖代谢、衰老和寿命。这一假设将通过以下具体目标来解决：1)检测携带Sir2 cDNA或siRNA的重组腺病毒感染小鼠原代胰岛后胰岛素基因的表达和胰岛素分泌；2)通过检测β细胞中重要转录调控因子的表达和修饰，阐明哺乳动物Sir2介导的转录调控的分子机制；3)通过测量β细胞特异性Sir2转基因小鼠体内葡萄糖稳态的多个生理参数，研究哺乳动物Sir2在b细胞中的体内功能。这些研究将为了解哺乳动物Sir2在β细胞、糖代谢和哺乳动物寿命控制中的功能提供一个分子框架。

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.