MOLECULAR INTERACTIONS AND SUBSTRATES OF MAMMALIAN SIRT6 LONGEVITY REGULATOR

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 Sir 2（Silent Information Regulator-2）蛋白在多种模式生物中将衰老和寿命调节、基因组稳定性和代谢联系起来。 最近的研究表明，哺乳动物Sir 2蛋白SIRT 6抑制基因组的不稳定性，并减弱了几个年龄相关的病理的发病。 SIRT 7是一种密切相关的蛋白质，在一些小鼠研究中也与衰老有关。然而，关于SIRT 6和SIRT 7功能的分子机制仍有许多有待了解。 我们的工作重点是通过SIRT 6和SIRT 7功能的基本分子机制的系统表征，使用生物化学和细胞生物学在人类细胞，基因组学和蛋白质组学分析的组合，并在果蝇中的SIRT 6和SIRT 7同源物的互补研究。这项工作将有助于阐明影响人类健康和衰老，癌症和新陈代谢的基本生物过程。 一系列的生化，细胞和全球蛋白质组学和基因组学分析正在进行，以确定SIRT 6和SIRT 7在哺乳动物和果蝇细胞中的分子功能。 我们建议： 1.阐明哺乳动物SIRT 6和SIRT 7调控的新分子通路。 采用蛋白质组学和生物化学方法分离和鉴定SIRT 6底物、蛋白质结合伴侣和大分子复合物。 2.阐明果蝇dSIRT 6和dSIRT 7调控的新分子通路。 蛋白质组学和生物化学方法被用来分离和鉴定它们的底物、蛋白质结合伴侣和大分子复合物。 质谱分析与UCSF质谱设施将是必不可少的这些目标。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Sir2 (Silent Information Regulator-2) proteins link aging and lifespan regulation, genomic stability, and metabolism in multiple model organisms. Recent work indicates that mammalian Sir2 protein SIRT6 suppresses genomic instability and attenuates the onset of several age-associated pathologies. SIRT7, a closely related protein, has also been linked to aging in some mouse studies. However, much remains to be learned about the molecular mechanisms of SIRT6 and SIRT7 function. Our work focuses on a systematic characterization of the basic molecular mechanisms through which SIRT6 and SIRT7 function, using a combination of biochemistry and cell biology in human cells, genomic and proteomic analyses, and complementary studies of the SIRT6 and SIRT7 homologs in drosophila flies. This work will be instrumental for elucidating fundamental biological processes that impact on human health and aging, cancer, and metabolism. A series of biochemical, cellular, and global proteomic and genomic analyses are being carried out to define the molecular functions of SIRT6 and SIRT7 in mammalian and drosophila cells. We propose: 1. To elucidate novel mammalian SIRT6 and SIRT7 regulated molecular pathways. Proteomic and biochemical approaches are taken to isolate and identify SIRT6 substrates, protein binding partners, and macromolecular complexes. 2. To elucidate novel molecular pathways regulated by drosophila dSIRT6 and dSIRT7. Proteomic and biochemical approaches are taken to isolate and identify their substrates, protein binding partners, and macromolecular complexes. Mass Spectrometry analysis with the UCSF Mass Spectrometry Facility will be essential for these aims.