MOLECULAR INTERACTIONS AND SUBSTRATES OF MAMMALIAN SIRT6 LONGEVITY REGULATOR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Sir2(沉默信息调节因子-2)蛋白在多种模式生物中将衰老和寿命调节、基因组稳定性和新陈代谢联系起来。最近的工作表明，哺乳动物Sir2蛋白SIRT6抑制了基因组的不稳定性，并减弱了几种与年龄相关的病理的发生。SIRT7是一种密切相关的蛋白质，在一些小鼠研究中也被认为与衰老有关。然而，关于SIRT6和SIRT7功能的分子机制仍有许多需要了解。我们的工作集中于系统地描述SIRT6和SIRT7发挥作用的基本分子机制，使用人类细胞的生物化学和细胞生物学的组合，基因组和蛋白质组分析，以及在果蝇中SIRT6和SIRT7同源物的补充研究。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学过程。为了确定SIRT6和SIRT7在哺乳动物和果蝇细胞中的分子功能，人们正在进行一系列的生化、细胞和全球蛋白质组和基因组分析。我们建议：1.阐明哺乳动物SIRT6和SIRT7调控的新的分子通路。蛋白质组学和生化方法被用来分离和鉴定SIRT6底物、蛋白质结合伙伴和大分子复合体。2.阐明果蝇dSIRT6和dSIRT7调控的新的分子途径。蛋白质组学和生化方法被用来分离和鉴定它们的底物、蛋白质结合伙伴和大分子复合体。使用加州大学旧金山分校的质谱学设施进行质谱学分析将是实现这些目标的关键。

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.