NAD Biosynthesis and the Regulation of Sirtuins

描述(申请人提供)：sirtuins是一个保守的NAD依赖的蛋白去乙酰基酶家族，在广泛的细胞过程中发挥作用，包括抑制基因表达(沉默)、细胞凋亡和寿命调节。这些蛋白质对NAD的需求重新引起了人们对酵母和其他模式生物中NAD生物合成途径的兴趣，这些生物被用作研究衰老和与年龄相关的疾病的模型。解剖这些通路对于了解sirtuins如何与细胞环境相互作用以及对新陈代谢或压力的变化做出反应至关重要。最近的实验室工作揭示了烟酰胺利用的一个以前未知的途径，该途径通过烟酰胺核苷途径，将成为特定目标1的主题。我们最近还发现硫胺的生物合成是由Sir2和Hst1 sirtuins控制的代谢途径，以响应NAD和烟酰胺浓度的变化。NAD和硫胺途径与衰老相关的有趣的共同调节是特定目标2的主题。在特定目标3中，我们计划通过鉴定每个酵母Sirtuins在转录水平上调节的基因来继续研究NAD和烟酰胺对细胞核中sirtuins的调节。这些研究有望促进新的保守的NAD生物合成和Sirtuin靶点的确定，以用于未来与年龄相关的疾病治疗的开发。公共卫生相关性：依赖于NAD的蛋白脱乙酰酶(Sirtuins)在多种模式生物的寿命调节中发挥重要作用，包括萌芽酵母，酿酒酵母。这项研究的目标是更好地了解在酵母和哺乳动物细胞中合成NAD的途径，并确定sirtuins在细胞NAD水平变化时控制哪些与衰老相关的细胞过程。酵母的生物合成途径和高等真核生物的合成途径之间的大量保守性，使酵母中的任何发现都适用于哺乳动物。

DESCRIPTION (provided by applicant): The Sirtuins are a conserved family of NAD-dependent protein deacetylases that function in a wide variety of cellular processes, including repression of gene expression (silencing), apoptosis, and lifespan regulation. The requirement of these proteins for NAD has led to renewed interest in the NAD biosynthesis pathways in yeast and other model organisms that are used as models for the study of aging and age-associated diseases. Dissecting these pathways is critical toward understanding how Sirtuins interact with the cellular environment and respond to changes in metabolism or stress. Recent work in the lab has revealed the existence of a previously uncharacterized pathway for nicotinamide utilization that feeds through the nicotinamide riboside pathway, and will be the subject of specific aim 1. We have also recently identified thiamine biosynthesis as a metabolic pathway controlled by the Sir2 and Hst1 Sirtuins in response to changes in NAD and nicotinamide concentrations. The interesting co-regulation of the NAD and thiamine pathways in relationship to aging is the subject of specific aim 2. In specific aim 3, we plan to continue the investigation of NAD and nicotinamide regulation of Sirtuins in the nucleus by identifying the genes that each of the yeast Sirtuins regulate at the transcriptional level. These studies are expected to spur the identification of new conserved NAD biosynthesis and Sirtuin targets for future development of age-related disease therapeutics. PUBLIC HEALTH RELEVANCE: The NAD-dependent protein deacetylases (the Sirtuins) play an important role in the regulation of lifespan in multiple model organisms, including the budding yeast, Saccharomyces cerevisiae. The goal of this research project is to better understand the pathways by which NAD is synthesized in both yeast and mammalian cells, and to determine what cellular processes related to aging are controlled by the Sirtuins in response to alterations in cellular NAD levels. The large amount of conservation between the yeast biosynthesis pathways and those in higher eukaryotes any findings in yeast applicable to mammals.