NAD Biosynthesis and the Regulation of Sirtuins

描述（由申请人提供）：Sirtuins是NAD依赖性蛋白脱乙酰酶的保守家族，在多种细胞过程中发挥作用，包括基因表达抑制（沉默）、细胞凋亡和寿命调节。这些蛋白质对NAD的需求导致了对酵母和其他模式生物中NAD生物合成途径的新兴趣，这些模式生物用作衰老和年龄相关疾病研究的模型。剖析这些途径对于理解Sirtuins如何与细胞环境相互作用以及如何响应代谢或应激的变化至关重要。实验室最近的工作揭示了存在一种以前未表征的烟酰胺利用途径，该途径通过烟酰胺核苷途径进料，并将成为具体目标1的主题。我们最近还确定了硫胺素的生物合成作为一个代谢途径控制的Sir2和Hst 1 Sirtuins在响应NAD和烟酰胺浓度的变化。NAD和硫胺素途径与衰老的关系的有趣的共同调节是具体目标2的主题。在具体目标3中，我们计划通过鉴定每种酵母Sirtuins在转录水平上调节的基因，继续研究NAD和烟酰胺对细胞核中Sirtuins的调节。这些研究有望刺激新的保守NAD生物合成和Sirtuin靶点的鉴定，用于未来开发年龄相关疾病的治疗方法。公共卫生相关性：NAD依赖性蛋白脱乙酰酶（Sirtuins）在多种模式生物（包括芽殖酵母、酿酒酵母）的寿命调节中发挥重要作用。该研究项目的目标是更好地了解NAD在酵母和哺乳动物细胞中合成的途径，并确定哪些与衰老相关的细胞过程由Sirtuins控制，以响应细胞NAD水平的改变。酵母生物合成途径与高等真核生物之间存在大量的保守性，因此酵母生物合成途径中的发现也适用于哺乳动物。

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.