Understanding the Regulation of NAD+ Homeostasis and Signaling

项目摘要 烟酰胺腺嘌呤二核苷酸（NAD+）是一种重要的代谢产物，参与多种细胞过程。 NAD+代谢也是几种人类疾病的新兴治疗靶点。NAD+池为 由三种生物合成途径维持，这三种生物合成途径在很大程度上从细菌到人类都是保守的。的 NAD+代谢的调节由于NAD+中间体的动态灵活性而不完全理解， 生物合成途径的冗余以及它们之间复杂的相互联系。的主要目标 这项计划旨在发现调节NAD+稳态的新型信号传导因子，并研究其潜在的 机制等我们的研究利用遗传上易于处理的芽殖酵母酿酒酵母， 一直作为一个有效的模型系统，以研究细胞机制广泛保守， 真核生物我们最近建立了一个NAD+中间体特异性遗传系统，以确定 调节NAD+生物合成途径的每个分支。我们的研究发现了新的NAD+ 稳态因子，包括转录因子、NAD+中间体转运蛋白和营养感应因子 信号通路目前的建议建立在我们最近对这些因素及其相互作用的研究基础上。 NAD+代谢和长寿相关的营养信号通路之间的组件。我们的研究在 项目1和项目2将讨论我们最近研究中的具体假设，以阐明 监管机制。我们对NAD+调节机制的认识存在一些主要空白 内稳态将被解决：1）哪些信号通路以及如何调节NAD+内稳态？2)这 以及细胞过程如何促进NAD+及其中间产物的周转？3)什么是分子 NAD+生物合成和营养感应途径交叉调节的基础？长期目标是 了解细胞如何维持NAD+稳态以应对生长条件的变化。主要 假设NAD+稳态是由营养物传感信号通路共同调节的。细胞内 NAD+中间体和稳态因子的区室化也有助于复杂的相互作用 NAD+稳态因子和营养传感途径。为了实现这些目标，我们将采用 结合分子遗传学和生物化学方法来分析基因、蛋白质和途径 涉案这些研究将增加我们对真核细胞如何调节NAD+稳态的理解， 对生长条件变化的反应，以及与长寿相关的营养传感信号通路 涉案总体意义：NAD+保存有助于改善年龄相关的代谢紊乱。我们 这些发现将有助于理解NAD+稳态的分子基础和调节， 与人类异常NAD+代谢相关的代谢紊乱的潜在机制。

Project Summary Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite involved in various cellular processes. NAD+ metabolism is also an emerging therapeutic target for several human diseases. The NAD+ pool is maintained by three biosynthesis pathways, which are largely conserved from bacteria to human. The regulation of NAD+ metabolism is incompletely understood due to the dynamic flexibility of NAD+ intermediates, the redundancy of biosynthesis pathways, and the complex interconnections among them. The major goal of this proposal is to uncover novel signaling factors that regulate NAD+ homeostasis and to study the underlying mechanisms. Our studies utilize the genetically tractable budding yeast Saccharomyces cerevisiae that has consistently served as an efficient model system to study cellular mechanisms broadly conserved among eukaryotes. We have recently established an NAD+ intermediate-specific genetic system to identify factors that regulate each branch of the NAD+ biosynthesis pathways. Our studies have uncovered novel NAD+ homeostasis factors including transcription factors, NAD+ intermediates transporters, and nutrient-sensing signaling pathways. The current proposal builds on our recent studies of these factors and the interplay between components in NAD+ metabolism and longevity-related nutrient signaling pathways. Our studies in Project 1 and Project 2 will address specific hypotheses derived from our recent studies to elucidate the mechanisms of regulation. A few major gaps in our knowledge of the mechanisms regulating NAD+ homeostasis will be addressed: 1) Which and how signaling pathways regulate NAD+ homeostasis? 2) Which and how cellular processes contribute to the turnover of NAD+ and its intermediates? 3) What is the molecular basis for the cross-regulation of NAD+ biosynthesis and nutrient-sensing pathways? The long-term goal is to understand how cells maintain NAD+ homeostasis in response to changes in growth conditions. The major hypothesis is that NAD+ homeostasis is co-regulated by nutrient-sensing signaling pathways. Intracellular compartmentalization of NAD+ intermediates and homeostasis factors also contribute to the complex interplay of NAD+ homeostasis factors and nutrient sensing pathways. To achieve theses goals we will employ a combination of molecular genetics and biochemical methods to analyze genes, proteins and pathways involved. These studies will increase our understanding of how eukaryotic cells regulate NAD+ homeostasis in response to changes in growth conditions, and which longevity-related nutrient sensing signaling pathways are involved. Overall Significance: NAD+ preservation helps ameliorate age-associated metabolic disorders. Our findings will contribute to understanding the molecular basis and regulation of NAD+ homeostasis as well as the mechanisms underlying metabolic disorders related to aberrant NAD+ metabolism in human.