Understanding the Regulation of NAD+ Homeostasis and Signaling

项目摘要 烟酰胺腺嘌呤二核苷酸(NAD+)是一种参与多种细胞过程的重要代谢物。 NAD+代谢也是几种人类疾病的新兴治疗靶点。NAD+池是 由三条生物合成途径维持，从细菌到人类在很大程度上是保守的。这个 由于NAD+中间体的动态灵活性，对NAD+代谢的调节还不完全清楚。 生物合成途径的冗余性以及它们之间复杂的相互联系。的主要目标是 这一建议旨在发现调节NAD+动态平衡的新信号因子，并研究潜在的 机械装置。我们的研究利用了遗传上易驯化的芽生酵母酿酒酵母，它具有 一直被用作研究广泛保守的细胞机制的有效模型系统 真核生物。我们最近建立了一个NAD+中间特异性遗传系统来识别 调控NAD+生物合成途径的各个分支。我们的研究发现了新的NAD+ 动态平衡因子包括转录因子、NAD+中间体转运体和营养感知 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+代谢的组成部分与长寿相关的营养信号通路之间的关系。我们在中国的学习 项目1和项目2将阐述从我们最近的研究中得出的具体假设，以阐明 监管机制。我们对NAD+调控机制的几个主要认识差距 动态平衡将被解决：1)哪些以及如何调节NAD+动态平衡的信号通路？2)哪一个 细胞过程如何影响NAD+及其中间体的周转？3)分子是什么？ NAD+生物合成和营养感知途径的交叉调节基础？长期目标是 了解细胞如何维持NAD+动态平衡，以应对生长条件的变化。少校 假设NAD+动态平衡是由营养感应信号通路共同调节的。细胞内 NAD+中间体和动态平衡因子的区隔作用也有助于复杂的相互作用 NAD+动态平衡因子和营养感知途径。为了实现这些目标，我们将聘请一名 分子遗传学和生化方法相结合分析基因、蛋白质和通路 牵涉其中。这些研究将增加我们对真核细胞如何调节NAD+动态平衡的理解 对生长条件变化的反应，以及哪些与长寿相关的营养感应信号通路 牵涉其中。总体意义：NAD+保存有助于改善与年龄相关的代谢紊乱。我们的 这些发现将有助于理解NAD+动态平衡的分子基础和调控，以及 人体内与NAD+代谢异常相关的代谢紊乱的机制。

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.