Understanding the regulation of NAD+ homeostasis and signaling

了解 NAD 稳态和信号传导的调节

• 批准号: 8518401
• 负责人: Su-Ju Lin
• 金额: $ 23.3万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518401
• 关键词: Affect; Anabolism; Autophagocytosis; Biochemical; Biochemical Reaction; Biological Assay; Biological Models; Caloric Restriction; Cells; Chromatin Structure; DNA Repair; Diabetes Mellitus; Disease; Enzymes; Eukaryota; Eukaryotic Cell; Food Supplements; Gene Proteins; Goals; Growth; Health; Homeostasis; Human; Longevity; Maintenance; Malignant Neoplasms; Mammalian Cell; Mammals; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Methods; Molecular; Molecular Genetics; Nature; Niacinamide; Nicotinamide adenine dinucleotide; Nicotinic Acids; Organism; Orthologous Gene; Pathway interactions; Play; Proteins; Reagent; Regulation; Reporter; Research; Role; Saccharomyces cerevisiae; Saccharomycetales; Signal Pathway; Signal Transduction; System; Yeasts; base; cofactor; detection of nutrient; fitness; improved; inorganic phosphate; insight; mutant; nicotinamide-beta-riboside; novel; nutrient metabolism; nutrition; protein transport; pyridine; pyridine nucleotide; response; riboside; therapeutic development

DESCRIPTION (provided by applicant): Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor involved in various cellular biochemical reactions and contributes to the regulation of Ca2+ signaling, chromatin structure, DNA repair and lifespan. To date, the signaling pathways that regulate NAD+ homeostasis remain unclear due to the dynamic nature and complexity of the NAD+ metabolic pathways and the difficulty of determining the levels of the interconvertible pyridine nucleotides. Nicotinamide riboside (NmR) is a key pyridine metabolite that plays important roles in the maintenance of NAD+ pool as well as calorie restriction (CR)-induced lifespan. In this proposal, we establish a NmR-specific reporter system and use it to identify yeast mutants with altered NmR/NAD+ metabolism. Our preliminary results show that the phosphate responsive signaling (PHO) pathway contributes to the control of NAD+ metabolism. We have also identified additional novel components in the NmR/NAD+ biosynthesis and homeostasis pathways. The current proposal builds on our recent studies of these factors and the interplay between components in NmR/NAD+ metabolism and the nutrient signaling pathways. The long-term goal of our research is to understand the mechanisms by which yeast and mammalian cells maintain NAD+ homeostasis in response to changes in growth conditions. The major hypothesis is that NAD+ homeostasis is modulated by nutrient-sensing signaling pathway(s), which plays an important role in determining cell fitness and survival. The specific aims of the projects are: Aim 1) To study the role of nutrient sensing pathways in NmR and NAD+ homeostasis, Aim 2) To characterize a putative NmR assimilating enzyme and to study its role in NAD+ metabolism and CR, Aim 3) To study the roles of a conserved NmR homeostasis factor Fun26 in NAD+ metabolism and CR, and Aim 4) To study the role of the human Fun26 orthologs in NAD+ homeostasis and CR. To achieve these goals we will employ a combination of molecular, genetic 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 of the nutrient sensing signaling pathways are involved. Our findings may also contribute to the understanding of the molecular basis of the regulation of NAD+ homeostasis as well as metabolic disorders related to aberrant NAD+ metabolism in human.

说明(申请人提供)：烟酰胺腺嘌呤二核苷酸(NAD+)是一种参与多种细胞生化反应的重要辅因子，有助于调节钙信号、染色质结构、DNA修复和寿命。到目前为止，由于NAD+代谢途径的动态性质和复杂性以及确定可相互转换的吡啶核苷酸水平的困难，调节NAD+动态平衡的信号通路仍然不清楚。烟酰胺核苷是一种重要的吡啶代谢产物，在维持NAD+库和卡路里限制(CR)诱导的寿命中起着重要作用。在这个方案中，我们建立了一个核磁共振特异的报告系统，并使用它来鉴定核磁共振/NAD+代谢发生变化的酵母突变株。我们的初步结果表明，磷酸反应信号通路(Pho)参与了NAD+代谢的调控。我们还在核磁共振/NAD+生物合成和动态平衡途径中发现了其他新的成分。目前的建议建立在我们最近对这些因素的研究以及核磁共振/NAD+代谢组分和营养信号通路之间的相互作用的基础上。我们研究的长期目标是了解酵母和哺乳动物细胞在应对生长条件变化时维持NAD+稳态的机制。主要的假设是NAD+的动态平衡是由营养感应信号通路(S)调节的，而营养感应信号通路在决定细胞的适合性和存活率中起着重要作用。这些项目的具体目的是：1)研究营养感知通路在核磁共振和NAD+稳态中的作用；2)鉴定一个可能的核磁共振同化酶并研究其在NAD+代谢和CR中的作用；3)研究保守的核磁共振稳态因子Fun26在NAD+代谢和CR中的作用；以及4)研究人类Fun26同源基因在NAD+稳态和CR中的作用。为了实现这些目标，我们将使用分子、遗传和生化方法相结合的方法来分析相关的基因、蛋白质和途径。这些研究将增加我们对真核细胞如何调节NAD+动态平衡以响应生长条件变化的理解，以及哪些营养感应信号通路参与其中。我们的发现也可能有助于理解NAD+稳态调节的分子基础，以及与人类异常NAD+代谢相关的代谢紊乱。