Understanding the regulation of NAD+ homeostasis and signaling

了解 NAD 稳态和信号传导的调节

• 批准号: 8345536
• 负责人: Su-Ju Lin
• 金额: $ 24.22万
• 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/8345536
• 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. PUBLIC HEALTH RELEVANCE: Niacin (vitamin B3, a NAD+ precursor) is widely used as a food supplement to improve heath. Administration of NAD+ precursors has also been shown to ameliorate human deficiencies related to aberrant NAD+ metabolism. This research utilizes the genetically amenable model system, budding yeast, and mammalian cells to study the regulation of NAD+ homeostasis and signaling. Many components in NAD+ biosynthesis and metabolic pathways are conserved from yeast to mammals. Therefore, our findings are likely to provide insight into the development of therapeutic reagents for NAD+ deficiency-associated diseases such as diabetes and cancers, and also have broad implications for improving human nutrition and health.

描述（由申请人提供）：烟酰胺腺嘌呤二核苷酸（NAD+）是参与各种细胞生化反应的重要辅因子，有助于调节Ca2+信号传导、染色质结构、DNA修复和寿命。迄今为止，由于NAD+代谢途径的动态性质和复杂性以及难以确定可相互转化的吡啶核苷酸的水平，调节NAD+稳态的信号传导途径仍不清楚。烟酰胺核苷（NmR）是一种关键的吡啶代谢产物，在维持NAD+库以及热量限制（CR）诱导的寿命中发挥重要作用。在这个建议中，我们建立了一个NmR特异性报告系统，并使用它来识别酵母突变体与改变NmR/NAD+代谢。我们的初步结果表明，磷酸盐响应信号（PHO）通路有助于控制NAD+代谢。我们还鉴定了NmR/NAD+生物合成和稳态途径中的其他新组分。目前的建议建立在我们最近对这些因素的研究以及NmR/NAD+代谢和营养信号通路中组分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生长条件变化时维持NAD+稳态的机制。主要假设是NAD+稳态受营养传感信号通路调节，其在决定细胞适应性和存活中起重要作用。这些项目的具体目标是：目的1）研究营养敏感途径在NmR和NAD+稳态中的作用;目的2）鉴定一种NmR同化酶，并研究其在NAD+代谢和CR中的作用;目的3）研究保守的NmR稳态因子Fun 26在NAD+代谢和CR中的作用。目的4）研究人Fun26同源基因在NAD+稳态和CR中的作用。为了实现这些目标，我们将采用分子，遗传和生物化学方法的组合来分析相关的基因，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+稳态以响应生长条件变化的理解，以及涉及哪些营养传感信号通路。我们的研究结果也可能有助于了解NAD+稳态调节的分子基础，以及与异常NAD+代谢相关的代谢紊乱。 公共卫生相关性：烟酸（维生素B3，NAD+前体）被广泛用作改善健康的食品补充剂。NAD+前体的施用也已显示改善与异常NAD+代谢相关的人类缺陷。本研究利用遗传上可接受的模型系统、芽殖酵母和哺乳动物细胞来研究NAD+稳态和信号传导的调节。从酵母到哺乳动物，NAD+生物合成和代谢途径中的许多组分是保守的。因此，我们的研究结果可能为开发NAD+缺乏相关疾病（如糖尿病和癌症）的治疗试剂提供见解，并对改善人类营养和健康具有广泛意义。