NAD Metabolism and Signaling

描述（由申请人提供）：维生素b3衍生的代谢物烟酰胺腺嘌呤二核苷酸（NAD）及其相关代谢物NADH、NADP和NADPH是氢化物转移酶的辅酶，在细胞能量代谢中起核心作用。人们普遍认为，NAD及其相关代谢物数量过多，无法发挥信号转导能力，因此不太可能参与调节细胞功能。然而，随着最近的发现表明NAD被以下酶所消耗：赖氨酸去乙酰化和产生可能的信号转导代谢产物（sirtuins），翻译后通过ADP核糖基化通过多ADP核糖聚合酶（PARPs）和单ADP核糖基转移酶（ARTs）修饰蛋白靶标，以及通过从NAD和NADP （CD38和ADP核糖基环化酶）产生钙动员代谢产物来调节细胞信号。现在很清楚，NAD代谢在细胞中发挥的作用比以前认识到的要复杂得多。事实上，分解NAD的酶以及那些有助于其合成和回收的酶现在被认为是生物学关键方面的全球调节剂，从DNA修复到基因转录，从癌症生物学到衰老。最近的研究强调了这些依赖NAD的过程相互交叉的许多方式，清楚地表明，对NAD代谢的更全面的系统范围的看法是理解个体过程如何被调节的核心。尽管科学家可以参加专注于NAD生物学单个方面的会议，但专注于NAD代谢组整体的会议并不容易获得。因此，有必要召开一次会议，汇集在NAD代谢组所有领域工作的主要科学家。即将召开的FASEB夏季会议“NAD代谢和信号传导”将通过涵盖NAD生物学的各个方面来满足这一需求。与会者和演讲者将包括NAD酶学，生物化学，信号转导，结构生物学，DNA修复，转录，营养，细胞生物学，生理学，免疫学/炎症，癌症生物学，衰老和临床应用领域的工作人员，包括癌症药物发现的新范式。会议的主题将包括NAD的生物合成和代谢、sirtuin、PARP、ART和cd38介导的信号和基因调控、NAD依赖性的串扰和NAD代谢组的治疗性调节。本次会议的主要目标是促进在工作过程中通常不见面的科学家之间的新互动，促进跨学科的互动，这将导致新的合作，这将推动该领域的发展，并促进新疗法的发展。我们期望在本次会议期间产生的科学见解将导致一种全系统方法的开始，以评估NAD代谢组在癌症，衰老，代谢综合征和炎症中的作用。本提案的目的是为杰出的年轻研究人员寻求资金支持会议费用，特别强调在科学领域代表性不足的个人。

DESCRIPTION (provided by applicant): The vitamin B3-derived metabolite, nicotinamide adenine dinucleotide (NAD), and its related metabolites, NADH, NADP and NADPH, are best known as co-enzymes for hydride transfer enzymes that play central roles in cellular energy metabolism. It was largely believed that NAD and its related metabolites were too abundant to function in a signal transduction capacity and that they were therefore unlikely to be involved in regulating cellular functions. However, with the more recent discoveries showing that NAD is consumed by enzymes that deacetylate lysine and generate putative signaling metabolites (sirtuins), that post-translationally modify protein targets by ADP-ribosylation via poly ADP ribose polymerases (PARPs) and mono ADP ribosyltransferases (ARTs) and that regulate cell signaling by generating calcium-mobilizing metabolites from NAD and NADP (CD38 and ADP-ribosyl cyclases), it is now clear that NAD metabolism plays a more complex role in cells than previously appreciated. Indeed, the enzymes that catabolize NAD as well as those that contribute to its synthesis and salvage are now known to be global regulators in key aspects of biology from DNA repair to gene transcription and from cancer biology to aging. Recent research has highlighted the many ways in which these NAD-dependent processes intersect, making it clear that a more global systems-wide view of NAD metabolism is central to understanding how the individual processes are regulated. Although scientists can attend conferences that focus on a single aspect of NAD biology, conferences that focus on the NAD metabolome as a whole are not readily available. Thus, there is a need for a conference that brings together the leading scientists working in all areas of the NAD metabolome. The upcoming FASEB summer conference "NAD metabolism and signaling" will meet this need by covering all aspects of NAD biology. Participants and speakers will include those working in the areas of NAD enzymology, biochemistry, signal transduction, structural biology, DNA repair, transcription, nutrition, cell biology, physiology, immunology/inflammation, cancer biology, aging and clinical applications that include a new paradigm for cancer drug discovery. Topics covered in the meeting will include NAD biosynthesis and metabolism, sirtuin, PARP, ART and CD38-mediated signaling and gene regulation, NAD-dependent crosstalk and therapeutic modulation of the NAD metabolome. The major goals of this conference are to foster new interactions between scientists that do not normally meet one another in the course of their work and to promote interdisciplinary interactions that will lead to new collaborations that will advance the field and facilitate development of new therapies. We expect that the scientific insights generated during the course of this meeting will result in the beginning of a systems-wide approach to evaluating the role of the NAD metabolome in cancer, aging, metabolic syndrome and inflammation. The objective of this proposal is to seek funds to support the conference fees for outstanding young investigators, with a particular emphasis on individuals that are under-represented in science. PUBLIC HEALTH RELEVANCE: The proposed meeting "NAD metabolism and signaling" is relevant to public health in that it will focus on establishing the cornerstones for a systems-wide approach to evaluating the role of the NAD metabolome in cancer, aging, obesity and inflammation. This is important to the mission of the NIH because the insights gained from this meeting may lead to the development of new diagnostics and treatments for diseases such as cancer and diabetes that affect the health and well-being of all US citizens.