Sir2 regulation and chemical modulation

Sir2调节和化学调节

• 批准号: 7568219
• 负责人: ANTHONY A. SAUVE
• 金额: $ 29.58万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568219
• 关键词: Abbreviations; Achievement; Adenine; Adenosine Diphosphate Ribose; Animals; Apoptosis; Binding; Biochemical; Biochemistry; Biological; Caloric Restriction; Cardiovascular Diseases; Catalysis; Cell Survival; Cells; Cellular Stress; Chemicals; Chemistry; Chromatin; Deacetylase; Deacetylation; Degenerative Disorder; Development; Diabetes Mellitus; Dinucleoside Phosphates; Enzymes; Event; Gene Expression; Gene Silencing; Genetic; Goals; Health; Health Benefit; Histones; Human; Insulin Resistance; Intervention; Knowledge; Longevity; Mammalian Cell; Mammals; Mass Spectrum Analysis; Mediating; Metabolic; Methods; Mus; Nerve Degeneration; Niacinamide; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; O-Acetyl-ADP-Ribose; Organism; Patients; Peroxisome Proliferator-Activated Receptors; Proteins; Reaction; Regulation; Research; Research Personnel; Resistance; Ribose; Sirtuins; Stress; TP53 gene; Testing; Therapeutic; Tissues; Yeasts; base; chemical reaction; derepression; design; human sirtuin 1; improved; in vitro activity; in vivo; insight; insulin sensitivity; interest; isonicotinamide; lipid biosynthesis; nicotinate; nicotinate mononucleotide; novel strategies; novel therapeutics; programs; response; small molecule; transcription factor

The objective of the proposed research is to deduce mechanistic and regulatory principles that control the activities of sirtuin enzymes in yeast and human cells. These principles will be used to design small molecules that can activate sirtuins in cells. Sirtuins regulate a host of biologically significant activities including stress resistance, gene silencing and longevity. Sirtuins are implicated in mediating biological effects associated with calorie restriction. Calorie restriction has been shown to have numerous positive health benefits in mammals including reduced adipogenesis, insulin sensitivity and increased lifespan. These biological effects have raised interest in the enzymatic mechanisms of sirtuins, the means by which they are regulated in cells and the ways in which they might be modulated pharmacologically for improved human health. Sirtuins are NAD dependent deacetylases that remove acetyl-groups of acetyllysine modified histones and transcription factors thereby regulating chromatin and gene expression. We and others have demonstrated that these actvitities are regulated by NAD and nicotinamide levels in cells, and that the sirtuins are able to integrate information from energy and metabolic states to control genetic events. As part of our goal to better understand the functions of these enzymes and how they can be modulated in cells we propose to investigate the following specific aims: In Aim1 we propose to characterize the biochemical functions of this unique class of enzymes, emphasizing their chemical novelty and the incorporation of NAD in deacetylation reactions. In Aim2 we propose to show how enzymatic activity provides a mechanism for nicotinamide regulation of sirtuin activity. In addition with a recently developed mass spectrometry method we hope to gain new insights into how nicotinamide regulates sirtuins in cells. In Aim 3 we explore the development of small molecule activators of sirtuins designed from knowledge of the sirtuin reaction mechanism and the mechanism of nicotinamide regulation. These activators embody a novel approach to upregulate sirtuin action in cells and provide a potential entrypoint for pharmacological intervention to increase cell stress resistance and cell survival. Achievement of these aims is expected to provide new insights into the biochemistry and regulation of these enzymes, and provide proof of concept for new therapeutics that can activate sirtuins to treat diabetes and degenerative disorders.

拟议研究的目的是推断控制机械和监管原则 Sirtuin酶在酵母和人类细胞中的活性。这些原则将用于设计小 可以激活细胞中sirtuins的分子。 Sirtuins调节许多具有生物学意义的活动 包括压力抗性，基因沉默和寿命。 Sirtuins与介导生物学有关 与卡路里限制相关的影响。卡路里限制已被证明具有许多积极 哺乳动物的健康益处，包括脂肪生成降低，胰岛素敏感性和寿命增加。 这些生物学作用引起了人们对Sirtuins酶机制的兴趣，这种手段是 它们在细胞中受到调节，以及可以通过药理调节的方式来改进它们 人类健康。 Sirtuins是NAD依赖性的脱乙酰基酶，去除乙酰透明苷修饰的乙酰基团 组蛋白和转录因子，从而调节染色质和基因表达。我们和其他人有 证明这些活性受细胞中NAD和烟酰胺水平调节，并且 Sirtuins能够整合来自能量和代谢状态的信息以控制遗传事件。作为一部分 我们的目标是更好地了解这些酶的功能以及如何在细胞中调节它们 建议研究以下特定目标：在AIM1中，我们建议表征生化 这种独特的酶的功能，强调它们的化学新颖性和NAD的掺入 在脱乙酰化反应中。在AIM2中，我们建议展示酶活性如何为 SIRTUIN活性的烟酰胺调节。除了最近开发的质谱法 我们希望对烟酰胺如何调节细胞中的Sirtuins有了新的见解。在AIM 3中，我们探索 根据Sirtuin反应知识设计的Sirtuins的小分子激活剂的开发 烟酰胺调节的机理和机制。这些激活剂体现了一种新颖的方法 上调细胞中的Sirtuin作用，并为药理学干预提供了潜在的入口点 增加细胞应激性和细胞存活。这些目标的实现有望提供新的 对这些酶的生物化学和调节的见解，并为新酶提供概念证明 可以激活Sirtuins以治疗糖尿病和退化性疾病的治疗剂。