Sir2 regulation and chemical modulation

Sir2调节和化学调节

• 批准号: 7179316
• 负责人: ANTHONY A. SAUVE
• 金额: $ 30.18万
• 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/7179316
• 关键词: Abbreviations; Achievement; Adenine; Adenosine Diphosphate Ribose; Animals; Apoptosis; Binding; Biochemical; Biochemistry; Biological; Caloric Restriction; Cardiovascular Diseases; Catalysis; Cell Survival; Cells; Chemicals; Chemistry; Chromatin; Class; Deacetylase; Deacetylation; Degenerative Disorder; Development; Diabetes Mellitus; Dinucleoside Phosphates; Enzymes; Event; Gene Expression; Gene Silencing; Genetic; Goals; Health; Health Benefit; Histones; Human; In Vitro; 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; concept; derepression; design; human sirtuin 1; improved; in vivo; insight; insulin sensitivity; interest; isonicotinamide; lipid biosynthesis; nicotinate; nicotinate mononucleotide; novel strategies; novel therapeutics; programs; response; small molecule; transcription factor

DESCRIPTION (provided by applicant): 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 activities 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.

描述（由申请人提供）：拟议研究的目的是推断控制酵母和人体细胞中去乙酰化酶活性的机制和调节原理。这些原理将用于设计能够激活细胞中去乙酰化酶的小分子。 Sirtuins 调节许多具有生物学意义的活动，包括抗应激、基因沉默和长寿。 Sirtuins 参与介导与热量限制相关的生物效应。热量限制已被证明对哺乳动物有许多积极的健康益处，包括减少脂肪生成、胰岛素敏感性和延长寿命。这些生物效应引起了人们对sirtuins的酶促机制、它们在细胞中调节的方式以及它们可能通过药理学调节以改善人类健康的方式的兴趣。 Sirtuins 是 NAD 依赖性脱乙酰酶，可去除乙酰赖氨酸修饰的组蛋白和转录因子的乙酰基，从而调节染色质和基因表达。我们和其他人已经证明，这些活动受到细胞中 NAD 和烟酰胺水平的调节，并且沉默调节蛋白能够整合来自能量和代谢状态的信息来控制遗传事件。作为我们更好地了解这些酶的功能以及如何在细胞中调节它们的目标的一部分，我们建议研究以下具体目标：在 Aim1 中，我们建议描述这类独特酶的生化功能，强调它们的化学新颖性以及 NAD 参与脱乙酰化反应。在 Aim2 中，我们建议展示酶活性如何提供烟酰胺调节沉默调节蛋白活性的机制。此外，通过最近开发的质谱方法，我们希望获得关于烟酰胺如何调节细胞中去乙酰化酶的新见解。在目标 3 中，我们探索了根据 Sirtuin 反应机制和烟酰胺调节机制的知识设计的 Sirtuins 小分子激活剂的开发。这些激活剂体现了一种上调细胞中沉默调节蛋白作用的新方法，并为药物干预提供了潜在的切入点，以提高细胞的应激抵抗力和细胞存活率。这些目标的实现预计将为这些酶的生物化学和调节提供新的见解，并为可以激活去乙酰化酶治疗糖尿病和退行性疾病的新疗法提供概念证明。