Studies on the Mechanisms by which SIRT5 Regulates Aging and Disease

SIRT5调节衰老和疾病的机制研究

• 批准号: 10661571
• 负责人: Matthew D Hirschey
• 金额: $ 51.66万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10661571
• 关键词: Ablation; Acceleration; Acyl Coenzyme A; Acylation; Adaptor Signaling Protein; Address; Aging; Apoptosis; Applications Grants; Biological; Biology; Biology of Aging; Carbon; Cardiac; Catabolism; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Death; Cell Proliferation; Cells; Chemicals; Chemistry; Chronic Disease; Communication; DNA Damage; Data; Development; Disease; Economic Burden; Elements; Equilibrium; Experimental Designs; FRAP1 gene; Foundations; Functional disorder; Funding; G1 Arrest; Genome; Goals; Growth; Health; Health Promotion; Heart; Homeostasis; Human; Knowledge; Lead; Lesion; Leucine; Maintenance; Measures; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Mission; Mitochondria; Modeling; Modification; Molecular; Mus; Muscle satellite cell; Normal Cell; Nutrient; Pathway interactions; Phenotype; Physiological; Play; Population; Positioning Attribute; Post-Translational Protein Processing; Process; Progress Reports; Proliferating; Protein Family; Proteins; Public Health; Publications; Regulation; Research; Research Proposals; Risk; Role; Signal Transduction; Sirtuins; Skeletal Muscle; Stress; Testing; Tissues; Ubiquitination; United States National Institutes of Health; Work; aged; cell type; data integration; deacylation; detection of nutrient; genetic approach; healthy aging; innovation; insight; model organism; multicatalytic endopeptidase complex; novel; novel therapeutics; oxidation; pharmacologic; premature; prevent; programs; response; social; stem; stem cell function; stem cell proliferation; stem cells; ubiquitin-protein ligase

Understanding the molecular mechanisms that contribute to the accelerated development of the diseases of aging is essential for healthy aging. Over the past 10 years, substantial evidence supports the notion that altered mitochondrial function and metabolic dysregulation play key roles. In this competitive renewal grant application of my first R01 as an independent PI, our overall goal is to identify how altered metabolism contributes to the diseases of aging and aging itself. We have made significant progress towards understanding how acyl-CoA species derived from metabolism induce protein modifications, and how mitochondrial sirtuin 5 removes them as a layer of metabolic control. Our body of work in the first 5-year funding period defines a new paradigm of protein acylation and deacylation, and identifies SIRT5 as a regulator of metabolism and nutrient homeostasis. In the course of these studies, we made the unexpected discovery that SIRT5 levels are physiologically regulated during normal cell cycle progression, and its absence leads to altered cell cycle control. This exciting finding identifies a long-sought-after condition under which sirtuin levels are controlled and is positioned to reveal the underlying biological role of this emerging regulator of aging. In this proposal, we will build upon these exciting preliminary data and focus on the following Specific Aims: Aim 1) interrogate the regulation of SIRT5 protein during cell cycle progression; Aim 2) determine how SIRT5 activity influences nutrient sensing; Aim 3) identify the physiological role of SIRT5 in skeletal muscle stem cells. Together, these studies combine an innovative conceptual framework and a comprehensive experimental design to determine the key biological role of SIRT5 in controlling specific nutrient-sensing responses. Furthermore, this study will build a foundation of knowledge to further understand how the metabolic state communicates with the cell cycle, and how loss of this communication contributes to the pathophysiology of aging. Ultimately, these studies will deepen our understanding of emergent, novel metabolic control mechanisms, and have the potential to inform the development of new therapies to maintain healthy aging.

了解有助于加速疾病发展的分子机制， 健康的老龄化是必不可少的。过去10年来，大量证据支持这样一种观点， 线粒体功能改变和代谢失调起关键作用。在这次竞争性的续约补助中 我的第一个R 01作为一个独立的PI的应用，我们的总体目标是确定如何改变代谢 会导致衰老和衰老本身的疾病。我们已经取得了重大进展， 了解代谢产生的酰基辅酶A物质如何诱导蛋白质修饰，以及 线粒体sirtuin 5将它们作为代谢控制层除去。我们在前五年的工作 基金期间定义了蛋白质酰化和去酰化的新范式，并将SIRT 5确定为 代谢和营养平衡的调节器。在这些研究的过程中，我们做了意想不到的 发现SIRT 5水平在正常细胞周期进程中受到生理调节， 导致细胞周期控制改变。这一令人兴奋的发现确定了一个长期寻求的条件下， 去乙酰化酶水平是受控的，并被定位以揭示这种新兴调节剂的潜在生物学作用。 衰老的迹象在本提案中，我们将以这些令人兴奋的初步数据为基础，重点关注以下具体问题： 目的：目的1）询问SIRT 5蛋白在细胞周期进程中的调控;目的2）确定如何 SIRT 5活性影响营养感知;目的3）确定SIRT 5在骨骼肌中的生理作用 干细胞总之，这些研究联合收割机结合了创新的概念框架和全面的 确定SIRT 5在控制特定营养物传感中的关键生物学作用的实验设计 应答此外，这项研究将建立一个知识基础，以进一步了解如何 代谢状态与细胞周期的沟通，以及这种沟通的损失如何有助于细胞周期的变化。 衰老的病理生理学最终，这些研究将加深我们对新兴的，新颖的 代谢控制机制，并有可能告知新疗法的发展，以维持 健康老龄化

项目成果

A Prob(e)able Route to Lysine Acylation.

赖氨酸酰化的可能途径。

• DOI: 10.1016/j.chembiol.2017.01.011
• 发表时间: 2017
• 期刊: Cell chemical biology
• 影响因子: 8.6
• 作者: Wagner,GregoryR;Hirschey,MatthewD
• 通讯作者: Hirschey,MatthewD

Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure.

• DOI: 10.1371/journal.pone.0104157
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Schechter MA;Hsieh MK;Njoroge LW;Thompson JW;Soderblom EJ;Feger BJ;Troupes CD;Hershberger KA;Ilkayeva OR;Nagel WL;Landinez GP;Shah KM;Burns VA;Santacruz L;Hirschey MD;Foster MW;Milano CA;Moseley MA;Piacentino V 3rd;Bowles DE
• 通讯作者: Bowles DE

Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight.

• DOI: 10.1002/anie.201709050
• 发表时间: 2017-11-20
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Rajabi N;Auth M;Troelsen KR;Pannek M;Bhatt DP;Fontenas M;Hirschey MD;Steegborn C;Madsen AS;Olsen CA
• 通讯作者: Olsen CA

Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling.

• DOI: 10.1016/j.cmet.2017.09.024
• 发表时间: 2017-12-05
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Weir HJ;Yao P;Huynh FK;Escoubas CC;Goncalves RL;Burkewitz K;Laboy R;Hirschey MD;Mair WB
• 通讯作者: Mair WB

Neuronal CRTC-1 governs systemic mitochondrial metabolism and lifespan via a catecholamine signal.

• DOI: 10.1016/j.cell.2015.02.004
• 发表时间: 2015-02-26
• 期刊: Cell
• 影响因子: 64.5
• 作者: Burkewitz K;Morantte I;Weir HJM;Yeo R;Zhang Y;Huynh FK;Ilkayeva OR;Hirschey MD;Grant AR;Mair WB
• 通讯作者: Mair WB