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 衰老对于健康衰老至关重要。在过去的十年中，大量证据支持这样的观念 线粒体功能和代谢失调的改变起关键作用。在这项竞争更新赠款中 我的第一个R01作为独立PI的应用，我们的总体目标是确定改变新陈代谢的方式 有助于衰老和衰老本身的疾病。我们已经取得了重大进步 了解来自新陈代谢的酰基辅酶A种如何诱导蛋白质修饰，以及如何 线粒体Sirtuin 5将它们作为代谢控制层除去。我们的第5年工作身体 资金期定义了蛋白质酰化和脱酰化的新范式，并将SIRT5识别为 代谢和营养稳态的调节剂。在这些研究过程中，我们使意外 发现SIRT5水平在正常细胞周期进程中受到生理调节，其缺失 导致细胞周期控制改变。这个令人兴奋的发现确定了长期的状况 Sirtuin水平受到控制，并有位置揭示该新兴调节剂的基本生物学作用 衰老。在此提案中，我们将基于这些令人兴奋的初步数据，并专注于以下特定的特定数据 目的：目标1）在细胞周期进程中询问SIRT5蛋白的调节；目标2）确定如何 SIRT5活性会影响营养感应；目标3）确定SIRT5在骨骼肌中的生理作用 干细胞。这些研究共同结合了一个创新的概念框架和一个全面的 实验设计以确定SIRT5在控制特定营养感应中的关键生物学作用 回答。此外，这项研究将建立知识的基础，以进一步了解 代谢状态与细胞周期交流，以及这种交流的损失如何有助于 衰老的病理生理学。最终，这些研究将加深我们对新兴，新颖的理解 代谢控制机制，并有可能告知新疗法的发展 健康衰老。

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

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

Discovering the landscape of protein modifications.

• DOI: 10.1016/j.molcel.2021.03.015
• 发表时间: 2021-05-06
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Keenan EK;Zachman DK;Hirschey MD
• 通讯作者: Hirschey MD