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.

了解导致疾病加速发展的分子机制 老龄化对于健康老龄化至关重要。过去10年，大量证据支持这一观点： 线粒体功能改变和代谢失调起着关键作用。在这项具有竞争性的续约补助金中 我的第一个 R01 作为独立 PI 的应用，我们的总体目标是确定新陈代谢如何改变 导致衰老疾病和衰老本身。我们在以下方面取得了重大进展 了解源自代谢的酰基辅酶 A 物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去除。我们第一个五年的工作 资助期定义了蛋白质酰化和脱酰化的新范式，并将 SIRT5 确定为 新陈代谢和营养稳态的调节剂。在这些研究过程中，我们取得了意想不到的成果 发现 SIRT5 水平在正常细胞周期进程中受到生理调节，及其缺失 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，在该条件下 Sirtuin 水平受到控制，旨在揭示这种新兴调节剂的潜在生物学作用 的老化。在本提案中，我们将以这些令人兴奋的初步数据为基础，并重点关注以下具体内容 目的：目的 1) 探究 SIRT5 蛋白在细胞周期进程中的调节作用；目标 2) 确定如何 SIRT5 活性影响营养感应；目标 3) 确定 SIRT5 在骨骼肌中的生理作用 干细胞。总之，这些研究结合了创新的概念框架和全面的研究 确定 SIRT5 在控制特定营养感应中的关键生物学作用的实验设计 回应。此外，本研究将为进一步了解如何 代谢状态与细胞周期进行通讯，以及这种通讯的丧失如何导致 衰老的病理生理学。最终，这些研究将加深我们对新兴的、新颖的理解 代谢控制机制，并有可能为新疗法的开发提供信息以维持 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。

• 发表时间: 2017
• 影响因子: 8.6
• 作者: Wagner, Gregory R;Hirschey, Matthew D
• 通讯作者: Hirschey, Matthew D

Statin therapy inhibits fatty acid synthase via dynamic protein modifications.

他汀类药物疗法通过动态蛋白质修饰抑制脂肪酸合酶。

• 发表时间: 2022-05-10
• 影响因子: 16.6
• 作者: Trub, Alec G;Wagner, Gregory R;Anderson, Kristin A;Crown, Scott B;Zhang, Guo;Thompson, J Will;Ilkayeva, Olga R;Stevens, Robert D;Grimsrud, Paul A;Kulkarni, Rhushikesh A;Backos, Donald S;Meier, Jordan L;Hirschey, Matthew D
• 通讯作者: Hirschey, Matthew D

High-Resolution Metabolomics with Acyl-CoA Profiling Reveals Widespread Remodeling in Response to Diet.

具有酰基辅酶A分析的高分辨率代谢组学揭示了饮食响应中的广泛重塑。

• 发表时间: 2015-06
• 作者: Liu, Xiaojing;Sadhukhan, Sushabhan;Sun, Shengyi;Wagner, Gregory R;Hirschey, Matthew D;Qi, Ling;Lin, Hening;Locasale, Jason W
• 通讯作者: Locasale, Jason W

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

神经元 CRTC-1 通过儿茶酚胺信号控制全身线粒体代谢和寿命。

• 发表时间: 2015-02-26
• 影响因子: 64.5
• 作者: Burkewitz, Kristopher;Morantte, Ianessa;Weir, Heather J M;Yeo, Robin;Zhang, Yue;Huynh, Frank K;Ilkayeva, Olga R;Hirschey, Matthew D;Grant, Ana R;Mair, William B
• 通讯作者: Mair, William B

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

基于机制的人 Sirtuin 5 脱酰酶抑制剂：结构-活性关系、生物结构和动力学见解。

• DOI: 10.1002/anie.201709050
• 发表时间: 2017-11-20
• 期刊: Angewandte Chemie
• 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