Studies on the Mechanisms by which SIRT5 Regulates Aging and Disease
SIRT5调节衰老和疾病的机制研究
基本信息
- 批准号:10661571
- 负责人:
- 金额:$ 51.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AblationAccelerationAcyl Coenzyme AAcylationAdaptor Signaling ProteinAddressAgingApoptosisApplications GrantsBiologicalBiologyBiology of AgingCarbonCardiacCatabolismCell CycleCell Cycle ProgressionCell Cycle RegulationCell DeathCell ProliferationCellsChemicalsChemistryChronic DiseaseCommunicationDNA DamageDataDevelopmentDiseaseEconomic BurdenElementsEquilibriumExperimental DesignsFRAP1 geneFoundationsFunctional disorderFundingG1 ArrestGenomeGoalsGrowthHealthHealth PromotionHeartHomeostasisHumanKnowledgeLeadLesionLeucineMaintenanceMeasuresMetabolicMetabolic ControlMetabolic PathwayMetabolismMissionMitochondriaModelingModificationMolecularMusMuscle satellite cellNormal CellNutrientPathway interactionsPhenotypePhysiologicalPlayPopulationPositioning AttributePost-Translational Protein ProcessingProcessProgress ReportsProliferatingProtein FamilyProteinsPublic HealthPublicationsRegulationResearchResearch ProposalsRiskRoleSignal TransductionSirtuinsSkeletal MuscleStressTestingTissuesUbiquitinationUnited States National Institutes of HealthWorkagedcell typedata integrationdeacylationdetection of nutrientgenetic approachhealthy aginginnovationinsightmodel organismmulticatalytic endopeptidase complexnovelnovel therapeuticsoxidationpharmacologicprematurepreventprogramsresponsesocialstemstem cell functionstem cell proliferationstem cellsubiquitin-protein ligase
项目摘要
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发挥着关键作用。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。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
期刊论文数量(17)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 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:
- 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:
- 影响因子:0
- 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:
- 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
Statin therapy inhibits fatty acid synthase via dynamic protein modifications.
- DOI:10.1038/s41467-022-30060-w
- 发表时间:2022-05-10
- 期刊:
- 影响因子:16.6
- 作者:
- 通讯作者:
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Matthew D Hirschey其他文献
Matthew D Hirschey的其他文献
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{{ truncateString('Matthew D Hirschey', 18)}}的其他基金
Studies on the impact of acetyl-cysteine on metabolism
乙酰半胱氨酸对代谢影响的研究
- 批准号:
10574934 - 财政年份:2022
- 资助金额:
$ 51.66万 - 项目类别:
Determining the Sub-Cellular Organelles that Link Lipid Signaling and Epigenetics
确定连接脂质信号传导和表观遗传学的亚细胞器
- 批准号:
9763211 - 财政年份:2019
- 资助金额:
$ 51.66万 - 项目类别:
Post-Translational and Epigenetic Control of Branched-Chain Amino Acid Metabolism
支链氨基酸代谢的翻译后和表观遗传控制
- 批准号:
10225807 - 财政年份:2018
- 资助金额:
$ 51.66万 - 项目类别:
Post-Translational and Epigenetic Control of Branched-Chain Amino Acid Metabolism
支链氨基酸代谢的翻译后和表观遗传控制
- 批准号:
9930167 - 财政年份:2018
- 资助金额:
$ 51.66万 - 项目类别:
Post-Translational and Epigenetic Control of Branched-Chain Amino Acid Metabolism
支链氨基酸代谢的翻译后和表观遗传控制
- 批准号:
10164761 - 财政年份:2018
- 资助金额:
$ 51.66万 - 项目类别:
Novel SIRT5 Enzymatic Activity Regulates Cellular Mechanisms of Aging and Disease
新型 SIRT5 酶活性调节衰老和疾病的细胞机制
- 批准号:
8650231 - 财政年份:2014
- 资助金额:
$ 51.66万 - 项目类别:
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:
10442722 - 财政年份:2014
- 资助金额:
$ 51.66万 - 项目类别:
Novel SIRT5 Enzymatic Activity Regulates Cellular Mechanisms of Aging and Disease
新型 SIRT5 酶活性调节衰老和疾病的细胞机制
- 批准号:
9210031 - 财政年份:2014
- 资助金额:
$ 51.66万 - 项目类别:
Novel SIRT5 Enzymatic Activity Regulates Cellular Mechanisms of Aging and Disease
新型 SIRT5 酶活性调节衰老和疾病的细胞机制
- 批准号:
8795651 - 财政年份:2014
- 资助金额:
$ 51.66万 - 项目类别:
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:
10183107 - 财政年份:2014
- 资助金额:
$ 51.66万 - 项目类别:
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