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：
10442722
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
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：
https://reporter.nih.gov/project-details/10442722
关键词：
Ablation Acyl Coenzyme A Acylation Adaptor Signaling Protein Address Aging Animal Model 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 Pharmacology Phenotype Physiological Play Population Positioning Attribute Post-Translational Protein Processing Process Progress Reports 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 base cell type data integration deacylation detection of nutrient genetic approach healthy aging innovation insight multicatalytic endopeptidase complex novel novel therapeutics oxidation premature prevent programs response social stem stem cell function stem cell proliferation stem cells ubiquitin-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展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。