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。