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
• 负责人: Matthew D Hirschey
• 金额: $ 35.73万
• 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 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8650231
• 关键词: Ablation; Acetylation; Acylation; Address; Advanced Development; Age; Aging; Aging-Related Process; Amino Acids; Autophagocytosis; Back; Biological Assay; Caloric Restriction; Cell Line; Cell Respiration; Cells; Cellular Assay; Charge; Chemicals; Chronic; Chronic Disease; Coenzyme A; Data; Deacetylase; Development; Diabetes Mellitus; Disease; Economic Burden; Ensure; Exhibits; Experimental Designs; Fasting; Foundations; Functional disorder; Glutaryl-CoA dehydrogenase; Goals; Health; Hepatic; Homeostasis; Human; In Vitro; Knowledge; Lead; Lipids; Lysine; Malignant Neoplasms; Mammalian Cell; Maps; Measures; Mission; Mitochondria; Mitochondrial Proteins; Modeling; Modification; Molecular; Mus; Nature; Nutrient; Pathway interactions; Physiological; Play; Population; Positioning Attribute; Post-Translational Protein Processing; Protein Acetylation; Proteins; Proteomics; Public Health; Regulation; Research; Research Personnel; Research Proposals; Resolution; Risk; Risk Factors; Role; Sampling; Side; Signal Pathway; Sirtuins; Site; Staging; Testing; United States National Institutes of Health; Work; age related; aged; base; deprivation; enzyme activity; feeding; healthy aging; human disease; in vivo; innovation; knock-down; middle age; mitochondrial dysfunction; mouse model; novel; oxidation; prevent; programs; protein function; public health relevance; social

Current research on aging has largely focused the molecular mechanisms of age-related diseases, and mitochondrial dysfunction has been associated with several human diseases of aging. However, the cellular mechanisms of mitochondrial dysfunction and how they lead to age-related diseases are not known. Chemical modifications to mitochondrial proteins control several aspects of mitochondrial function, and the long-term goal of this project is to understand how these modifications are regulated by the NAD(+)-dependent sirtuin deacylases and influence the diseases of aging. The objective of this proposal is to define the role of SIRT5 in the molecular mechanisms of aging. The central hypothesis is that SIRT5 regulates mitochondrial function by removing a newly discovered acyl modification from mitochondrial proteins. In the absence of SIRT5, mitochondrial proteins will become hyper-acylated, have reduced mitochondrial function, and exhibit several markers of accelerated aging. The rationale for this hypothesis is based on preliminary data, which suggests an important role for SIRT5 in the cellular mechanisms of aging and disease. To test these hypotheses, three specific aims will be pursued: 1. Determine the changes in protein acylation as a function of age, using a proteomic strategy to quantify hepatic mitochondrial protein acylation from young, middle-aged, and old mice; 2. Determine the effect of this novel acyl modification on protein function by using a combination of cell and murine models, in order to to measure the changes in protein activity of specific proteins, as well as the overall function of mitochondria; 3. Determine role of SIRT5 on aging by measuring several physiological parameters of aging using both in vitro cellular assays and in vivo assays in mice, to determine how SIRT5 maintains mitochondrial and cellular homeostasis during aging. This study combines a novel protein modification, a comprehensive experimental design, and an innovative conceptual framework. Furthermore, this study will build a foundation for this early-stage investigator and ensure a successful research program focused on the cellular mechanisms of aging and disease. Importantly, the proposed research is significant because it is expected to advance and expand understanding how mitochondrial dysfunction can lead to age-related diseases. Ultimately such knowledge has the potential to inform the development of new therapies against several diseases of aging.

目前关于衰老的研究主要集中在与年龄相关的分子机制上 线粒体功能障碍与多种人类疾病有关 老化。然而，线粒体功能障碍的细胞机制及其如何导致 与年龄相关的疾病尚不清楚。线粒体蛋白质控制的化学修饰 线粒体功能的几个方面，该项目的长期目标是了解 NAD(+) 依赖性沉默调节蛋白脱酰酶如何调节这些修饰以及 影响衰老疾病。该提案的目标是定义 SIRT5 在以下方面的作用： 衰老的分子机制。中心假设是 SIRT5 调节 通过从线粒体中去除新发现的酰基修饰来实现线粒体功能 蛋白质。在缺乏 SIRT5 的情况下，线粒体蛋白将变得过度酰化， 线粒体功能降低，并表现出多种加速衰老的标志。理由 该假设基于初步数据，这表明 SIRT5 在 衰老和疾病的细胞机制。为了检验这些假设，三个具体目标将 追求： 1. 使用 量化年轻、中年、中年人肝线粒体蛋白酰化的蛋白质组学策略 还有老老鼠； 2. 通过使用确定这种新型酰基修饰对蛋白质功能的影响 细胞和小鼠模型的组合，以测量蛋白质活性的变化 特定蛋白质以及线粒体的整体功能； 3.确定SIRT5的作用 通过使用体外细胞测量衰老的几个生理参数来研究衰老 小鼠体内检测和体内检测，以确定 SIRT5 如何维持线粒体和细胞 衰老过程中的体内平衡。这项研究结合了一种新颖的蛋白质修饰、综合 实验设计和创新的概念框架。此外，本研究将建立 为这个早期研究人员奠定基础，并确保成功的研究计划重点关注 衰老和疾病的细胞机制。重要的是，拟议的研究是 意义重大，因为它有望推进和扩大对线粒体如何 功能障碍可能导致与年龄相关的疾病。最终，这些知识有可能 为针对多种衰老疾病的新疗法的开发提供信息。