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
• 负责人: Matthew D Hirschey
• 金额: $ 34.9万
• 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/8795651
• 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; social

DESCRIPTION (provided by applicant): 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 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.

描述（由申请人提供）：当前的衰老研究主要集中在与年龄相关疾病的分子机制，线粒体功能障碍与几种人类衰老疾病有关。然而，线粒体功能障碍的细胞机制及其如何导致与年龄有关的疾病。对线粒体蛋白的化学修饰控制了线粒体功能的几个方面，并且该项目的长期目标是了解这些修饰如何受NAD（+） - 依赖性的Sirtuin脱酰酶调节并影响老年人的疾病。该建议的目的是定义SIRT5在衰老的分子机制中的作用。中心假设是SIRT5通过从线粒体蛋白中去除新发现的酰基修饰来调节线粒体功能。在没有SIRT5的情况下，线粒体蛋白将变得过度酰化，线粒体功能降低，并显示出多种加速衰老的标记。该假设的理由是基于初步数据，这表明SIRT5在衰老和疾病的细胞机制中起着重要作用。为了检验这些假设，将采用三个具体目标：1。使用蛋白质组学策略来确定蛋白质酰化的变化，使用蛋白质组学策略来量化幼年，中年和老鼠的肝线粒体蛋白酰化。 2。通过使用细胞和鼠模型的组合来确定这种新型酰基修饰对蛋白质功能的影响，以衡量特定蛋白质的蛋白质活性的变化以及 线粒体； 3。通过使用体外细胞测定和小鼠体内测定的几个生理参数来确定SIRT5对衰老的作用，以确定SIRT5在衰老过程中如何保持线粒体和细胞稳态。这项研究结合了一种新颖的蛋白质修饰，全面的实验设计和创新的概念框架。此外，这项研究将为这位早期研究者建立基础，并确保成功的研究计划着重于衰老和疾病的细胞机制。重要的是，拟议的研究很重要，因为它有望促进和扩展了解线粒体功能障碍如何导致与年龄有关的疾病。最终，这种知识有可能告知针对几种衰老疾病的新疗法的发展。