Novel SIRT5 Enzymatic Activity Regulates Cellular Mechanisms of Aging and Disease

目前对衰老的研究主要集中在衰老的分子机制上。 疾病，线粒体功能障碍与几种人类疾病有关 衰老。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。线粒体蛋白控制的化学修饰 线粒体功能的几个方面，这个项目的长期目标是了解 这些修饰是如何被依赖于NAD()的sirtuin脱脂酶和 影响衰老的疾病。这项提案的目标是定义SIRT5在 衰老的分子机制。中心假说是SIRT5调节 线粒体去掉一个新发现的酰基修饰后的功能 蛋白质。在没有SIRT5的情况下，线粒体蛋白质将变得超酰化， 线粒体功能降低，并表现出几个加速衰老的标志。其基本原理是 因为这一假设是基于初步数据，这表明SIRT5在 衰老和疾病的细胞机制。为了检验这些假说，有三个具体目标 继续研究：1.确定蛋白质酰化的变化作为年龄的函数，使用 用蛋白质组学方法定量检测青年、中年和老年人群肝脏线粒体蛋白质酰化 和老年小鼠；2.通过测定这种新的酰基修饰对蛋白质功能的影响 结合细胞和小鼠模型，以测量蛋白质活性的变化 3.确定SIRT5的作用 用两种体外细胞测量衰老的几个生理参数研究衰老 在小鼠体内的检测，以确定SIRT5如何维持线粒体和细胞 衰老过程中的动态平衡。这项研究结合了一种新的蛋白质修饰，一种全面的 实验设计，以及创新的概念框架。此外，这项研究将建立 为早期研究人员奠定基础，并确保成功的研究计划专注于 关于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 功能障碍会导致与年龄相关的疾病。最终，这样的知识有可能 告知针对几种衰老疾病的新疗法的发展。

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.