Novel SIRT5 Enzymatic Activity Regulates Cellular Mechanisms of Aging and Disease

目前对衰老的研究主要集中在与年龄相关的分子机制， 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以及它们如何导致 与年龄有关的疾病尚不清楚。线粒体蛋白质控制的化学修饰 线粒体功能的几个方面，这个项目的长期目标是了解 这些修饰如何受NAD（+）依赖性沉默调节蛋白脱酰基酶的调节， 影响衰老的疾病。该提案的目的是确定SIRT 5在以下方面的作用： 衰老的分子机制核心假设是SIRT 5调节 通过去除线粒体中新发现的酰基修饰来实现线粒体功能 proteins.在缺乏SIRT 5的情况下，线粒体蛋白将变得过度酰化， 线粒体功能降低，并表现出加速老化的几个标志。的理由 这一假设是基于初步数据，这表明SIRT 5在 衰老和疾病的细胞机制为了验证这些假设，三个具体目标将 追求：1。使用一种新的方法，确定蛋白质酰化的变化作为年龄的函数， 蛋白质组学策略，以定量从年轻，中年， 老鼠会; 2。使用以下方法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 具体的蛋白质，以及线粒体的整体功能; 3.确定SIRT 5的作用 通过测量衰老的几个生理参数，使用体外细胞 在小鼠中进行的测定和体内测定，以确定SIRT 5如何维持线粒体和细胞内的 衰老过程中的体内平衡这项研究结合了一种新的蛋白质修饰， 实验设计和创新的概念框架。此外，本研究将建立 为这个早期阶段的研究者奠定基础，并确保成功的研究计划， 衰老和疾病的细胞机制重要的是，拟议的研究是 重要的是，它有望推进和扩大理解线粒体如何 功能障碍可能导致与年龄有关的疾病。最终，这些知识有可能 为针对几种衰老疾病的新疗法的开发提供信息。

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.