Studies on the Mechanisms by which SIRT5 Regulates Aging and Disease

了解导致慢性阻塞性肺疾病加速发展的分子机制 衰老是健康衰老的关键。在过去的10年里，大量证据支持这样的观点 线粒体功能改变和代谢失调起着关键作用。在这项竞争性续签拨款中 应用我的第一个R01作为独立的PI，我们的总体目标是确定如何改变新陈代谢 导致衰老的疾病和衰老本身。我们在以下方面取得了重大进展 了解来自新陈代谢的酰基辅酶A如何引起蛋白质修饰，以及如何 线粒体sirtuin 5作为代谢控制层去除了它们。我们在头5年的工作内容 资助期定义了蛋白质酰化和脱酰化的新范式，并确定SIRT5是一种 代谢和营养动态平衡的调节剂。在这些研究过程中，我们做出了意想不到的事情 发现SIRT5水平在正常细胞周期进程中受到生理调节，以及它的缺失 导致细胞周期控制的改变。这一令人兴奋的发现确定了一种长期追求的条件，在这种情况下 Sirtuin水平受到控制，并被定位为揭示这种新兴调节因子的潜在生物学作用。 衰老的问题。在这份提案中，我们将以这些令人振奋的初步数据为基础，重点关注以下具体内容 目的：目的：1)询问SIRT5蛋白在细胞周期进程中的调节；目的2)确定 SIRT5活性影响营养感知；目的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 确定SIRT5在控制特定营养传感中的关键生物学作用的实验设计 回应。此外，这项研究将建立一个知识基础，以进一步了解 新陈代谢状态与细胞周期沟通，以及这种沟通的丧失如何导致 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 代谢控制机制，并有可能为新疗法的开发提供信息，以保持 健康的衰老。

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.