Defining the landscape and mechanisms of protein redox regulation during aging

定义衰老过程中蛋白质氧化还原调节的景观和机制

• 批准号: 10701867
• 负责人: Edward Thomas Chouchani
• 金额: $ 57.38万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701867
• 关键词: Age; Aging; Biochemical; Biological; Biological Process; Caenorhabditis elegans; Chronology; Complex; Cysteine; Data; Data Set; Dietary Intervention; Disease; Evolution; Genetic; Intervention; Link; Liver; Longevity; Mammals; Maps; Mediating; Metabolic; Metabolism; Methods; Modeling; Modification; Molecular; Mus; Oxidation-Reduction; Pathology; Peripheral; Physiological; Physiology; Play; Post-Translational Protein Processing; Process; Protein Family; Proteins; Proteome; Proteomics; Reactive Oxygen Species; Regulation; Role; Signal Transduction; Site; Technology; Testing; Time; Tissues; Translations; age related; aged; alpha ketoglutarate; dietary restriction; healthspan; in vivo; oxidation; pharmacologic; protein complex; protein function; sex

PROJECT SUMMARY: Mammalian tissues engage in specialized physiology that is regulated through reversible modification of protein cysteine residues by reactive oxygen species (ROS). ROS regulate a myriad of biological processes, and dysregulation of ROS and redox signaling is one of the longest postulated underlying causes of physiological decline of tissues with age. Despite the widespread importance of redox regulation of tissue-specific physiology and mammalian aging, there is a persistent lack of information regarding the specific protein modifications that explain the molecular basis for these processes in vivo. We recently developed a mass spectrometric (MS) technology for the first comprehensive and quantitative mapping of the mouse cysteine redox proteome in vivo. Our current objective is to define the landscape and mechanisms of cysteine oxidation networks that underlie age-dependent tissue pathology and lifespan. Our preliminary data demonstrate a fundamental remodeling of cysteine oxidation networks occurs in all aged tissues, and many of these networks map to established disease-relevant protein families. We will test the hypothesis that coordinated redox regulation governs spatial organization, assembly, and function of protein networks already known to be relevant to age-related disease. Building on additional preliminary data, we will test the hypothesis that interventions that robustly extend lifespan and healthspan exert systematic remodeling of protein cysteine oxidation networks. To test these hypotheses, we will pursue the following specific aims. In Aim 1 we will systematically determine the role that cysteine oxidation plays in coordinating these protein complex network assemblies. Moreover, for two priority protein networks already associated with diseases of aging, we will define the role of cysteine oxidation on corresponding biological function and lifespan. In Aim 2 we will redox regulated networks that are regulated by the longevity promoting intervention of dietary restriction will determine those pro-longevity cysteine oxidation networks that are conserved across sexes and throughout evolution by applying parallel redox proteomics analyses in models of C. elegans aging and DR. We will additionally determine the mechanisms and metabolic consequences of redox regulation of newfound redox regulated targets of α-ketoglutarate metabolism, which we hypothesize play a central role in DR-mediated metabolic regulation. Taken together, we propose to define, for the first time, the proteome-wide redox regulatory landscape that defines tissue aging and DR- dependent promotion of lifespan. Successful completion of these Aims will define mechanisms for a mode of biological regulation by ROS that has long been associated with aging, but for decades has remained elusive.

项目摘要：哺乳动物组织参与专门的生理学，其调节通过 活性氧（ROS）对蛋白质半胱氨酸残基的可逆修饰。 ROS 调节无数 生物过程的失调，ROS 和氧化还原信号传导的失调是最长的假设基础之一 随着年龄的增长，组织的生理衰退的原因。尽管氧化还原调节具有广泛的重要性 组织特异性生理学和哺乳动物衰老，但始终缺乏有关具体组织特异性生理学和哺乳动物衰老的信息 蛋白质修饰解释了体内这些过程的分子基础。 我们最近开发了质谱 (MS) 技术，首次全面定量 小鼠体内半胱氨酸氧化还原蛋白质组图谱。我们当前的目标是定义景观和 半胱氨酸氧化网络的机制是年龄依赖性组织病理学和寿命的基础。我们的 初步数据表明，所有老年人的半胱氨酸氧化网络都发生了根本性重塑 组织，其中许多网络映射到已建立的与疾病相关的蛋白质家族。我们将测试 协调氧化还原调节控制蛋白质的空间组织、组装和功能的假设 已知与年龄相关疾病相关的网络。根据额外的初步数据，我们将 检验以下假设：强有力地延长寿命和健康寿命的干预措施会进行系统重塑 蛋白质半胱氨酸氧化网络。 为了检验这些假设，我们将追求以下具体目标。在目标 1 中，我们将系统地确定 半胱氨酸氧化在协调这些蛋白质复合物网络组装中发挥的作用。此外，对于 两个优先蛋白质网络已经与衰老疾病相关，我们将定义半胱氨酸的作用 氧化对相应的生物功能和寿命的影响。在目标 2 中，我们将氧化还原调节网络 受饮食限制的长寿干预的调节将决定那些长寿的半胱氨酸 通过应用平行氧化还原，氧化网络在性别和整个进化过程中都是保守的 线虫衰老和 DR 模型中的蛋白质组学分析。我们将另外确定机制和 新发现的氧化还原调节α-酮戊二酸代谢目标的氧化还原调节的代谢后果， 我们假设其在 DR 介导的代谢调节中发挥核心作用。综上所述，我们建议 首次定义了蛋白质组范围内的氧化还原调控景观，该景观定义了组织衰老和 DR- 寿命的依赖促进。成功完成这些目标将定义一种模式的机制 ROS 的生物调节长期以来一直与衰老相关，但几十年来一直难以捉摸。