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：哺乳动物组织从事专业生理学的调节 通过活性氧（ROS）对蛋白质半胱氨酸残基的可逆修饰。 ROS规范无数 生物过程以及ROS和氧化还原信号的失调是张贴最长的基础之一 随着年龄的增长而导致组织身体下降的原因。尽管氧化还原调节的重要性很大 组织特异性生理学和哺乳动物衰老，关于特定的信息持续缺乏信息 蛋白质修饰解释了这些过程中这些过程的分子基础。 我们最近为第一个综合和定量开发了质谱（MS）技术 小鼠半胱氨酸氧化还原蛋白质组在体内的映射。我们目前的目标是定义景观和 基于年龄依赖性组织病理和寿命的基础的半胱氨酸氧化网络的机制。我们的 初步数据表明，在所有年龄段 组织和许多网络映射到建立的与疾病相关的蛋白质家族。我们将测试 协调的氧化还原调节的假设控制蛋白质的空间组织，组装和功能 已知已经与年龄相关疾病有关的网络。在其他初步数据的基础上，我们将 测试以下假设，即干预措施可延长寿命和健康范围的施加系统重塑 蛋白质半胱氨酸氧化网络。 为了检验这些假设，我们将追求以下特定目标。在目标1中，我们将系统地确定 半胱氨酸氧化物在配位这些蛋白质复合网络组件中起的作用。而且， 两个优先蛋白网络已经与衰老疾病有关，我们将定义半胱氨酸的作用 相应的生物功能和寿命上的氧化。在AIM 2中，我们将氧化还原监管的网络 受长寿促进饮食限制干预的调节将确定那些亲糖性半胱氨酸 通过应用平行氧化还原，跨性别和整个演变配置的氧化网络 秀丽隐杆线虫老化和DR的模型中的蛋白质组学分析。我们还将确定机制和 新发现的氧化还原调节靶标的氧化还原调节的代谢后果，α-酮戊二酸代谢， 我们假设这在DR介导的代谢调节中起着核心作用。两者一起，我们建议 首次定义蛋白质组范围的氧化还原调节景观，该景观定义了组织衰老和DR- 依赖寿命的依赖。这些目标成功完成将定义一种机制 长期以来与衰老有关的ROS生物调节，但数十年来一直难以捉摸。