Defining the landscape and mechanisms of redox regulation of metabolism during aging

定义衰老过程中氧化还原代谢调节的景观和机制

• 批准号: 10448564
• 负责人: Haopeng Xiao
• 金额: $ 10.99万
• 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: 2022-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448564
• 关键词: ATP1A2 gene; Adipose tissue; Adrenergic Agents; Affect; Age; Aging; Animals; Atlases; Big Data; Biological Process; Biology; Biology of Aging; Brown Fat; Caloric Restriction; Cells; Communities; Cysteine; Data; Development; Disease; Energy Metabolism; Environment; Functional disorder; Future; Genetic; Genetic Transcription; Genetic Variation; Health Benefit; Human; Individual; Intervention; Knowledge; Lead; Learning; Link; Liver; Longevity; Maps; Mass Spectrum Analysis; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolism; Methods; Mission; Mitochondria; Modification; Molecular; Molecular Target; Mus; National Institute on Aging; Obesity; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Pharmacology; Phase; Physiological; Physiology; Play; Population; Population Heterogeneity; Post-Translational Protein Processing; Protein Family; Proteins; Proteome; Proteomics; Reactive Oxygen Species; Regulation; Research Personnel; Resources; Role; Signal Transduction; Site; Technology; Testing; Thermogenesis; Tissues; Validation; Work; age related; aged; base; cohort; healthspan; improved; in vivo; insight; metabolic abnormality assessment; mouse model; new technology; novel therapeutics; oxidation; programs; response; stoichiometry; therapeutic development; translational potential; translational therapeutics

PROJECT SUMMARY: Mammalian tissues engage in specialized physiology that is regulated through reversible modification of protein cysteine residues by reactive oxygen species (ROS). Despite the longstanding links between ROS dysregulation and aging, technological limitations have resulted in a persistent absence of information on the exact protein cysteines are modified by ROS that explain the molecular basis for this dysfunction in vivo. Using the cysteine-phospho tag (CPT) proteomics technology that I developed, I have determined that a fundamental remodeling of protein cysteine oxidation networks occurs with caloric restriction (CR) in aging. Building on this, I will determine the functional role of redox regulation of newfound protein networks that are linked to the lifespan and healthspan benefits of CR in aging. I have also extended Oximouse to diversity outbred (DO) mouse populations to recapitulate the genetic diversity of human population, in search for redox signaling targets that have high translational potential. Preliminary data from this effort has identified conserved redox signaling targets on proteins that may have critical implications in age-dependent decline of thermogenesis leading to age-related obesity. I will study metabolic redox signaling nodes underlying longevity- modifying interventions and delineate the mechanisms through which these targets are redox-regulated with age that lead to a decline in thermogenic activity. The proteomics data will provide a rich resource for the community to explore ROS and aging. The mechanistic studies will validate redox signaling nodes that can potentially be manipulated to extend lifespan and healthspan, in line with the mission of the National Institute of Aging. Objectives: (1) Defining mitochondrial cysteine oxidation mechanisms underlying the health benefits of CR. (2) Determining adipose metabolic redox signaling nodes underlying longevity-modifying interventions. (3) Investigating the mechanisms of redox control in age-related obesity. The first two objectives will be completed during the K99 phase, and the last objective will be carried out during the R00 phase. This work builds on a redox proteomics technology that I developed, which quantifies absolute cysteine redox modification stoichiometry at orders of magnitude deeper proteome coverage than previous methods. From this big data, I will mechanistically validate individual redox signaling nodes that have important roles in metabolism and longevity. I will be mentored by Drs. Chouchani and Gygi, who are experts in the fields of ROS biology, metabolism, animal physiology, and mass spectrometry (MS)-based proteomics. I will additionally learn from my collaborators/consultants, Drs. Mair, Gladyshev, Banks, Gupta, and Spiegelman, who have extensive expertise in aging, animal physiology, and metabolism. The rich scientific environment at DFCI and HMS adds fuel to my enthusiasm to establish myself as an independent investigator. My unique skillset will allow me to develop novel technologies to study the biology of aging in a “big-data” driven manner, then select targets for mechanistic validation to provide insights for future translational therapeutic development.

项目摘要：哺乳动物组织参与通过可逆调节的专门生理学 蛋白质半胱氨酸残基的ROS修饰。尽管两国之间有着长期的联系 在ROS失调和衰老之间，技术限制导致了持续的缺乏 有关蛋白质半胱氨酸的信息被ROS修饰，这解释了这一现象的分子基础 体内功能障碍。使用我开发的半胱氨酸-磷酸标签(CPT)蛋白质组学技术，我已经 确定卡路里限制使蛋白质半胱氨酸氧化网络发生根本性重构 (Cr)在老化中。在此基础上，我将确定新发现的蛋白质的氧化还原调节的功能作用 与CR在衰老过程中的寿命和健康寿命相关的网络。我还延长了奥昔莫斯 为了使杂交(DO)小鼠种群多样化，以概括人类种群的遗传多样性，正在寻找 用于具有高翻译潜力的氧化还原信号靶标。这项工作的初步数据已经确定 蛋白质上保守的氧化还原信号靶点，可能在年龄相关性下降中具有关键意义 生热作用导致与年龄相关的肥胖。我将研究影响长寿的代谢氧化还原信号节点- 修改干预措施，并描绘这些靶点随年龄变化进行氧化还原调节的机制 这导致了产热活性的下降。蛋白质组学数据将为社区提供丰富的资源 探索ROS与衰老的关系。这些机制研究将验证氧化还原信号节点可能是 经过处理以延长寿命和健康寿命，符合国家老龄研究所的使命。 目的：(1)明确CR对健康有益的线粒体半胱氨酸氧化机制。 (2)确定延年益寿干预下的脂肪代谢氧化还原信号节点。 (3)探讨年龄相关性肥胖的氧化还原控制机制。 前两个目标将在K99阶段完成，最后一个目标将在 R00阶段。这项工作建立在我开发的氧化还原蛋白质组学技术的基础上，该技术可以量化绝对 半胱氨酸氧化还原修饰的化学计量比比以前的蛋白质组覆盖率高出数量级 方法：研究方法。从这个大数据中，我将机械地验证具有重要影响的单个氧化还原信号节点 在新陈代谢和长寿方面的作用。我将由这一领域的专家Chouchani博士和Gygi博士指导 ROS生物学、新陈代谢、动物生理学和基于质谱仪(MS)的蛋白质组学。这就做 此外，我还向我的合作者/顾问Mair、Gladyshev、Banks、Gupta和Spiegelman博士学习，他们 在衰老、动物生理学和新陈代谢方面有丰富的专业知识。DFCI丰富的科学环境 而HMS增加了我将自己确立为独立调查员的热情。我独一无二的技能将 请允许我开发新技术，以大数据驱动的方式研究衰老的生物学，然后选择 机制验证的目标，为未来的转化性治疗开发提供见解。