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: 10616788
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616788
• 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; Learning; Link; Liver; Longevity; Maps; Mass Spectrum Analysis; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolism; Methods; Mission; Mitochondria; Modeling; Modification; Molecular; Molecular Target; Mus; National Institute on Aging; Obesity; Oxidation-Reduction; Oxidative Stress; Pathway interactions; 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; cohort; healthspan; improved; in vivo; insight; metabolic abnormality assessment; mouse model; new technology; novel therapeutics; oxidation; pharmacologic; programs; response; skills; 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性调节的特殊生理学 尽管存在长期的联系，但活性氧（ROS）对蛋白质半胱氨酸残基进行修饰。 在 ROS 失调和衰老之间，技术限制导致持续缺乏 有关确切蛋白质半胱氨酸的信息由 ROS 修改，解释了其分子基础 使用我开发的半胱氨酸磷酸标签（CPT）蛋白质组学技术，我得到了体内功能障碍。 确定蛋白质半胱氨酸氧化网络的根本重塑发生在热量限制下 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 对衰老的寿命和健康益处相关的网络我还扩展了 Oximouse。 近交（DO）小鼠群体的多样性以概括人类群体的遗传多样性，在搜索中 这项工作的初步数据已确定具有高转化潜力的氧化还原信号目标。 蛋白质上保守的氧化还原信号传导靶标可能对年龄依赖性衰退具有重要影响 产热导致与年龄相关的肥胖 我将研究长寿背后的代谢氧化还原信号节点。 修改干预措施并描述这些目标随年龄的氧化还原调节的机制 导致产热活动下降的蛋白质组学数据将为社区提供丰富的资源。 探索 ROS 和衰老的机制研究将验证可能的氧化还原信号节点。 旨在延长寿命和健康寿命，这符合国家老龄化研究所的使命。 目标：（1）定义 CR 健康益处背后的线粒体半胱氨酸氧化机制。 (2) 确定节点寿命修改干预措施背后的脂肪代谢氧化还原信号传导。 (3)研究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K99阶段实现 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，该技术可量化绝对值。 半胱氨酸氧化还原修饰化学计量比以前更深几个数量级的蛋白质组覆盖 根据这些大数据，我将机械地验证具有重要意义的各个氧化还原信号节点。 我将得到该领域专家 Chochani 和 Gygi 博士的指导。 我将研究 ROS 生物学、新陈代谢、动物生理学和基于质谱 (MS) 的蛋白质组学。 另外还向我的合作者/顾问 Mair、Gladyshev、Banks、Gupta 和 Spiegelman 博士学习，他们 DFCI 拥有丰富的衰老、动物生理学和新陈代谢方面的专业知识。 HMS 激发了我成为一名独立调查员的热情，我独特的技能将进一步激发我的热情。 让我开发新技术，以“大数据”驱动的方式研究衰老生物学，然后选择 机制验证的目标，为未来的转化治疗开发提供见解。