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：哺乳动物组织从事专业生理学，通​​过可逆 通过活性氧（ROS）修饰蛋白质半胱氨酸残留物。尽管有长期的链接 在ROS失调和衰老之间，技术限制导致持续缺乏 关于确切蛋白质半胱氨酸的信息通过ROS修改，解释了这一点的分子基础 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，我有 确定蛋白质半胱氨酸氧化网络的基本重塑发生在热量限制下 （CR）衰老。在此基础上，我将确定新发现蛋白的氧化还原调节的功能作用 与CR在衰老中的寿命和健康范围益处相关的网络。我也扩展了Oximouse 多样性杂种（DO）小鼠种群概括了人口的遗传多样性，在搜索中 对于具有较高翻译电位的氧化还原信号传导目标。这项工作的初步数据已经确定 蛋白质的保守氧化还原信号靶标可能对年龄依赖性下降具有关键影响 热发生导致与年龄相关的肥胖症。我将研究寿命延长的代谢氧化还原信号传导节点 - 修改干预措施并描述这些目标随着年龄的增长而进行的机制 这导致热活动的下降。蛋白质组学数据将为社区提供丰富的资源 探索ROS和老化。机械研究将验证可能是可能是的氧化还原信号节点 操纵以延长寿命和健康范围，并符合美国国家老化研究所的任务。 目标：（1）定义CR的健康益处的线粒体半胱氨酸氧化机制。 （2）确定寿命延长寿命改造的干预措施的脂肪代谢氧化还原信号节点。 （3）研究与年龄相关对象性氧化还原控制的机制。 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，该技术量化了绝对 与以前 方法。从这些大数据中，我将机械地验证具有重要的单个氧化还原信号节点 在新陈代谢和寿命中的角色。我将被Drs修补。 Chouchani和Gygi，他们是该领域的专家 ROS生物学，代谢，动物生理学和质谱法（MS）的蛋白质组学。我会 另外，向我的合作者/顾问Drs学习。 Mair，Gladyshev，Banks，Gupta和Spiegelman，他们 在衰老，动物生理和代谢方面拥有广泛的专业知识。 DFCI的丰富科学环境 HM为我的热情增添了燃料，以确立自己为独立调查员。我独特的技能将 允许我开发新型技术来以“大数据”驱动的方式研究衰老的生物学，然后选择 机械验证的目标，可为将来的翻译治疗发展提供见解。