Flavin-containing monooxygenases in endogenous metabolism and aging

内源性代谢和衰老中的含黄素单加氧酶

• 批准号: 10558600
• 负责人: SCOTT F LEISER
• 金额: $ 39.03万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558600
• 关键词: Affect; Age; Aging; Archaea; Biochemical Pathway; Biological Assay; Biology; Caenorhabditis elegans; Carbon; Cardiovascular Diseases; Cells; Collaborations; Communities; Complex; Data; Data Analyses; Dietary intake; Disease; Drug Metabolic Detoxication; Energy Intake; Ensure; Environment; Enzymes; FMO2; Family; Fatty Acids; Food; Genes; Genetic; Genetic Epistasis; Goals; Health; Health Benefit; Heavy Metals; Homeostasis; Homologous Gene; Human; In Vitro; Intervention; Knowledge; Kynurenine; Link; Lipids; Longevity; Longevity Pathway; Malnutrition; Measures; Mediating; Medical; Metabolic; Metabolic Pathway; Metabolism; Methylation; Methyltransferase; Modeling; Modification; Nature; Nematoda; Organism; Outcome; Output; Oxygen Isotopes; Oxygenases; Paraquat; Pathway interactions; Phase; Play; Process; Production; Proteins; Publishing; Regulation; Reporting; Reproducibility; Research; Resistance; Role; Scientist; Source; Stress; System; Techniques; Testing; Tryptophan; Work; Xenobiotics; biological adaptation to stress; dietary restriction; drug metabolism; endoplasmic reticulum stress; environmental intervention; flavin-containing monooxygenase; gene therapy; healthspan; improved; innovation; knock-down; metabolomics; novel; overexpression; programs; response; success; targeted treatment; therapy development; tool

Project Summary/Abstract The link between dietary intake/metabolism and long-term health and disease was first established nearly a century ago. Dietary restriction (DR), defined as a decrease in caloric intake without malnutrition, remains the most potent and reproducible intervention to improve health and longevity across multiple species. Unfortunately, long-term DR is both relatively untested and very difficult to implement in humans, leading scientists to better define the mechanisms through which DR improves health in an effort to mimic the benefits in the absence of true DR. This project focuses on a family of xenobiotic metabolizing enzymes, flavin- containing monooxygenases, or FMOs, that are induced downstream of DR and were recently reported to be both necessary and sufficient to increase health, stress resistance, and longevity in the nematode C. elegans. Interestingly, previous reports also show induction of FMO homologs in mammalian systems under DR and other conditions known to increase longevity. Unfortunately, the mechanism(s) for the effects of these well- conserved FMO proteins on health and longevity are largely unknown, as their primary role in phase I xenobiotic detoxification is not clearly linked to the observed effects on health and longevity. This project will build upon recently published and preliminary data that support a role for FMO enzymes in regulating endogenous metabolism. Utilizing recently developed tools, including a novel food source for nematodes to better measure their metabolism and a metabolomics based technique to use oxygen isotopes and identify substrates of oxygenases, this project will identify the mechanisms and implications for FMO activity within the simple nematode, Caenorhabditis elegans. The preliminary data clearly establish one-carbon metabolism (OCM) as the key intermediate metabolic network affected by FMO-2 to improve health and increase longevity. The data produced by this project will provide evidence as to 1) what the key endogenous target(s) of FMO-2 are and how they connect to OCM, 2) how OCM flux is modified by FMO-2 expression and activity and how this may be replicated through exogenous metabolites, and 3) what mechanisms are downstream of OCM and how they play into understanding the intertwined nature of stress response and longevity. To ensure the success of this project, all assays will be performed by experts in nematode biology and aging in collaboration with experts in metabolomics profiling and data analysis. The resulting data will provide a model for the metabolic impact of FMO enzymes that can then be further interrogated in mammalian systems. In addition, since the pathways focused on are important for multiple age-associated diseases, they may lead to approaches that improve health with or without exploiting the mechanism(s) of FMO activity.

项目摘要/摘要 饮食摄入/代谢与长期健康和疾病之间的联系几乎建立了 世纪前。饮食限制（DR）定义为无营养不良的热量摄入量减少，仍然是 最有效和可再现的干预措施，以改善多种物种的健康和寿命。 不幸的是，长期DR是相对未经测试的，并且在人类中很难实施，领导 科学家更好地定义了DR改善健康的机制，以模仿好处 在没有真正的博士的情况下。该项目着重于一个异生物代谢酶，黄素 - 含有DR下游诱导的单加氧酶或FMO，最近据报道为 在线虫秀丽隐杆线虫中，必要且足够的足以提高健康，抗压力和寿命。 有趣的是，以前的报告还显示了DR和DR下的哺乳动物系统中FMO同源物的诱导 其他已知会增加寿命的条件。不幸的是，这些井的影响的机制 保守的FMO蛋白在健康和寿命方面是未知的，因为它们在I期中的主要作用 异生元解毒与观察到的对健康和寿命的影响没有明确关联。这个项目将 基于最近发布的初步数据，该数据支持FMO酶在调节中的作用 内源代谢。利用最近开发的工具，包括线虫的新食物来源 更好地衡量其代谢和基于代谢组学的技术使用氧同位素并识别 氧合酶的底物，该项目将确定对FMO活动的机制和意义 简单的线虫，秀丽隐杆线虫。初步数据清楚地建立了一碳代谢 （OCM）作为受FMO-2影响的关键中级代谢网络，以改善健康并增加寿命。 该项目产生的数据将提供证据：1）FMO-2的关键内源性目标是什么 是以及它们如何连接到OCM，2）如何通过FMO-2表达和活动来修改OCM通量以及如何修饰 这可以通过外源代谢物复制，以及3）哪些机制在OCM的下游和 他们如何理解压力反应和寿命的交织性质。确保 该项目的成功，所有测定法将由线虫生物学专家和衰老合作进行 具有代谢组学分析和数据分析的专家。结果数据将为 FMO酶的代谢影​​响可以在哺乳动物系统中进一步审查。此外， 由于专注于多种年龄相关的疾病很重要，因此它们可能导致 在不利用FMO活动机制的情况下改善健康的方法。