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.

项目概要/摘要 膳食摄入/代谢与长期健康和疾病之间的联系最初是在近百年来首次建立的。 一个世纪前。饮食限制（DR），定义为在不造成营养不良的情况下减少热量摄入，仍然是 最有效和可重复的干预措施，以改善多个物种的健康和寿命。 不幸的是，长期 DR 相对未经测试，而且很难在人类身上实施，导致 科学家们需要更好地定义 DR 改善健康的机制，以模仿其益处 在没有真正的 DR 的情况下。该项目重点研究一系列外源代谢酶，黄素- 含有单加氧酶 (FMO)，这些酶是在 DR 下游诱导的，最近有报道称 对于提高线虫的健康、抗压能力和寿命来说，这既是必要的又是充分的。 有趣的是，之前的报告还表明在 DR 和 其他已知可延长寿命的条件。不幸的是，这些效果的机制 保守的 FMO 蛋白对健康和长寿的影响很大程度上未知，因为它们在第一阶段的主要作用 异生物质解毒与观察到的对健康和长寿的影响没有明确的联系。该项目将 以最近发表的初步数据为基础，这些数据支持 FMO 酶在调节中的作用 内源性代谢。利用最近开发的工具，包括线虫的新食物来源 更好地测量他们的新陈代谢和基于代谢组学的技术来使用氧同位素并识别 氧酶底物，该项目将确定 FMO 活性的机制和影响 简单线虫，秀丽隐杆线虫。初步数据明确建立了一碳代谢 (OCM) 作为受 FMO-2 影响的关键中间代谢网络，可改善健康并延长寿命。 该项目产生的数据将提供以下证据：1) FMO-2 的关键内源靶标是什么 以及它们如何连接到 OCM，2) FMO-2 表达和活性如何修改 OCM 通量以及如何 这可以通过外源代谢物复制，3) OCM 下游有哪些机制和 它们如何帮助理解压力反应和长寿之间相互交织的本质。为确保 如果该项目取得成功，所有检测都将由线虫生物学和衰老领域的专家合作进行 与代谢组学分析和数据分析专家一起。由此产生的数据将提供一个模型 FMO 酶的代谢影​​响，然后可以在哺乳动物系统中进一步研究。此外， 由于所关注的途径对于多种与年龄相关的疾病很重要，因此它们可能会导致 利用或不利用 FMO 活动机制来改善健康的方法。