Novel approaches to study emerging roles of xenobiotic enzymes

研究异生酶新兴作用的新方法

• 批准号: 9761416
• 负责人: SCOTT F LEISER
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761416
• 关键词: Affect; Aging; Animal Model; Archaea; Award; Bacteria; Biological Assay; Biology; Biology of Aging; Caenorhabditis elegans; Cardiovascular Diseases; Cells; Collaborations; Communities; Data; Data Analyses; Development; Dietary intake; Disease; Dose; Drug Metabolic Detoxication; Energy Intake; Ensure; Environment; Enzymes; FMO2; Family; Family member; Food; Foundations; Genetic; Goals; Health; Heavy Metals; Homeostasis; Human; Intervention; Knowledge; Lead; Link; Longevity; Malnutrition; Measurement; Measures; Medical; Metabolic; Metabolic Pathway; Metabolism; Methods; Mixed Function Oxygenases; Modification; Nematoda; Nutrient; Organism; Outcome; Oxygen; Oxygen Isotopes; Oxygenases; Paraquat; Pathway interactions; Perception; Phase; Play; Process; Protein Family; Proteins; Publications; Reaction; Regimen; Reporting; Reproducibility; Research Personnel; Resistance; Role; Scientist; Source; Stress; Sulfur Amino Acids; System; Techniques; Technology; Testing; Validation; Work; Xenobiotics; bacterial metabolism; base; biological adaptation to stress; dietary restriction; direct application; drug metabolism; experimental study; feeding; flavin-containing monooxygenase; healthspan; improved; innovation; member; metabolic abnormality assessment; metabolomics; novel; novel strategies; overexpression; paraform; stress reduction; success; therapy development; tool

Project Summary/Abstract Many researchers over the past 75 years have found a clear link between dietary intake/metabolism and long- term health and disease. 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 researchers 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 explore the endogenous role and substrates of FMO proteins by developing and utilizing important tools for measuring their metabolic effects and enzyme-specific activities. Focusing on the latest metabolomics technology, the project will 1) develop a novel food source for nematodes to better measure their metabolism on and off xenobiotic compounds, 2) develop a metabolomics based technique to use oxygen isotopes and identify substrates of oxygenases, 3) identify and validate candidate endogenous substrates for nematode FMO proteins, and 4) test whether the nematode endogenous substrates are also substrates of mammalian FMO proteins. To ensure their success, these assays will be performed by experts in nematode and mammalian biology and aging in collaboration with experts in metabolomics profiling and data analysis. The resulting data will provide important tools for nematode biologists measuring the metabolic impact of genetic and environmental perturbations that can effect both worm and bacterial biology and for biochemists looking for new ways to characterize enzymatic substrate profiles. In addition, the results focused on FMO protein activity will produce foundational data for publications and award applications based on understanding and exploiting the mechanism(s) of FMO activity and their role modifying health and longevity.

项目摘要/摘要 在过去的75年中，许多研究人员发现饮食摄入/代谢与长期之间存在明确的联系 术语健康和疾病。饮食限制（DR），定义为无营养不良的热量摄入量减少， 仍然是改善多种物种的健康和寿命的最有效和可重复的干预措施。 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 研究人员更好地定义了DR改善健康的机制，以模仿 在没有真正的博士的情况下有益。该项目着重于一个异生物代谢酶的家族， 含黄素的单加氧酶或FMO，这些酶是DR下游诱导的，最近被报道 在线虫C中既有必要又足以提高健康，抗压力和寿命。 秀丽隐杆线。有趣的是，先前的报告还显示了哺乳动物系统中FMO同源物的诱导 DR和其他已知会增加寿命的条件。不幸的是，这些作用的机制 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 通过开发和利用重要工具来探索FMO蛋白的内源性作用和底物 测量其代谢作用和酶特异性活性。专注于最新的代谢组学 技术，该项目将1）开发一种新型的线虫食品来源，以更好地测量其新陈代谢 在异种生物元素中，2）开发一种基于代谢组学的技术，用于使用氧同位素和 识别氧合酶的底物，3）识别并验证候选候选内源性底物的线虫 FMO蛋白和4）测试线虫内源性底物是否也是哺乳动物的底物 FMO蛋白。为了确保它们的成功，这些测定将由线虫专家和 哺乳动物的生物学和衰老与代谢组学分析和数据分析专家合作。这 结果数据将为线虫生物学家提供重要的工具，以测量遗传的代谢影响 以及可以影响蠕虫和细菌生物学的环境扰动，以及对外观的生物化学家 用于表征酶促底物曲线的新方法。另外，结果集中在FMO蛋白上 活动将基于理解和 利用FMO活动的机制及其作用改变了健康和寿命。