Determining the role of flavin-containing monooxygenase-2 in longevity regulation

确定含黄素单加氧酶 2 在长寿调节中的作用

• 批准号: 10393591
• 负责人: Christopher Ian Choi
• 金额: $ 0.66万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-16 至 2022-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393591
• 关键词: Aging; Alzheimer' s Disease; Animal Model; Bacteria; Biochemical Pathway; Biochemistry; Biological Assay; Biology of Aging; Caenorhabditis elegans; Carbon; Cardiovascular Diseases; Catalytic Domain; Cause of Death; Computer Models; Data; Data Analyses; Disease; Economics; Energy Metabolism; Ensure; Enzymes; FMO2; FMO3; Family; Family member; Fishes; Folic Acid; Gene Expression; Gene Proteins; Genes; Genetic; Goals; Health; Health Benefit; Heart Diseases; Human; Hypoxia; In Vitro; Isotope Labeling; Isotopes; Knock-out; Knowledge; Life Extension; Longevity; Longevity Pathway; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methylation; Methyltransferase; Modeling; Molecular; Mus; Mutation; Nematoda; Nitrogen; Odors; Output; Pathway interactions; Persons; Play; Process; Protein Family; Proteins; RNA Interference; Reaction; Regulation; Reporting; Research; Risk Factors; Role; Signal Transduction; Sulfur; Sulfur Amino Acids; Syndrome; System; Systems Analysis; Testing; Tracer; Xenobiotics; aging population; amino acid metabolism; base; cancer type; dietary; dietary restriction; experimental study; flavin-containing monooxygenase; follow-up; glucose metabolism; human old age (65+); improved; in silico; in vitro activity; knock-down; lipid metabolism; member; metabolomics; mouse model; nucleotide metabolism; overexpression; predictive modeling; prevent; response; small molecule; success; therapeutic target; transcriptomics; transmethylation; trimethylamine; trimethyloxamine

Project summary. Aging is the greatest risk factor for multiple leading causes of death, such as heart diseases, multiple types of cancer, and Alzheimer’s disease. Aging is thus a growing economic and health concern worldwide as the number of people over the age of 65 continues to increase. Multiple genetic and environmental pathways that slow aging, such as dietary restriction (DR) and hypoxic response, have been discovered using animal models. However, the mechanisms by which these pathways extend lifespan remain largely unclear. This project focuses on a member of the family of xenobiotic metabolizing enzymes, flavin-containing monooxygenases, called fmo-2, that is induced downstream of DR and hypoxic response and was recently reported to be both necessary and sufficient to increase health and longevity in the nematode C. elegans. Interestingly, previous studies also report induction of FMO homologs in mammalian systems under DR and other longevity- increasing conditions. These results, combined with the knowledge that FMOs are well-conserved across taxa, make understanding the mechanisms of FMO-2-mediated life extension a crucial next step. This project will investigate the endogenous substrates and downstream processes of FMO-2 that are necessary for its longevity benefits. To this end, I will determine the key substrate(s) of FMO-2 protein that are required for its longevity benefits by first identifying potential substrates using untargeted metabolomics approach, validating the substrates using enzymatic assay, and testing the necessity of these substrates using RNAi lifespan analysis (Aim 1). Concurrently, I will determine the downstream metabolic processes that are required for fmo- 2-mediated longevity benefits by generating and improving on my current computational model, and testing the model prediction using isotope tracer flux analysis and RNAi lifespan screen (Aim 2). To ensure their success, these assays will be performed under the guidance of experts in nematode biology and aging, metabolomics profiling and data analysis, in silico modeling, and in vitro biochemistry. Collectively, these aims will further our mechanistic understanding of a highly conserved enzyme family whose member serves as a critical convergence point for multiple longevity pathways. This knowledge will allow us to identify potential therapeutic targets in the form of small molecules, genes, or proteins that can be utilized to improve human health.

项目总结。 衰老是多种主要死亡原因的最大风险因素，如心脏病、多种类型的 癌症和阿尔茨海默氏症。因此，老龄化在全球范围内是一个日益严重的经济和健康问题，因为 65岁以上的人口数量继续增加。多条遗传和环境途径 缓慢的衰老，如饮食限制(DR)和低氧反应，已在动物模型中发现。 然而，这些途径延长寿命的机制在很大程度上仍不清楚。这个项目 重点介绍了异源代谢酶家族中的一种，含有黄素的单加氧酶， 称为FMO-2，它是在DR下游诱导的，最近被报道两者都是 对于增加线虫的健康和寿命来说是必要的和充分的。有趣的是，之前 研究还报告了在DR和其他长寿情况下，哺乳动物系统中FMO同源物的诱导。 不断增加的条件。这些结果，再加上FMO在不同类群中保存良好的知识， 了解FMO-2介导的寿命延长机制是下一步至关重要的一步。这个项目将 研究FMO-2的内源底物和下游过程是其必需的 长寿福利。为此，我将确定FMO-2蛋白的关键底物(S)，这是其 首先使用非靶向代谢组学方法确定潜在的底物，验证 用酶法检测底物，并用RNAi寿命检验这些底物的必要性 分析(目标1)。同时，我将确定FMO所需的下游代谢过程- 2-通过生成和改进我当前的计算模型并测试 使用同位素示踪剂流量分析和RNAi寿命筛选进行模型预测(目标2)。为了确保他们的成功， 这些化验将在线虫生物学和衰老、代谢组学专家的指导下进行 分析和数据分析，在硅胶模型和体外生物化学。总的来说，这些目标将推动我们的 对一个高度保守的酶家族的机械理解，该家族的成员是一个关键的 多条长寿路径的汇合点。这一知识将使我们能够识别潜在的治疗方法 小分子、基因或蛋白质形式的靶标，可用于改善人类健康。