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: 10194340
• 负责人: Christopher Ian Choi
• 金额: $ 3.84万
• 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/10194340
• 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; 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.

项目摘要。 衰老是多种导致死亡原因的最大风险因素，例如心脏病，多种类型 癌症和阿尔茨海默氏病。因此，衰老是全世界不断增长的经济和健康关注 65岁以上的人数继续增加。多种遗传和环境途径 使用动物模型发现了缓慢的衰老，例如饮食限制（DR）和低氧反应。 但是，这些途径延长寿命的机制在很大程度上不清楚。这个项目 专注于异生物代谢酶的一家，含黄素的单加氧酶， 称为FMO-2，是DR和低氧反应下游的诱导的，最近据报道是 在线虫秀丽隐杆线虫中的健康和寿命足以增加健康和寿命。有趣的是，以前 研究还报告了DR和其他寿命下的哺乳动物系统中FMO同源物的诱导 - 条件增加。这些结果，加上FMO在整个分类单元中保存良好的知识， 使了解FMO-2介导的寿命延长的机制成为至关重要的下一步。这个项目将 研究FMO-2的内源性底物和下游过程 寿命福利。为此，我将确定其所需的FMO-2蛋白的密钥底物 使用不靶向的代谢组学方法首先识别潜在底物，从而验证寿命的益处。 使用酶测定的底物，并使用RNAi寿命测试这些底物的必要 分析（目标1）。同时，我将确定FMO-所需的下游代谢过程 通过在我当前的计算模型上产生和改进并测试2个介导的寿命益处 使用同位素示踪剂通量分析和RNAi寿命屏幕模型预测（AIM 2）。为了确保他们的成功， 这些测定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，计算机建模和体外生物化学。总的来说，这些目标将进一步 对高度保守的酶家族的机械理解，其成员是关键的 多个寿命途径的收敛点。这些知识将使我们能够识别潜在的疗法 可以用来改善人类健康的小分子，基因或蛋白质形式的靶标。