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
基本信息
- 批准号:10558600
- 负责人:
- 金额:$ 39.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffectAgeAgingArchaeaBiochemical PathwayBiological AssayBiologyCaenorhabditis elegansCarbonCardiovascular DiseasesCellsCollaborationsCommunitiesComplexDataData AnalysesDietary intakeDiseaseDrug Metabolic DetoxicationEnergy IntakeEnsureEnvironmentEnzymesFMO2FamilyFatty AcidsFoodGenesGeneticGenetic EpistasisGoalsHealthHealth BenefitHeavy MetalsHomeostasisHomologous GeneHumanIn VitroInterventionKnowledgeKynurenineLinkLipidsLongevityLongevity PathwayMalnutritionMeasuresMediatingMedicalMetabolicMetabolic PathwayMetabolismMethylationMethyltransferaseModelingModificationNatureNematodaOrganismOutcomeOutputOxygen IsotopesOxygenasesParaquatPathway interactionsPhasePlayProcessProductionProteinsPublishingRegulationReportingReproducibilityResearchResistanceRoleScientistSourceStressSystemTechniquesTestingTryptophanWorkXenobioticsbiological adaptation to stressdietary restrictiondrug metabolismendoplasmic reticulum stressenvironmental interventionflavin-containing monooxygenasegene therapyhealthspanimprovedinnovationknock-downmetabolomicsnoveloverexpressionprogramsresponsesuccesstargeted treatmenttherapy developmenttool
项目摘要
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.
项目总结/摘要
饮食摄入/代谢与长期健康和疾病之间的联系首次建立近20年。
世纪前。饮食限制(DR),定义为热量摄入减少而不营养不良,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,并且很难在人类中实施,
科学家们更好地定义DR改善健康的机制,以模拟其益处
该项目的重点是一个家庭的异生素代谢酶,黄素-
含有在DR下游诱导的单加氧酶或FMOs,最近报道
这两个都是必要的和足够的,以增加线虫C的健康,抗应激能力和寿命。优美的
有趣的是,先前的报道也显示了在哺乳动物系统中,在DR下FMO同源物的诱导,
其他已知能延长寿命的条件。不幸的是,这些影响的机制-
保守的FMO蛋白对健康和长寿的作用在很大程度上是未知的,因为它们在I期的主要作用是
异生物质解毒与观察到的对健康和寿命的影响没有明确的联系。该项目将
基于最近发表的初步数据,支持FMO酶在调节
内源代谢利用最近开发的工具,包括线虫的新食物来源,
更好地测量他们的新陈代谢和代谢组学为基础的技术,使用氧同位素,
该项目将确定FMO活性的机制和影响,
简单的线虫,秀丽隐杆线虫。初步数据清楚地确立了一碳代谢
(OCM)作为受FMO-2影响的关键中间代谢网络,以改善健康和延长寿命。
本项目产生的数据将提供以下证据:1)FMO-2的关键内源性靶点
以及它们如何与OCM连接,2)OCM通量如何被FMO-2表达和活性修饰,以及它们如何与OCM连接。
这可能通过外源性代谢物复制,以及3)OCM的下游机制是什么,
它们如何帮助理解压力反应和寿命相互交织的本质。确保
该项目的成功,所有的分析将由线虫生物学和老化方面的专家合作进行
代谢组学分析和数据分析的专家。由此产生的数据将为
FMO酶的代谢影响,然后可以在哺乳动物系统中进一步询问。此外,本发明还提供了一种方法,
由于关注的途径对多种年龄相关疾病很重要,它们可能导致
在利用或不利用FMO活性机制的情况下改善健康的方法。
项目成果
期刊论文数量(0)
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{{ truncateString('SCOTT F LEISER', 18)}}的其他基金
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:
10833744 - 财政年份:2022
- 资助金额:
$ 39.03万 - 项目类别:
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:
10341409 - 财政年份:2022
- 资助金额:
$ 39.03万 - 项目类别:
Mechanisms of cell non-autonomous signaling through the hypoxic response
通过缺氧反应的细胞非自主信号传导机制
- 批准号:
10532756 - 财政年份:2019
- 资助金额:
$ 39.03万 - 项目类别:
Mechanisms of cell non-autonomous signaling through the hypoxic response
通过缺氧反应的细胞非自主信号传导机制
- 批准号:
10066299 - 财政年份:2019
- 资助金额:
$ 39.03万 - 项目类别:
Mechanisms of cell non-autonomous signaling through the hypoxic response
通过缺氧反应的细胞非自主信号传导机制
- 批准号:
10341075 - 财政年份:2019
- 资助金额:
$ 39.03万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 39.03万 - 项目类别:
Mechanisms of the cell non-autonomous dietary restriction pathway
细胞非自主饮食限制途径的机制
- 批准号:
10406885 - 财政年份:2018
- 资助金额:
$ 39.03万 - 项目类别:
Mechanisms of the cell non-autonomous dietary restriction pathway
细胞非自主饮食限制途径的机制
- 批准号:
9757654 - 财政年份:2018
- 资助金额:
$ 39.03万 - 项目类别:
Mechanisms of the cell non-autonomous dietary restriction pathway
细胞非自主饮食限制途径的机制
- 批准号:
9918231 - 财政年份:2018
- 资助金额:
$ 39.03万 - 项目类别:
Conserved longevity mechanisms of the hypoxic response pathway
缺氧反应途径的保守长寿机制
- 批准号:
9193857 - 财政年份:2016
- 资助金额:
$ 39.03万 - 项目类别:
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