Defining the landscape and mechanisms of protein redox regulation during aging
定义衰老过程中蛋白质氧化还原调节的景观和机制
基本信息
- 批准号:10358250
- 负责人:
- 金额:$ 34.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-15 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAgingBiochemicalBiologicalBiological ProcessCaenorhabditis elegansComplexCysteineDataData SetDietary InterventionDiseaseEventEvolutionGeneticInterventionLinkLiverLongevityMapsMediatingMetabolicMetabolismMethodsModelingModificationMolecularMusOxidation-ReductionPathologyPeripheralPharmacologyPhysiologicalPhysiologyPlayPost-Translational Protein ProcessingProcessProtein FamilyProteinsProteomeProteomicsReactive Oxygen SpeciesRegulationRoleSignal TransductionSiteTechnologyTestingTimeTissuesTranslationsage relatedagedalpha ketoglutaratedietary restrictionhealthspanin vivooxidationprotein complexprotein functionsex
项目摘要
PROJECT SUMMARY: Mammalian tissues engage in specialized physiology that is regulated through
reversible modification of protein cysteine residues by reactive oxygen species (ROS). ROS regulate a myriad
of biological processes, and dysregulation of ROS and redox signaling is one of the longest postulated underlying
causes of physiological decline of tissues with age. Despite the widespread importance of redox regulation of
tissue-specific physiology and mammalian aging, there is a persistent lack of information regarding the specific
protein modifications that explain the molecular basis for these processes in vivo.
We recently developed a mass spectrometric (MS) technology for the first comprehensive and quantitative
mapping of the mouse cysteine redox proteome in vivo. Our current objective is to define the landscape and
mechanisms of cysteine oxidation networks that underlie age-dependent tissue pathology and lifespan. Our
preliminary data demonstrate a fundamental remodeling of cysteine oxidation networks occurs in all aged
tissues, and many of these networks map to established disease-relevant protein families. We will test the
hypothesis that coordinated redox regulation governs spatial organization, assembly, and function of protein
networks already known to be relevant to age-related disease. Building on additional preliminary data, we will
test the hypothesis that interventions that robustly extend lifespan and healthspan exert systematic remodeling
of protein cysteine oxidation networks.
To test these hypotheses, we will pursue the following specific aims. In Aim 1 we will systematically determine
the role that cysteine oxidation plays in coordinating these protein complex network assemblies. Moreover, for
two priority protein networks already associated with diseases of aging, we will define the role of cysteine
oxidation on corresponding biological function and lifespan. In Aim 2 we will redox regulated networks that are
regulated by the longevity promoting intervention of dietary restriction will determine those pro-longevity cysteine
oxidation networks that are conserved across sexes and throughout evolution by applying parallel redox
proteomics analyses in models of C. elegans aging and DR. We will additionally determine the mechanisms and
metabolic consequences of redox regulation of newfound redox regulated targets of α-ketoglutarate metabolism,
which we hypothesize play a central role in DR-mediated metabolic regulation. Taken together, we propose to
define, for the first time, the proteome-wide redox regulatory landscape that defines tissue aging and DR-
dependent promotion of lifespan. Successful completion of these Aims will define mechanisms for a mode of
biological regulation by ROS that has long been associated with aging, but for decades has remained elusive.
项目总结:哺乳动物组织参与特殊的生理活动,通过
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Edward Thomas Chouchani其他文献
Edward Thomas Chouchani的其他文献
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{{ truncateString('Edward Thomas Chouchani', 18)}}的其他基金
Targeting SHP-1 through a newfound metabolite-regulated cysteine activation site
通过新发现的代谢物调节的半胱氨酸激活位点靶向 SHP-1
- 批准号:
10802649 - 财政年份:2023
- 资助金额:
$ 34.39万 - 项目类别:
Defining the landscape and mechanisms of protein redox regulation during aging
定义衰老过程中蛋白质氧化还原调节的景观和机制
- 批准号:
10701867 - 财政年份:2022
- 资助金额:
$ 34.39万 - 项目类别:
Determining mechanisms of the succinate thermogenesis pathways on UCP1-dependent and UCP1-independent thermogenesis
确定 UCP1 依赖性和 UCP1 独立产热作用的琥珀酸产热途径的机制
- 批准号:
10294363 - 财政年份:2021
- 资助金额:
$ 34.39万 - 项目类别:
Chemical manipulation of creatine kinases to treat acute myeloid leukemia
肌酸激酶的化学操作治疗急性髓系白血病
- 批准号:
10198222 - 财政年份:2021
- 资助金额:
$ 34.39万 - 项目类别:
Defining mechanisms of succinate regulation over adipose tissue thermogenesis
琥珀酸对脂肪组织产热调节的定义机制
- 批准号:
10502818 - 财政年份:2019
- 资助金额:
$ 34.39万 - 项目类别:
Defining mechanisms of succinate regulation over adipose tissue thermogenesis
琥珀酸对脂肪组织产热调节的定义机制
- 批准号:
10649729 - 财政年份:2019
- 资助金额:
$ 34.39万 - 项目类别:
Defining mechanisms of succinate regulation over adipose tissue thermogenesis
琥珀酸对脂肪组织产热调节的定义机制
- 批准号:
10017983 - 财政年份:2019
- 资助金额:
$ 34.39万 - 项目类别:
Defining mechanisms of succinate regulation over adipose tissue thermogenesis
琥珀酸对脂肪组织产热调节的定义机制
- 批准号:
10194488 - 财政年份:2019
- 资助金额:
$ 34.39万 - 项目类别:
Defining mechanisms of succinate regulation over adipose tissue thermogenesis
琥珀酸对脂肪组织产热调节的定义机制
- 批准号:
10440227 - 财政年份:2019
- 资助金额:
$ 34.39万 - 项目类别:
Defining mechanisms of succinate regulation over adipose tissue thermogenesis
琥珀酸对脂肪组织产热调节的定义机制
- 批准号:
10442498 - 财政年份:2019
- 资助金额:
$ 34.39万 - 项目类别:
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