Discovering novel metabolic targets to mitigate cyanide toxicity
Discovering novel metabolic targets to mitigate cyanide toxicity
批准号:
10426371
负责人:
Jared P Rutter
金额:
$66.28万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-08-01 至 2024-05-31
关键词:
AffectAgonistAnimal ModelAntidotesBindingBiologicalBrainCarbonCell Culture TechniquesCitric Acid CycleClinicalCollaborationsCoupledCyanidesCytosolDataDevelopmentDoseDrug FormulationsDrug KineticsEnzymesFoundationsFunctional disorderGeneticGoalsHeartHeme IronHomeostasisInterventionInvestigationLeadLibrariesMammalsMediatingMetabolicMetabolic PathwayMetabolismMitochondriaModelingMolecularMolecular TargetMusNew AgentsOrganOryctolagus cuniculusOxidation-ReductionOxygenPathologicPharmacologyPhysiologyPoisoningReactionResistanceRespirationRoleSeriesSiteSpecificityTestingTherapeuticTissuesToxic effectToxinZebrafishanimal efficacybasecell typeclinical developmentcomplex IVcytochrome c oxidaseexperimental studyfolic acid metabolismglyoxylatelead candidatemetabolic poisonmetabolomicsnovelpleiotropismpreventproduct developmentpyruvate dehydrogenaseresponsesuccesstool
中文摘要
总结
氰化物基本上是一种代谢毒素。虽然它有许多已知的目标,
其病理后果可归因于抑制线粒体
通过电子传递链的复合物IV的失活来呼吸。鉴于这种
代谢在氰化物中毒的病理生理学中的重要作用,我们期望
代谢调节剂有可能作为治疗对策。在
事实上,该中心最近发现,代谢物乙醛酸深刻
减轻斑马鱼、小鼠和兔子的氰化物致死性。我们建议以此为基础,
通过定义这种和其他试剂的代谢功能,并测试
氧化还原失衡是氰化物毒性的基础。我们进一步发现
TCA循环的活化剂和底物也赋予抗氰化物性,
建议进一步开发这种药物作为治疗剂,并完成我们的高度
代谢物和代谢调节剂的集中筛选。我们还提出了一系列
机械实验,以询问复合物IV抑制的程度,
氰化物毒性的机制和介导毒性的器官。这些研究
将与旨在了解代谢生理学的实验协同作用,
氰化物毒性和对各种缓解方法的反应。我们假设
更深入地了解氰化物毒性和缓解的代谢基础,
为采取合理的反措施及其适当应用提供了信息。
英文摘要
Summary
Cyanide is fundamentally a metabolic toxin. Although it has many known targets, many
of its pathological consequences can be ascribed to inhibition of mitochondrial
respiration through inactivation of Complex IV of the electron transport chain. Given this
prominent role of metabolism in the pathophysiology of cyanide poisoning, we expect
that modulators of metabolism might have potential as therapeutic countermeasures. In
fact, this Center has recently discovered that the metabolite glyoxylate profoundly
mitigates cyanide lethality in zebrafish, mice and rabbits. We propose to build upon this
foundation by defining the metabolic functions of this and other agents and testing the
hypothesis that redox imbalance underlies cyanide toxicity. We have further discovered
that activators and substrates of the TCA cycle also confer cyanide resistance and
propose to further develop such agents as therapeutics as well as complete our highly
focused screen of metabolites and metabolic modulators. We also propose a series of
mechanistic experiments to interrogate the extent to which Complex IV inhibition is the
mechanism of cyanide toxicity and the organs that mediate that toxicity. These studies
will synergize with experiments aimed at understanding the metabolic physiology of
cyanide toxicity and the response to various mitigating approaches. We hypothesize
that a deeper understanding of the metabolic basis of cyanide toxicity and mitigation will
inform a rational approach to countermeasures and their appropriate application.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mitochondrial Biochemistry: From Mechanisms to Disease
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批准号:9893007
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项目类别:
-
资助金额:$38.13万
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财政年份:2019
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负责人:Jared P Rutter
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依托单位:
Discovering novel metabolic targets to mitigate cyanide toxicity
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批准号:10671673
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项目类别:
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资助金额:$35.35万
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财政年份:2019
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负责人:Jared P Rutter
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依托单位:
Mitochondrial Biochemistry: From Mechanisms to Disease
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批准号:10592253
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项目类别:
-
资助金额:$38.13万
-
财政年份:2019
-
负责人:Jared P Rutter
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依托单位:
Mitochondrial Biochemistry: From Mechanisms to Disease
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批准号:10372005
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项目类别:
-
资助金额:$38.13万
-
财政年份:2019
-
负责人:Jared P Rutter
-
依托单位:
Mitochondrial Biochemistry: From Mechanisms to Disease
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批准号:10673325
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项目类别:
-
资助金额:$7.31万
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财政年份:2019
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负责人:Jared P Rutter
-
依托单位:
Mitochondrial Biochemistry: From Mechanisms to Disease
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批准号:10728410
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项目类别:
-
资助金额:$12.26万
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财政年份:2019
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负责人:Jared P Rutter
-
依托单位:
Discovering novel metabolic targets to mitigate cyanide toxicity
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批准号:10241503
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项目类别:
-
资助金额:$35.12万
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财政年份:2019
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负责人:Jared P Rutter
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依托单位:
Discovering novel metabolic targets to mitigate cyanide toxicity
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批准号:9981044
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项目类别:
-
资助金额:$36.06万
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财政年份:2019
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负责人:Jared P Rutter
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依托单位:
Metabolic regulation of intestinal stem cell homeostasis
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批准号:10189530
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项目类别:
-
资助金额:$45.5万
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财政年份:2018
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负责人:Jared P Rutter
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依托单位:
Metabolic regulation of intestinal stem cell homeostasis
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批准号:10463558
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项目类别:
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资助金额:$44.59万
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财政年份:2018
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负责人:Jared P Rutter
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依托单位:
Msp1/ATAD1: mitochondrial and peroxisomal protein sorting
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批准号:9099862
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项目类别:
-
资助金额:$25.72万
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财政年份:2015
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负责人:Jared P Rutter
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依托单位:
Msp1/ATAD1: mitochondrial and peroxisomal protein sorting
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批准号:8988080
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项目类别:
-
资助金额:$26.15万
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财政年份:2015
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负责人:Jared P Rutter
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依托单位:
Succinate Dehydrogenase: Biogenesis and Role in Disease
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批准号:8831703
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项目类别:
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资助金额:$27.2万
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财政年份:2014
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负责人:Jared P Rutter
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依托单位:
Succinate Dehydrogenase: Biogenesis and Role in Disease
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批准号:9013487
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项目类别:
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资助金额:$26.09万
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财政年份:2014
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负责人:Jared P Rutter
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依托单位:
Functions of the Mitochondrial Proteome: An Integrated Multi-Species Approach
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批准号:8605196
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项目类别:
-
资助金额:$29.8万
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财政年份:2012
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负责人:Jared P Rutter
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依托单位:
Functions of the Mitochondrial Proteome: An Integrated Multi-Species Approach
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批准号:8791321
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项目类别:
-
资助金额:$26.73万
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财政年份:2012
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负责人:Jared P Rutter
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依托单位:
Functions of the Mitochondrial Proteome: An Integrated Multi-Species Approach
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批准号:8238935
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项目类别:
-
资助金额:$29.9万
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财政年份:2012
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负责人:Jared P Rutter
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依托单位:
Functions of the Mitochondrial Proteome: An Integrated Multi-Species Approach
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批准号:8412769
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项目类别:
-
资助金额:$28.8万
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财政年份:2012
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负责人:Jared P Rutter
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依托单位:
A conserved module required for mitochondrial function and viability under stress
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批准号:8025943
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项目类别:
-
资助金额:$30.21万
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财政年份:2009
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负责人:Jared P Rutter
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依托单位:
A conserved module required for mitochondrial function and viability under stress
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批准号:7781405
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项目类别:
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资助金额:$31.96万
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财政年份:2009
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负责人:Jared P Rutter
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依托单位:
国内基金
海外基金
Agonist-GPR119-Gs复合物的结构生物学研究
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批准号:32000851
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项目类别:青年科学基金项目
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资助金额:24.0万元
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批准年份:2020
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负责人:乔安娜
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依托单位: