Mechanisms of elesclomol-mediated copper delivery to cuproenzymes in cells
来氯醇介导的铜向细胞内铜酶的传递机制
基本信息
- 批准号:10468271
- 负责人:
- 金额:$ 30.86万
- 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:2021-09-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAffinityAnimal ModelAnimalsAntineoplastic AgentsBehavioralBindingBiochemicalBiochemical GeneticsBiochemical ProcessBiogenesisBiologicalBiological ModelsBrainCancer PatientCarrier ProteinsCellsCellular MembraneChildComplexConnective TissueCopperDefectDevelopmentDiseaseDoseEnzymesExhibitsFree RadicalsFunctional disorderGenesGeneticGoalsGrowthGrowth and Development functionHumanImpairmentIn VitroIronLocationMalignant NeoplasmsMammalian CellMediatingMembraneMenkes Kinky Hair SyndromeMetabolismMicronutrientsMitochondriaMitochondrial DiseasesModelingMusMutationOrganellesOxidasesPathologyPathway interactionsPharmacologyPharmacotherapyPhenotypePhysiological ProcessesPhysiologyPositioning AttributeProductionRegimenResearchRespiratory ChainRoleSaltsSiteSpecificitySulfurSymptomsTestingTherapeuticToxic effectTrace metalTransition ElementsWorkYeastsZebrafishabsorptionbasebody systemcell injurycofactorcytochrome c oxidasedietarydisease phenotypeeffective therapygenetic approachhuman modelhydrophilicityhypocupremiainfancyloss of function mutationmortalitymouse modelnanomolarneuropathologyneurotransmitter biosynthesisoxidative damageprevent
项目摘要
PROJECT SUMMARY
Copper (Cu) is an essential micronutrient that is required for growth and development of humans. The
requirement of Cu is attributed to its role as a catalytic cofactor for a number of enzymes involved in various
physiological processes, including mitochondrial energy production, neurotransmitter biosynthesis, and
connective tissue formation. Owing to its diverse roles in cellular and organismal physiology, loss-of-function
mutations in genes required for Cu absorption or transport to cuproenzymes often result in fatal infantile
disorders. For example, defects in the steps involved in the mitochondrial Cu delivery pathway to cytochrome c
oxidase (CcO), a mitochondrial cuproenzyme, are associated with a subset of mitochondrial disorders, while
disruption in delivering dietary Cu to different organ systems results in Menkes disease. Currently, therapies for
these diseases are experimental and largely ineffective at preventing early mortality. To identify compounds
that can deliver Cu to cuproenzymes and thus overcome these defects, we performed a targeted screen for
Cu-binding pharmacological agents and identified elesclomol (ES) as a potent Cu-transporting molecule. Our
initial studies have shown that low nanomolar concentrations of ES can deliver Cu to CcO in yeast, zebrafish,
and mouse models of Cu deficiency. Having made this breakthrough, we are now in position to test our
hypothesis that ES, which was originally developed as a cancer drug, can be repurposed to safely deliver Cu
to different cuproenzymes and rescue disease phenotypes associated with Cu deficiency disorders. To do this,
we will first determine where and how ES releases Cu inside cells and whether this can be achieved without
damaging cells. Second, we will utilize our newly constructed zebrafish models with specific defects in
systemic or mitochondrial Cu metabolism and a mouse model of Menkes disease to test the efficiency of ES in
rescuing mitochondrial, cellular, and organismal phenotypes by delivering Cu to cuproenzymes. Thus, the
proposed work will uncover the mechanism of ES-mediated intracellular Cu transport and advance a promising
therapeutic molecule for the treatment of debilitating and frequently fatal Cu deficiency disorders.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Vishal Mahendrasingh Gohil其他文献
Vishal Mahendrasingh Gohil的其他文献
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{{ truncateString('Vishal Mahendrasingh Gohil', 18)}}的其他基金
Mechanisms of elesclomol-mediated copper delivery to cuproenzymes in cells
来氯醇介导的铜向细胞内铜酶的传递机制
- 批准号:
10280110 - 财政年份:2021
- 资助金额:
$ 30.86万 - 项目类别:
Mechanisms of elesclomol-mediated copper delivery to cuproenzymes in cells
来氯醇介导的铜向细胞内铜酶的传递机制
- 批准号:
10640244 - 财政年份:2021
- 资助金额:
$ 30.86万 - 项目类别:
Mechanisms of elesclomol-mediated copper delivery to cuproenzymes in cells
来氯醇介导的铜向细胞内铜酶的传递机制
- 批准号:
10580489 - 财政年份:2021
- 资助金额:
$ 30.86万 - 项目类别:
Molecular Mechanisms of Copper Delivery to Mitochondrial Cytochrome c Oxidase
铜传递至线粒体细胞色素 c 氧化酶的分子机制
- 批准号:
10250356 - 财政年份:2014
- 资助金额:
$ 30.86万 - 项目类别:
A Genomic and Biochemical Analysis of Mitochondrial Respiratory Chain Biogenesis
线粒体呼吸链生物发生的基因组和生化分析
- 批准号:
8895365 - 财政年份:2014
- 资助金额:
$ 30.86万 - 项目类别:
Molecular Mechanisms of Copper Delivery to Mitochondrial Cytochrome c Oxidase
铜传递至线粒体细胞色素 c 氧化酶的分子机制
- 批准号:
10044168 - 财政年份:2014
- 资助金额:
$ 30.86万 - 项目类别:
Molecular Mechanisms of Copper Delivery to Mitochondrial Cytochrome c Oxidase
铜传递至线粒体细胞色素 c 氧化酶的分子机制
- 批准号:
10467011 - 财政年份:2014
- 资助金额:
$ 30.86万 - 项目类别:
A Genomic and Biochemical Analysis of Mitochondrial Respiratory Chain Biogenesis
线粒体呼吸链生物发生的基因组和生化分析
- 批准号:
9033123 - 财政年份:2014
- 资助金额:
$ 30.86万 - 项目类别:
A Genomic and Biochemical Analysis of Mitochondrial Respiratory Chain Biogenesis
线粒体呼吸链生物发生的基因组和生化分析
- 批准号:
8757173 - 财政年份:2014
- 资助金额:
$ 30.86万 - 项目类别:
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