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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：
Vishal Mahendrasingh Gohil
金额：
$ 30.86万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
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：
https://reporter.nih.gov/project-details/10468271
关键词：
Affect Affinity Animal Model Animals Antineoplastic Agents Behavioral Binding Biochemical Biochemical Genetics Biochemical Process Biogenesis Biological Biological Models Brain Cancer Patient Carrier Proteins Cells Cellular Membrane Child Complex Connective Tissue Copper Defect Development Disease Dose Enzymes Exhibits Free Radicals Functional disorder Genes Genetic Goals Growth Growth and Development function Human Impairment In Vitro Iron Location Malignant Neoplasms Mammalian Cell Mediating Membrane Menkes Kinky Hair Syndrome Metabolism Micronutrients Mitochondria Mitochondrial Diseases Modeling Mus Mutation Organelles Oxidases Pathology Pathway interactions Pharmacology Pharmacotherapy Phenotype Physiological Processes Physiology Positioning Attribute Production Regimen Research Respiratory Chain Role Salts Site Specificity Sulfur Symptoms Testing Therapeutic Toxic effect Trace metal Transition Elements Work Yeasts Zebrafish absorption base body system cell injury cofactor cytochrome c oxidase dietary disease phenotype effective therapy genetic approach human model hydrophilicity hypocupremia infancy loss of function mutation mortality mouse model nanomolar neuropathology neurotransmitter biosynthesis oxidative damage prevent

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