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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：
10280110
负责人：
Vishal Mahendrasingh Gohil
金额：
$ 30.9万
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/10280110
关键词：
Affect Affinity Animal Model Animals Antineoplastic Agents Behavioral Binding Bioavailable Biochemical Biochemical Genetics Biochemical Process Biogenesis Biological Biological Models Brain 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 Iron Location Malignant Neoplasms Mammalian Cell Mediating Membrane Menkes Kinky Hair Syndrome Metabolism Micronutrients Mitochondria Mitochondrial Diseases Modeling Mus Mutation Neurotransmitters 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.

项目摘要铜（Cu）是人体生长发育所必需的微量营养素。的对铜的需求归因于其作为参与多种酶的催化辅因子的作用。生理过程，包括线粒体能量产生，神经递质生物合成，结缔组织形成。由于其在细胞和生物体生理学中的不同作用，铜吸收或转运到铜酶所需的基因突变往往导致致命的婴儿紊乱例如，在线粒体铜传递途径中涉及到细胞色素c的步骤中的缺陷氧化酶（CcO），一种线粒体铜酶，与线粒体疾病的子集有关，而将膳食铜输送到不同器官系统的中断导致门克斯病。目前，治疗这些疾病是实验性的，在预防早期死亡方面基本无效。鉴定化合物可以将铜传递给铜酶，从而克服这些缺陷，我们进行了有针对性的筛选，铜结合药理学试剂和确定elesclomol（ES）作为一个强大的铜转运分子。我们最初的研究表明，低纳摩尔浓度的ES可以在酵母，斑马鱼，和铜缺乏小鼠模型。取得这一突破后，我们现在可以测试我们的假设ES最初是作为癌症药物开发的，可以重新用于安全地递送Cu 不同的铜酶和救援与铜缺乏症相关的疾病表型。要执行此操作，我们将首先确定ES在细胞内释放Cu的位置和方式，以及这是否可以在没有破坏细胞。其次，我们将利用我们新构建的具有特定缺陷的斑马鱼模型，系统或线粒体Cu代谢和Menkes病小鼠模型，以测试ES在拯救线粒体，细胞和有机体的表型，通过提供铜铜酶。因此这项工作将揭示ES介导的细胞内铜转运的机制，并提出一种有前途的用于治疗使人衰弱和经常致命的铜缺乏症的治疗分子。