Integrative Analysis of Wilson's Disease

威尔逊病的综合分析

• 批准号: 9448230
• 负责人: SVETLANA LUTSENKO
• 金额: $ 43.06万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9448230
• 关键词: ATP phosphohydrolase; Affect; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Anabolism; Binding Proteins; Biochemical; Biochemical Process; Brain; Catecholamines; Cell physiology; Cells; Copper; Data; Development; Disease; Disease Progression; Dopamine; Dopamine-beta-monooxygenase; Enterobacteria phage P1 Cre recombinase; Enzymes; Equilibrium; Feedback; Fibroblasts; Fluorescence; Functional disorder; Goals; Hepatocyte; Hepatolenticular Degeneration; Homeostasis; Human; Immune response; In Vitro; Individual; Link; Maintenance; Menkes Kinky Hair Syndrome; Messenger RNA; Metabolic; Mitochondria; Mixed Function Oxygenases; Molecular; Molecular Chaperones; Motor; Mus; Neuraxis; Neurodegenerative Disorders; Neurons; Neurosecretory Systems; Norepinephrine; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Peptides; Physiological; Physiological Processes; Process; Production; Reactive Oxygen Species; Regulation; Research; Respiration; Roentgen Rays; Role; Syndrome; Testing; Up-Regulation; Wilson disease protein; Work; base; design; disturbance in affect; experimental study; in vivo; locus ceruleus structure; myelination; noradrenergic; novel; overexpression; oxidation; programs; protein transport; trafficking

PROJECT SUMMARY The long-term goal of this project is to understand the fundamental mechanisms that regulate human copper (Cu) homeostasis in the central nervous system. Cu is essential for numerous physiologic processes, including myelination of neurons, immune response, catecholamines balance, mitochondria respiration, and protection against oxygen radicals. Disrupted Cu homeostasis causes or significantly contributes to the pathogenesis of several neurodegenerative disorders including Menkes disease, Wilson disease, MEDNIK syndrome, and Alzheimer's disease. The molecular mechanisms that govern Cu homeostasis in most cells of the central nervous system, especially during metabolic changes, are greatly understudied and poorly understood. This project will feel the information gap by characterizing the biochemical mechanisms of Cu transport and utilization in noradrenergic neurons (NEN) of locus coeruleus. The experiments will determine specific roles of the two Cu-transporting ATPases (Cu-ATPase) ATP7A and ATP7B in the maintenance of the cytosolic Cu balance in these neurons and in activation of dopamine-β-hydroxylase (DBH), the key enzyme involved in biosynthesis of norepinephrine. The studies will also characterize the NEN-specific regulatory mechanisms that coordinate the Cu-ATPases activity with DBH secretion. The research program has three specific aims. Experiments under Aim 1 will elucidate how ATP7A, ATP7B and the Cu chaperone Atox1 work together to maintain Cu homeostasis in noradrenergic neurons. Studies under Aim 2 will determine the role of Cu- ATPases ATP7A and ATP7B in activation and secretion of dopamine-β-hydroxylase (DBH), and Aim 3 will characterize the novel feedback pathway by investigating how Cu counteracts the inhibitory effect of NE on DBH secretion. The results will help to develop new mechanistic paradigms of Cu homeostasis in the brain, contribute to understanding of Wilson disease pathogenesis, and, ultimately, help to design better treatments for disorders of Cu misbalance.

项目总结 该项目的长期目标是了解调节人类铜的基本机制。 (铜)中枢神经系统的动态平衡。铜对许多生理过程都是必不可少的，包括 神经元的髓鞘形成、免疫反应、儿茶酚胺平衡、线粒体呼吸和保护 对抗氧自由基。铜稳态失调导致或显著参与了糖尿病的发病 几种神经退行性疾病，包括门克斯病、威尔逊病、梅德尼克综合征和 阿尔茨海默氏症。中央动脉大多数细胞内铜稳态的分子机制 神经系统，特别是在新陈代谢变化过程中，对神经系统的研究很少，了解得也很少。这 该项目将通过表征铜运输和铜的生物化学机制来感受信息差距 去甲肾上腺素能神经元在蓝斑的应用。实验将确定特定的角色 维持胞内铜含量的两种铜转运酶ATP7A和ATP7B 这些神经元的平衡和多巴胺-β-羟基酶的激活，这是参与 去甲肾上腺素的生物合成。这些研究还将表征NEN特有的调控机制，这些机制 使铜-ATPase活性与胸径分泌相协调。该研究计划有三个具体目标。 目标1下的实验将阐明ATP7A、ATP7B和铜伴侣Atox1是如何协同工作的 维持去甲肾上腺素能神经元铜的动态平衡。目标2下的研究将确定铜的作用- ATP7A和ATP7B在多巴胺-β-羟基酶的激活和分泌中的作用，AIM 3将 通过研究铜如何抵消去甲肾上腺素的抑制作用来表征这一新的反馈途径 胸径分泌物。这一结果将有助于开发大脑中铜稳态的新机制范式， 有助于了解肝豆状核变性的发病机制，并最终有助于设计更好的治疗方法 治疗铜失衡障碍。