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.

项目摘要 该项目的长期目标是了解调节人类铜的基本机制 （CU）中枢神经系统中的稳态。 CU对于许多生理过程至关重要，包括 神经元，免疫响应，儿茶酚胺平衡，线粒体呼吸和保护的髓鞘化 反对氧自由基。干扰CU稳态的原因或显着促进 几种神经退行性疾病，包括Menkes病，Wilson病，Mednik综合征和 阿尔茨海默氏病。在中央大多数细胞中控制Cu稳态的分子机制 神经系统，尤其是在代谢变化期间，人们对其进行了广泛理解和了解。这 项目将通过表征CU运输的生化机制和 核基因座的去肾上腺素能神经元（NEN）的利用。实验将确定 维持胞质Cu的两个Cu传输ATPases（Cu-ATPase）ATP7A和ATP7B 在这些神经元和多巴胺-β-羟化酶（DBH）激活中的平衡，涉及的关键酶 去甲肾上腺素的生物合成。这些研究还将表征NEN特定的调节机制 与DBH分泌协调Cu-atpases活性。该研究计划具有三个具体目标。 AIM 1下的实验将阐明ATP7A，ATP7B和Cu Chaperone Atox1如何共同起作用 维持脱甲肾上腺素能神经元中的CU稳态。 AIM 2的研究将确定Cu-的作用 ATPases ATP7A和ATP7B在多巴胺-β-羟化酶（DBH）的激活和分泌中，AIM 3将 通过研究CU如何抵消NE对NE的抑制作用来表征新的反馈途径 DBH分泌。结果将有助于发展大脑中Cu稳态的新机械范例， 有助于理解威尔逊病发病机理，并最终有助于设计更好的治疗方法 用于CU失误的疾病。