Integrative Analysis of Wilson's Disease

威尔逊病的综合分析

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要该项目的长期目标是了解调节人体铜的基本机制 (Cu) 中枢神经系统的稳态对于许多生理过程至关重要，包括。神经元髓鞘形成、免疫反应、儿茶酚胺平衡、线粒体呼吸和保护对抗氧自由基。铜稳态的破坏会导致或显着促进以下疾病的发病机制。多种神经退行性疾病，包括门克斯病、威尔逊病、MEDNIK 综合征和阿尔茨海默氏病控制大多数中枢细胞铜稳态的分子机制。神经系统，特别是在代谢变化期间，人们对此的研究和了解还很有限。项目将通过表征铜转运的生化机制来感受信息差距蓝斑去甲肾上腺素能神经元（NEN）中的利用实验将确定其具体作用。两种铜转运 ATP 酶 (Cu-ATP 酶) ATP7A 和 ATP7B 在维持细胞质铜这些神经元的平衡以及多巴胺-β-羟化酶 (DBH) 的激活，多巴胺-β-羟化酶 (DBH) 是参与这些研究还将描述 NEN 的特异性调节机制。协调 Cu-ATPase 活性与 DBH 分泌该研究项目有三个具体目标。目标 1 下的实验将阐明 ATP7A、ATP7B 和 Cu 伴侣 Atox1 如何协同工作维持去甲肾上腺素能神经元中的铜稳态。目标 2 下的研究将确定铜的作用。 ATP酶 ATP7A 和 ATP7B 参与多巴胺-β-羟化酶 (DBH) 的激活和分泌，目标 3 将通过研究 Cu 如何抵消 NE 的抑制作用来表征新的反馈途径 DBH 分泌的结果将有助于开发大脑中铜稳态的新机制范例，有助于了解威尔逊病的发病机制，并最终帮助设计更好的治疗方法用于铜失衡疾病。