Integrative Analysis of Wilson's Disease

项目摘要 这个项目的长期目标是了解调节人体铜的基本机制 (Cu)中枢神经系统的内稳态。铜是许多生理过程所必需的，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导致或显著促进了 几种神经退行性疾病，包括Menkes病、Wilson病、MEDNIK综合征和 老年痴呆症在中枢神经系统的大多数细胞中控制铜稳态的分子机制 神经系统，特别是在代谢变化期间，研究得非常不足，了解得很少。这 该项目将通过表征铜运输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）的利用。这些实验将确定 两种铜转运ATP酶（Cu-ATP酶）ATP 7A和ATP 7 B在维持细胞内铜离子浓度中的作用 在这些神经元中的平衡和多巴胺-β-羟化酶（DBH）的激活中， 去甲肾上腺素的生物合成。这些研究还将描述NEN特异性调节机制， 协调Cu-ATP酶活性与胸径分泌。该研究计划有三个具体目标。 目标1下的实验将阐明ATP 7A、ATP 7 B和Cu分子伴侣Atox 1如何一起工作， 维持去甲肾上腺素能神经元中Cu的稳态。目标2下的研究将确定铜的作用。 ATP酶ATP 7A和ATP 7 B参与多巴胺-β-羟化酶（DBH）的激活和分泌，Aim 3参与多巴胺-β-羟化酶（DBH）的激活和分泌。 通过研究Cu如何抵消NE对细胞增殖的抑制作用来表征新的反馈途径。 胸径分泌。这些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 治疗铜失衡

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.