The Atp7b-/- mouse model of neurological copper toxicity and Wilson Disease

Atp7b-/- 神经铜毒性和威尔逊病小鼠模型

• 批准号: 10574028
• 负责人: JASON L BURKHEAD
• 金额: $ 41.48万
• 依托单位: UNIVERSITY OF ALASKA ANCHORAGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574028
• 关键词: Age; Age of Onset; Alzheimer' s Disease; Animal Model; Animals; Anxiety; Ataxia; Behavioral; Brain; Brain region; Chelating Agents; Cholesterol Homeostasis; Copper; Data; Defect; Disease; Dystonia; Equilibrium; Exhibits; Female; Foundations; Gene Frequency; Genes; Genetically Engineered Mouse; Genotype; Goals; Grouping; Hepatic; Hepatolenticular Degeneration; Hereditary Disease; Human; Inbred LEC Rats; Knock-out; Knockout Mice; Life; Liver; Liver diseases; Location; Mental Depression; Metabolism; Metals; Milk; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurologic Deficit; Neurologic Symptoms; Neurological Models; Nuclear Receptors; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Pathogenicity; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Penicillamine; Personality; Pharmaceutical Preparations; Phenotype; Proteins; Publishing; Receptor Signaling; Research; Rodent Model; Salts; Syndrome; Testing; Toxic effect; Trace metal; Treatment Efficacy; Tremor; Triethylenetetramine; Variant; Wild Type Mouse; Wilson disease protein; Work; Zinc; alternative treatment; behavioral impairment; behavioral phenotyping; comparative; disease diagnosis; disease mechanisms study; experimental study; improved; insight; lipid metabolism; liver injury; male; molecular phenotype; motor impairment; mouse model; nervous system disorder; neurobehavioral; pre-clinical; preclinical development; preclinical study; psychiatric symptom; response; standard of care; tetrathiomolybdate

Wilson Disease (WD) is an inherited disorder of copper metabolism caused by mutation in the ATP7B gene that causes pathogenic copper accumulation in the brain and liver. WD neurologic symptoms can be severe or fatal and include dystonia, ataxia and Parkinson-like tremor. Patients often present a combination of features. WD patients may also present with psychiatric symptoms (often prior to WD diagnosis) including behavioral changes, personality changes, anxiety and depression. A major challenge in WD treatment is that neurological symptoms often worsen when copper-lowering drugs such as D-penicillamine are administered. Zinc salts are an alternative treatment for WD and less associated with neurological degradation. However, treatment efficacy of zinc for liver disease appears to be limited, and improvement in neurologic symptoms is comparatively slow. A significant obstacle in research on neurologic WD treatment is the limited development of pre-clinical animal models to study disease mechanisms and treatments. Rodent models of WD have been invaluable to define hepatic mechanisms of copper toxicosis, while utility in neurologic WD is not well explored. The Atp7b-/- mouse is a highly characterized rodent model of WD liver pathology, revealing defects in lipid metabolism, liver damage and relative age-of-onset compared to humans. We recently used this model to identify altered zinc metabolism as mechanism of copper toxicity in WD. Brain copper in the Atp7b-/- mouse increases throughout life, which parallels brain copper accumulation in WD patients. This work will determine the utility of the Atp7b-/- mouse for pre-clinical studies of neurologic WD. Proposed experiments will define behavioral and molecular responses of altered brain copper levels as well as the impacts of WD treatments on these phenotypes. An integrative approach will test the hypothesis that the Atp7b-/- mouse models neurologic WD for mechanistic disease and treatment studies. This hypothesis will be tested through execution of the following three Specific Aims: Aim 1: Determine the extent to which Atp7b-/-, Atp7b+/- mice exhibit motor and behavioral impairments. Behavioral phenotypes will be determined for male and female animals of both wildtype/heterozygous (Atp7b+/+/Atp7b+/-) and knockout (Atp7b-/-) genotypes for three treatment conditions (untreated, D-penicillamine, or zinc); Aim 2: Determine the effects of Zn or D-penicillamine treatment on the concentration of trace metals and markers of oxidative stress in the brain for Atp7b-/-, Atp7b+/- and wild type mice; Aim 3: Determine the changes in Cu and Zn handling protein levels in target brain regions of animals subjected to control, Zn or chelator treatments. Completion of this study will provide a foundation for treatment-focused experiments in the Atp7b-/- mouse and WD patients to improve patient outcomes. Identifying effects of copper toxicity in the brain will also build insight into other neurological disorders with copper accumulation including Parkinson’s and Alzheimer’s diseases.

威尔逊病 (WD) 是一种由 ATP7B 基因突变引起的铜代谢遗传性疾病 导致致病性铜在大脑和肝脏中积聚。 WD 神经系统症状可能很严重或 致命的包括肌张力障碍、共济失调和帕金森样震颤。患者常常表现出多种特征的组合。 WD 患者还可能出现精神症状（通常在 WD 诊断之前），包括行为症状 变化、性格变化、焦虑和抑郁。 WD 治疗的一个主要挑战是神经系统 当服用 D-青霉胺等降低铜含量的药物时，症状往往会恶化。锌盐是 WD 的替代治疗方法，与神经功能退化的关系较小。然而，治疗 锌对肝病的疗效似乎有限，并且对神经系统症状的改善也很有限 比较慢。神经WD治疗研究的一个重大障碍是发展有限 临床前动物模型来研究疾病机制和治疗方法。 WD 的啮齿动物模型已 对于定义铜中毒的肝脏机制非常有价值，但在神经系统 WD 中的实用性并不好 探索过。 Atp7b-/- 小鼠是 WD 肝脏病理学的高度特征化的啮齿动物模型，揭示了 与人类相比，脂质代谢、肝损伤和相对发病年龄。我们最近使用这个模型 确定锌代谢改变是 WD 中铜毒性的机制。 Atp7b-/- 小鼠的脑铜 终生增加，这与 WD 患者的脑铜积累相似。这项工作将决定 Atp7b-/- 小鼠在神经学 WD 临床前研究中的用途。拟议的实验将定义 脑铜水平改变的行为和分子反应以及 WD 治疗对 这些表型。综合方法将检验 Atp7b-/- 小鼠神经系统模型的假设 WD 用于机械性疾病和治疗研究。该假设将通过执行来检验 以下三个具体目标： 目标 1：确定 Atp7b-/-、Atp7b+/- 小鼠表现出运动的程度 和行为障碍。将确定雄性和雌性动物的行为表型 三种治疗条件下的野生型/杂合 (Atp7b+/+/Atp7b+/-) 和敲除 (Atp7b-/-) 基因型 （未经处理的 D-青霉胺或锌）；目标 2：确定 Zn 或 D-青霉胺处理对 Atp7b-/-、Atp7b+/- 和野生型脑中微量金属浓度和氧化应激标记物 老鼠；目标 3：确定动物目标大脑区域中铜和锌处理蛋白水平的变化 进行对照、锌或螯合剂处理。完成本研究将为以下工作奠定基础 在 Atp7b-/- 小鼠和 WD 患者中进行以治疗为重点的实验，以改善患者的治疗结果。 识别铜毒性对大脑的影响也将有助于深入了解其他神经系统疾病 铜积累，包括帕金森病和阿尔茨海默病。