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.

肝豆状核变性（Wilson Disease，WD）是一种由ATP 7 B基因突变引起的遗传性铜代谢障碍 导致铜在大脑和肝脏中的致病性积累。WD神经系统症状可能严重， 包括肌张力障碍、共济失调和帕金森样震颤。患者通常表现出多种特征的组合。 WD患者也可能出现精神症状（通常在WD诊断之前），包括行为 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 当施用诸如D-青霉胺的降铜药物时，症状常常恶化。锌盐 WD的替代治疗，与神经退化的相关性较小。然而，治疗 锌对肝病的疗效似乎有限， 比较慢。神经系统WD治疗研究的一个重要障碍是其发展有限 研究疾病机制和治疗的临床前动物模型。WD的啮齿动物模型已经 对于确定铜中毒的肝脏机制是非常有价值的，而在神经系统WD中的实用性并不好 探讨了Atp 7 b-/-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 脂质代谢、肝损伤和与人类相比的相对发病年龄。我们最近用这个模型 确定锌代谢改变是WD铜中毒的机制。Atp 7 b-/-小鼠的脑铜 在整个生命过程中增加，这与WD患者的脑铜积累平行。这项工作将决定 Atp 7 b-/-小鼠用于神经系统WD的临床前研究的效用。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治疗对脑铜水平的影响。 这些表型。一种综合方法将检验Atp 7 b-/-小鼠模型的神经功能 WD用于机制性疾病和治疗研究。这一假设将通过执行 以下三个具体目的：目的1：确定Atp 7 b-/-、Atp 7 b +/-小鼠表现出运动的程度 和行为障碍。将测定两种动物的雄性和雌性动物的行为表型 三种处理条件下的野生型/杂合型（Atp 7 b +/+/Atp 7 b +/-）和敲除型（Atp 7 b-/-）基因型 目的2：确定Zn或D-青霉胺处理对小鼠脑缺血再灌注损伤的影响。 Atp 7 b-/-、Atp 7 b +/-和野生型的脑中痕量金属和氧化应激标志物的浓度 目的3：确定动物靶脑区Cu和Zn处理蛋白水平的变化 进行对照、Zn或螯合剂处理。本研究的完成将为 在Atp 7 b-/-小鼠和WD患者中进行以治疗为重点的实验，以改善患者的结局。 确定铜毒性对大脑的影响也将有助于了解其他神经系统疾病， 铜的积累，包括帕金森氏症和阿尔茨海默氏症。