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）是由ATP7B基因突变引起的铜代谢遗传疾病 这会导致致病铜在大脑和肝脏中的积累。 WD神经系统符号可能很严重或 致命，包括肌张力障碍，共济失调和帕金森氏症状震颤。患者经常表现出特征的组合。 WD患者还可能出现精神病症状（通常是在WD诊断之前），包括行为 变化，人格变化，焦虑和抑郁。 WD治疗的主要挑战是神经学 当服用降低铜药物（如D-苯胺）时，通常需要症状。锌盐是 WD的替代治疗方法，与神经系统降解相关。但是，治疗 锌对肝病的功效似乎有限，神经系统符号的改善为 相对较慢。神经科WD治疗研究的重要障碍是有限的发展 临床前动物模型研究疾病机制和治疗。 WD的啮齿动物模型已经 无价定义铜毒性症的肝机制，而神经WD中的实用性不好 探索。 ATP7B - / - 小鼠是WD肝脏病理学高度特征的啮齿动物模型，揭示了缺陷 与人类相比，脂质代谢，肝损伤和相对发病的年龄。我们最近将此模型用于 确定锌代谢改变为WD中铜毒性的机理。 ATP7B - / - 鼠标中的脑铜 终生增加，这与WD患者的脑铜积累相似。这项工作将决定 ATP7B - / - 小鼠的实用性用于神经系统WD的临床前研究。建议的实验将定义 脑铜水平改变的行为和分子反应以及WD处理对 这些表型。综合方法将检验ATP7B - / - 小鼠模型神经系统的假设 WD用于机械疾病和治疗研究。该假设将通过执行 以下三个具体目标：目标1：确定ATP7B - / - ，ATP7B +/-鼠标表现出的程度 和行为障碍。将针对两者的男性和雌性动物确定行为表型 WildType/杂合（ATP7B+/+/ATP7B +/-）和敲除（ATP7B - / - ）基因型，用于三种治疗条件 （未经处理，D-苯胺胺或锌）； AIM 2：确定Zn或D-苯胺治疗对 ATP7B - / - ，ATP7B +/-和野生型的痕量金属和氧化应激的标记的浓度 小鼠； AIM 3：确定动物目标脑区域中Cu和Zn处理蛋白水平的变化 受到控制，锌或螯合剂的治疗。这项研究的完成将为 在ATP7B - / - 小鼠和WD患者中以治疗为重点的实验，以改善患者预后。 确定铜毒性在大脑中的影响也将建立对其他神经系统疾病的见识 铜的积累，包括帕金森氏症和阿尔茨海默氏症疾病。