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