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Rethinking the zinc-copper relationship in Wilson Disease

重新思考威尔逊病中锌-铜的关系

基本信息

批准号：
10515079
负责人：
JASON L BURKHEAD
金额：
$ 43.97万
依托单位：
UNIVERSITY OF ALASKA ANCHORAGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10515079
关键词：
Affect Animal Experiments Animal Model Animals Biochemical Biological Markers Brain Cell model Cells Cellular Structures Chelating Agents Cholesterol Cholesterol Homeostasis Communities Complex Copper Data Data Set Deterioration Diet Disease Disease Progression Epithelial Etiology Excision Excretory function Female Food Gene Expression Gene Frequency Genes Genetic Engineering Goals Health Hepatolenticular Degeneration Hereditary Disease High Prevalence Human Injury Intestines Island Knowledge Lipids Liver Liver diseases Malignant Neoplasms Measurable Measures Metabolic Metabolism Metallothionein Metals Mitochondria Molecular Mus Mutation Neurologic Organ Oxidative Stress Pathogenesis Pathogenicity Pathologic Pathology Persons Prevalence Proteins Reporting Salts Schedule Series Serinus Serum Sex Differences Sex Differentiation South Korea Symptoms System Therapeutic Time Transition Elements Treatment Cost Treatment Efficacy Wild Type Mouse Wilson disease protein Work Zinc Zinc supplementation absorption candidate marker chelation disease diagnosis hepatoma cell lipid metabolism liver injury liver transplantation male metabolomics mortality mouse model oxidative damage personalized medicine response sex side effect specific biomarkers transcriptomics treatment response urinary

项目摘要

Wilson Disease (WD) is an inherited disorder of copper (Cu) metabolism that results in pathogenic Cu accumulation in the liver and brain as well as secondary organ damage largely related to liver injury. WD diagnosis and treatment are challenging, while an important gap in treatment includes a lack of measurable biomarkers that specifically report on treatment. An estimated 1:100 people carry a pathogenic mutation in the ATP7B Cu transporter that is deficient in WD, while the global prevalence estimate for WD is 1:30,000, with higher prevalence in specific communities (e.g., Canary Islands 1:2,600 and South Korea 1:3,500). The current understanding of WD progression is that pathogenesis develops from damage to the liver and its key functions. Cu excess is expected to induce oxidative damage to cellular structures; this injury appears to be more important later in disease progression, while the early and specific molecular effects of Cu accumulation appear to be in liver metabolic function, specifically lipid metabolism and mitochondrial activity. WD treatments can be classified as either zinc (Zn) salts or Cu chelators. Poor response to these therapies necessitates liver transplant. One major challenge in successful treatment is a lack of compliance, which is influenced by adverse side effects or cumbersome therapeutic schedules. Treatment sometimes induces paradoxical neurological deterioration. Given these challenges, knowledge of biomarkers that respond to treatment will be valuable to personalize WD therapy. Recent work, including our own, indicates that Zn-containing proteins are specifically affected in WD and that liver metabolic processes, many regulated by Zn proteins, are changed. The proposed work will build on this knowledge to define candidate biomarkers responsive to WD treatment. We will leverage a well-characterized WD mouse model in a treatment study to identify metabolite, gene expression and metal responses in liver and serum that are induced by Cu chelator or Zn treatments. The project executes the following Specific Aims: 1) Define treatment-responsive metabolite biomarkers induced by Cu chelator or Zn treatment in the Atp7b-/- mouse model of WD. Prior work has identified candidate biomarkers of WD in mice and humans, but these biomarkers are indicative of several liver diseases. Our approach will define candidate markers in liver and serum that respond specifically to WD treatment. 2) Determine sex-specific transition metal responses to WD treatments. Both animal models and humans appear to have sex- differentiated Cu and Zn homeostatic control, indicating it is important to understand how WD treatments have differential impacts by sex. 3) Define Cu and Zn interactions in cell health. Crosstalk between Cu and Zn is not well defined and may be important beyond WD treatment. This aim will use a non-WD hepatoma cell and wild-type mouse models to determine impacts of Cu chelation or zinc supplementation. This translational project will leverage existing data and a new, rich, sex-specific, dataset of metabolites, metals, and cellular Cu- Zn interactions to identify candidate biomarkers for enhancement of WD treatment.

威尔逊病（WD）是一种遗传性铜（Cu）代谢紊乱，导致致病性铜