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，导致致病性Cu 肝脏和大脑中的积累以及次要器官损伤与肝损伤主要有关。 WD 诊断和治疗具有挑战性，而治疗的重要差距包括缺乏可测量的专门报告治疗的生物标志物。估计有1：100人在 WD缺乏的ATP7B CU运输蛋白，而WD的全球患病率估计为1：30,000 特定社区的较高患病率（例如加那利群岛1：2,600和韩国1：3,500）。电流对WD进展的理解是，发病机理从对肝脏及其关键功能的损害发展。预计过量的铜会诱导细胞结构氧化损伤。这种伤害似乎更多在疾病进展的后期重要，而Cu积累的早期和特定分子效应出现在肝脏代谢功能中，特别是脂质代谢和线粒体活性。 WD治疗可以被归类为锌（Zn）盐或铜螯合剂。对这些疗法的反应不佳需要肝脏移植。成功治疗中的一个主要挑战是缺乏合规性，这受到不利影响副作用或繁琐的治疗时间表。治疗有时会诱导矛盾的神经系统恶化。鉴于这些挑战，对治疗反应的生物标志物的了解对于个性化WD疗法。最近的工作，包括我们自己的工作，表明含锌的蛋白质是专门的在WD中受到影响，并且改变了许多受Zn蛋白调节的肝脏代谢过程。提议工作将以这些知识为基础，以定义对WD治疗响应的候选生物标志物。我们将在治疗研究中利用良好的WD小鼠模型来鉴定代谢物，基因表达由Cu螯合剂或Zn处理诱导的肝脏和血清中的金属反应。该项目执行以下具体目的：1）定义由Cu螯合剂诱导的治疗响应代谢物生物标志物 WD的ATP7B - / - 小鼠模型中的Zn处理。先前的工作已经确定了WD的候选生物标志物小鼠和人类，但这些生物标志物表明了几种肝病。我们的方法将定义肝脏和血清中专门反应WD治疗的候选标记。 2）确定性别特定过渡金属对WD处理的反应。动物模型和人类似乎都有性 - 差异化的Cu和Zn稳态控制，表明了解WD治疗是很重要的通过性产生不同的影响。 3）定义细胞健康中的Cu和Zn相互作用。 Cu和Zn之间的串扰是除了WD处理之外，定义不当，可能很重要。此目标将使用非WD肝癌细胞和野生型小鼠模型，以确定Cu螯合或补充锌的影响。这种翻译项目将利用现有的数据以及新的，丰富的，特定的，代谢物，金属和细胞Cu-的数据集 Zn相互作用以识别候选生物标志物来增强WD处理。