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) 是一种铜 (Cu) 代谢遗传性疾病，可导致致病性铜肝脏和大脑中的蓄积以及继发性器官损害很大程度上与肝损伤有关。西数诊断和治疗具有挑战性，而治疗中的一个重要差距包括缺乏可测量的专门报告治疗情况的生物标志物。估计有 1:100 人携带致病性突变 WD 缺乏 ATP7B Cu 转运蛋白，而 WD 的全球患病率估计为 1:30,000，特定社区的患病率较高（例如加那利群岛 1:2,600 和韩国 1:3,500）。目前的对 WD 进展的理解是，发病机制是由肝脏及其关键功能受损而发展而来。铜过量预计会引起细胞结构的氧化损伤；这次伤害似乎更严重在疾病进展后期很重要，而铜积累的早期和特定分子效应出现肝脏代谢功能，特别是脂质代谢和线粒体活性。 WD 治疗可以可分为锌 (Zn) 盐或铜螯合剂。对这些疗法的反应不佳需要肝脏移植。成功治疗的一大挑战是缺乏依从性，这受到不利因素的影响副作用或繁琐的治疗方案。治疗有时会引起矛盾的神经学症状恶化。考虑到这些挑战，对治疗有反应的生物标志物的知识对于个性化 WD 治疗。最近的工作，包括我们自己的工作，表明含锌蛋白质特别 WD 的影响以及肝脏代谢过程（许多由锌蛋白调节）发生了改变。拟议的工作将基于这些知识来定义对 WD 治疗有反应的候选生物标志物。我们将在治疗研究中利用特征良好的 WD 小鼠模型来识别代谢物、基因表达以及由铜螯合剂或锌处理诱导的肝脏和血清中的金属反应。项目执行以下具体目标： 1) 定义由铜螯合剂或铜螯合剂诱导的治疗响应代谢物生物标志物 Atp7b-/- WD 小鼠模型中的锌治疗。先前的工作已确定 WD 的候选生物标志物小鼠和人类，但这些生物标志物可以指示多种肝脏疾病。我们的方法将定义肝脏和血清中对 WD 治疗有特异性反应的候选标志物。 2) 确定性别特异性过渡金属对 WD 处理的反应。动物模型和人类似乎都有性行为—— 差异化的铜和锌稳态控制，表明了解 WD 治疗方式很重要性别有不同的影响。 3) 定义细胞健康中铜和锌的相互作用。 Cu 和 Zn 之间的串扰为没有明确定义，并且可能比 WD 治疗更重要。该目标将使用非 WD 肝癌细胞和野生型小鼠模型以确定铜螯合或锌补充剂的影响。这个翻译项目将利用现有数据和一个新的、丰富的、特定性别的代谢物、金属和细胞铜数据集锌相互作用，以确定增强 WD 治疗的候选生物标志物。