Rethinking the zinc-copper relationship in Wilson Disease

肝豆状核变性(WD)是一种遗传性铜代谢紊乱，导致致病铜 肝脏和大脑中的蓄积以及继发性器官损伤主要与肝脏损伤有关。WD 诊断和治疗具有挑战性，而治疗方面的一个重要差距包括缺乏可衡量的 专门报告治疗情况的生物标志物。据估计，有1：100的人携带一种致病突变 ATP7B铜转运蛋白缺乏WD，而全球WD患病率估计为1：30,000， 在特定社区的患病率较高(例如，加那利群岛1：2,600，韩国1：3,500)。海流 对WD进展的理解是，发病机制是从对肝脏及其关键功能的损害发展而来的。 铜过量预计会导致细胞结构的氧化损伤；这种损伤似乎更严重 在疾病进展的后期很重要，而铜积累的早期和特定的分子效应出现 以达到肝脏代谢功能，特别是脂质代谢和线粒体活性。WD治疗可以 可归类为锌(锌)盐或铜络合剂。对这些疗法的不良反应需要肝脏 移植。成功治疗的一个主要挑战是缺乏依从性，这受到不良反应的影响。 副作用或繁琐的治疗计划。治疗有时会导致自相矛盾的神经学 恶化。考虑到这些挑战，对治疗有反应的生物标志物的知识将对 个性化的WD治疗。最近的工作，包括我们自己的工作，表明含锌的蛋白质是特定的 在WD中受到影响，肝脏的代谢过程也发生了变化，其中许多过程受到锌蛋白的调节。建议数 这项工作将建立在这一知识的基础上，以定义对WD治疗反应的候选生物标记物。我们会 在治疗研究中利用特征良好的WD小鼠模型来确定代谢物、基因表达 铜络合剂或锌处理诱导的肝脏和血清中的金属反应。该项目将执行 具体目标如下：1)确定铜络合剂或铜诱导的治疗反应代谢产物生物标志物 锌对WD ATP7B-/-小鼠模型的影响先前的工作已经确定了WD的候选生物标记物 老鼠和人类，但这些生物标记物指示了几种肝病。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记物。2)确定特定性别 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- 不同的铜和锌的动态平衡控制，表明了解WD是如何处理的很重要 因性别而有不同的影响。3)确定铜和锌在细胞健康中的相互作用。铜和锌之间的串扰是 定义不明确，可能比WD治疗更重要。这个目标将使用非WD肝癌细胞和 野生型小鼠模型，以确定铜螯合或锌补充的影响。此翻译 该项目将利用现有数据和一个新的、丰富的、特定于性别的代谢物、金属和细胞铜数据集- 锌的相互作用，以确定加强WD治疗的候选生物标记物。

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.