Copper Homeostasis and Liver Function

这个合作项目结合了三个拥有互补专业知识的实验室的努力，以阐明组织对遗传诱导的铜失衡做出反应的基本机制。这项研究的主要长期目标是产生必要的信息，以开发治疗肝豆状核变性(WD)和其他与肝脏铜失衡相关的疾病的新方法。WD是一种潜在的致命的肝神经疾病，由铜转运蛋白ATP7B的失活突变引起。这种疾病与肝脏中的铜超载以及显著的代谢和转录变化有关。症状的很大变异性，以及对铜螯合反应缓慢且往往不理想，使诊断和治疗都变得复杂。为了制定克服这些持续挑战的战略，提出了三个具体目标。AIM 1下的研究将确定ATP7BΔHEP小鼠肝脏病理减轻的分子基础(肝细胞特异性ATP7B缺失)与！ATP7B-/-小鼠(ATP7B的全球敲除)。这将通过比较肝细胞的氧化还原环境来完成，研究是否可以通过富铜饮食诱导ATP7BΔHEP小鼠的炎症反应，或者是否可以通过替换非实质肝细胞来减轻ATP7B-/-小鼠的炎症反应。在第二个目标中，我们将探讨铜依赖降血脂的机制。这将通过表征铜在ATP7BΔHEP肝细胞中的细胞内分布，确定铜超载对ATP7BΔHEP小鼠的信号和代谢途径的影响，并将这些参数与ATP7B/-肝中的参数进行比较来完成。目标3下的实验将确定核受体激动剂T0901317对ATP7B-/-小鼠有益效果的分子基础。这些实验将确定药物治疗所改变的代谢和信号通路，并确定如果在疾病晚期开始治疗是否可以达到有益的效果。这些实验结果有望极大地更新目前关于肝豆状核变性发病机制的模型，并为铜超载疾病的新的治疗方法提供基本依据。

This collaborative project combines efforts of three laboratories with complementary expertise to elucidate the fundamental mechanisms underlying tissue response to a genetically-induced copper misbalance. The overarching, long-term goal of this study is to generate information necessary for the development of novel approaches to treatment of Wilson disease (WD) and other disorders associated with copper misbalance in the liver. WD is a potentially lethal hepato-neurologic disease caused by inactivating mutations in the copper transporter ATP7B. The disease is associated with copper overload in the liver and significant metabolic and transcriptional changes. A large variability in symptoms, as well as slow and often suboptimal response to copper chelation complicate both diagnosis and treatment. To develop strategies overcoming these persistent challenges, three specific aims are proposed. Studies under Aim 1 will identify the molecular basis for reduced liver pathology in Atp7bΔHep mice (hepatocyte-specific deletion of Atp7b) compared to! Atp7b-/-mice (global knockout of Atp7b). This will be done by comparing the redox environment of liver cells, investigating whether the inflammatory response in Atp7bΔHep mice can be induced by a Cu-enriched diet, or be diminished in Atp7b-/- mice by the replacement of non-parenchymal liver cells. In Aim 2, we will investigate the mechanism of Cu- dependent dis-lipidemic. This will be done by characterizing the intracellular distribution of elevated Cu in Atp7bΔHep hepatocytes, identifying the signaling and metabolic pathways affected by Cu overload in Atp7bΔHep mice and comparing these parameters to those in Atp7b-/- livers. Experiments under Aim 3 will define the molecular basis for the beneficial effects of the nuclear receptor agonist T0901317 in Atp7b-/- mice. The experiments will determine the metabolic and signaling pathways that are altered by the treatment with the drug and determine whether beneficial effect can be achieved if treatment is initiated at the late disease stage. The results of the proposed experiments are expected to significantly update the current model of Wilson disease pathogenesis, and provide a fundamental basis for new therapeutic approaches to diseases of Cu overload.