Copper Homeostasis and Liver Function

铜稳态和肝功能

• 批准号: 9925227
• 负责人: JAMES P HAMILTON
• 金额: $ 50.65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925227
• 关键词: Acute Liver Failure; Affect; Age; Agonist; Animals; Basic Science; Cells; Child; Clinical; Copper; Copper Chelation; Data; Defect; Detection; Deterioration; Development; Diagnosis; Diet; Disease; Down-Regulation; Dyslipidemias; Environment; Fatty Liver; Gene Expression Regulation; Genetic; Genetic Transcription; Goals; Hepatic; Hepatocyte; Hepatolenticular Degeneration; Homeostasis; Human; Inflammatory; Inflammatory Response; Knock-out; Kupffer Cells; LXRalpha protein; Laboratories; Life; Lipids; Liver; Liver diseases; Longevity; Malignant neoplasm of gastrointestinal tract; Maps; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Metallothionein; Modeling; Modernization; Molecular; Monitor; Morphology; Mus; Mutation; Neurologic; Nuclear Receptors; Oxidation-Reduction; Pathogenesis; Pathogenicity; Pathology; Pharmaceutical Preparations; Phenotype; Population; RXR; Risk; Role; Signal Pathway; Signal Transduction; Symptoms; Testing; Therapeutic Effect; Tissues; Up-Regulation; Update; Wilson disease protein; Work; base; bench to bedside; chelation; cholesterol biosynthesis; clinically relevant; compliance behavior; cost; disease diagnosis; experimental study; improved; in vivo; intrahepatic; lipid metabolism; liver function; liver inflammation; liver transplantation; mouse model; nervous system disorder; novel; novel strategies; novel therapeutic intervention; novel therapeutics; receptor; response; restoration; side effect; tool; young adult

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.

该合作项目结合了三个实验室的努力，并具有互补的专业知识，以阐明组织对遗传诱导的铜失衡反应的基本机制。本研究的总体长期目标是产生必要的信息，用于开发治疗威尔逊病（WD）和其他与肝脏铜失衡相关的疾病的新方法。WD是由铜转运蛋白ATP 7 B失活突变引起的潜在致死性肝神经系统疾病。该疾病与肝脏中的铜过载以及显著的代谢和转录变化有关。症状的大变异性，以及对铜螯合的缓慢且通常次优的反应使诊断和治疗复杂化。为了制定克服这些持续挑战的战略，提出了三个具体目标。目标1下的研究将确定Atp 7 b ΔHep小鼠（Atp 7 b的肝细胞特异性缺失）中肝脏病理学降低的分子基础，与！Atp 7 b-/-小鼠（Atp 7 b的整体敲除）。这将通过比较肝细胞的氧化还原环境来完成，研究Atp 7 b ΔHep小鼠中的炎症反应是否可以通过富含Cu的饮食诱导，或者通过替代非实质肝细胞来减少Atp 7 b-/-小鼠中的炎症反应。目的二是探讨铜依赖性糖尿病的发病机制。这将通过表征Atp 7 b ΔHep肝细胞中升高的Cu的细胞内分布，鉴定Atp 7 b ΔHep小鼠中受Cu过载影响的信号传导和代谢途径，并将这些参数与Atp 7 b-/-肝脏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在Atp 7 b-/-小鼠中有益作用的分子基础。这些实验将确定通过药物治疗改变的代谢和信号传导途径，并确定如果在疾病晚期开始治疗是否可以实现有益效果。该实验结果有望显著更新Wilson病发病机制的现有模型，并为Cu超载疾病的新治疗方法提供基础。