Nuclear Receptor Dysfunction Reprograms Metabolism and Cellular Proliferation in Wilson's Disease

项目总结 肝豆状核变性是一种常染色体隐性遗传病，由铜转运蛋白基因突变引起。 类型ATPase，ATP7B，导致铜过度堆积，主要是在肝脏和大脑。高程 游离铜导致氧化应激和线粒体功能障碍、炎症、脂肪变性、纤维化和 肝硬变。肝豆状核变性的治疗仅限于螯合疗法或锌疗法，通常与 副作用很多。ATP7B-/-小鼠表现出肝豆状核变性进行性肝脏病理的特征 病人。通过使用在肝脏和肠道中表达的特定核受体，我们将解决转录 和代谢变化来了解铜是如何重新编程代谢和细胞信号通路的 在ATP7B-/-小鼠的肝脏中。缺乏明确的治疗靶向分子机制代表了 在我们对肝病的科学理解上的一个关键差距。我们在ATP7B-/-小鼠身上的初步数据显示 肝脏动态变化的代谢性核受体活性和靶基因表达降低 代谢成分。我们还发现，老年ATP7B-/-小鼠的肝脏结节形成加剧 通过在ATP7B-/-小鼠中缺失PXR。这些发现表明，重新编程的新陈代谢和细胞周期 调节导致ATP7B-/-小鼠的肝脏表型，并与其他慢性肝病重叠。 理论基础：确定铜离子毒性的分子靶点将为WD的治疗提供新的治疗靶点。 我们提议的研究将检验中心假设：铜++-妥协PXR活性并促进肝脏 肝豆状核变性的功能障碍。

PROJECT SUMMARY Wilson’s disease is an autosomal recessive disorder caused by mutations in the copper-transporting P- type ATPase, ATP7b, resulting in excessive copper accumulation primarily in the liver and brain. Elevation of free copper leads to oxidative stress and mitochondrial dysfunction, inflammation, steatosis, fibrosis, and cirrhosis. Treatments for Wilson’s disease are limited to chelation or zinc therapies and often associated with many side effects. Atp7b-/- mice exhibit hallmarks of the progressive liver pathology present in Wilson’s disease patients. By using specific nuclear receptors expressed in the liver and intestine, we will address transcriptomic and metabolomic changes to understand how copper reprograms the metabolic and cellular signaling pathways in the liver of Atp7b-/- mice. The lack of well-defined molecular mechanisms for therapeutic targeting represents a critical gap in our scientific understanding of liver disease. Our preliminary data in Atp7b-/- mice revealed decreased metabolic nuclear receptor activity and target gene expression that dynamic changes in hepatic metabolic composition. We also discovered that hepatic nodule formation in older Atp7b-/- mice is exacerbated by deletion of PXR in Atp7b-/- mice. These findings suggest that reprogrammed metabolism and cell cycle regulation contribute to the hepatic phenotype of Atp7b-/- mice, and overlap other chronic hepatic disorders. Rationale: definition of molecular targets of Cu++ toxicity will provide novel therapeutic targets for WD treatment. Our proposed studies will test the central hypothesis: Cu++-compromises PXR activities and promotes liver dysfunction in Wilson’s disease.