Nuclear Receptors as Novel Therapeutic Targets for Wilson’s Disease

项目总结/摘要 这个建议的目的是扩大我的训练，作为一个独立的科学家在分子领域， 肝脏学和发现肝代谢核受体调节机制。为此，我 我选择了贝勒医学院的分子和细胞生物学系来继续我的过渡 成为学术机构的独立调查员该提案概述了广泛的 研究战略，由几个培训领域补充，其中包括几个直接课程 与我在具体目标1中的学习有关，与我的初级教师研究委员会会议，以及出席和 在整个德州医疗中心参加多个研讨会。我的研究策略将决定 Wilson病动物模型（Atp 7 b-/-小鼠）中核受体结合的全基因组变化。 Wilson病是一种常染色体隐性遗传疾病，由Cu- 转运P型ATP酶，ATP 7 b，导致各种症状，包括肝铜 肝硬化、肝衰竭和神经功能障碍。威尔逊的治疗 疾病的治疗仅限于螯合疗法、锌疗法或肝移植。螯合疗法一直是 与一些副作用和患者依从性差相关，并且可导致不受控制的威尔逊病 肝衰竭患者需要肝移植才能生存。尽管威尔逊氏病很严重， 关于铜介导的代谢变化的认识是有限的。我的博士后研究建立了一个 Atp 7 b-/-小鼠和威尔逊病患者的核受体活性缺陷。建议的K 01 实验继续这些研究，以确定核受体启动子占有率的更广泛变化 和靶基因mRNA表达，以及测试靶向核受体是否会降低肝脏 在Atp 7 b-/-小鼠中观察到的病理学。

Project Summary/Abstract The goal of this proposal is to extend my training as an independent scientist in the field of molecular hepatology and discover mechanisms of nuclear receptor regulation of hepatic metabolism. To this end, I have selected the Molecular and Cellular Biology Department at Baylor College of Medicine to continue my transition to become an independent investigator at an academic institution. This proposal outlines an extensive Research Strategy that is complemented by several areas of training, which includes several courses directly related to my studies in Specific Aim 1, meeting with my junior faculty research committee, and attendance and participation of multiple seminars throughout the Texas Medical Center. My Research Strategy will determine whole genomic-changes in nuclear receptor binding in a Wilson's disease animal model (Atp7b-/- mouse). Wilson's disease is an autosomal recessive disorder caused by loss of function mutations in the Cu- transporting P-type ATPase, ATP7b, which results in a variety of symptoms, including hepatic copper accumulation, cholestasis, cirrhosis, liver failure, and neurological dysfunction. Treatments for Wilson's disease are limited to chelation therapy, zinc therapy, or liver transplantation. Chelation therapy has been associated with several side-effects and poor patient compliance, and uncontrolled Wilson's disease can result in liver failure and requires liver transplantation for patient survival. Despite the severity of Wilson's disease, insights regarding copper-mediated changes in metabolism are limited. My post-doctoral studies established a defect in nuclear receptor activity in the Atp7b-/- mouse and Wilson's disease patients. The proposed K01 experiments continue those studies to determine the broader changes in nuclear receptor promoter occupancy and target gene mRNA expression, as well as test if targeting the nuclear receptors decreases the liver pathology observed in the Atp7b-/- mouse.