Nuclear Receptors as Novel Therapeutic Targets for Wilson’s Disease

核受体作为威尔逊病的新治疗靶点

基本信息

批准号：
9437798
负责人：
Clavia Ruth Wooton-Kee
金额：
$ 14.9万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-17 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9437798
关键词：
ATP phosphohydrolase Adverse effects Animal Disease Models Animal Model Area Autophagocytosis Binding ChIP-seq Chelation Therapy Cholestasis Cirrhosis Complement Copper Correlative Study Cysteine Defect Diabetes Mellitus Diagnosis Dietary Zinc Disease Disease Progression Disease model Drug Metabolic Detoxication Dyslipidemias Functional disorder Future Gene Expression Gene Targeting Genomics Goals Hepatic Hepatolenticular Degeneration Hepatology Homeostasis Impairment Institution Ligands Ligation Link Lipids Liver Liver Dysfunction Liver Failure Liver diseases Lysosomes Mediating Medical center Medicine Metabolic Metabolism Mitochondria Molecular Molecular and Cellular Biology Mus Neurologic Dysfunctions Nuclear Receptors Nutrient Oxidative Stress PPAR alpha Pathology Pathway interactions Patients Postdoctoral Fellow Primary biliary cirrhosis RXR Regulation Reporting Research Research Personnel Response Elements Role Scientist Severities Signal Pathway Signal Transduction Symptoms Testing Texas Therapeutic Toxic effect Training Zinc acetaminophen overdose bile duct college compliance behavior dietary excess experimental study faculty research improved insight liver injury liver metabolism liver transplantation loss of function mutation mRNA Expression meetings mouse model new therapeutic target nonalcoholic steatohepatitis novel novel strategies predictive test promoter receptor binding receptor function response stress reduction therapeutic target transcriptome transcriptome sequencing whole genome

项目摘要

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.

项目概要/摘要该提案的目标是扩展我作为分子领域独立科学家的培训肝病学并发现核受体调节肝脏代谢的机制。为此，我有选择贝勒医学院分子和细胞生物学系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策略辅以多个培训领域，其中直接包括几门课程与我在具体目标 1 中的研究、与我的初级教师研究委员会的会议以及出席和参加整个德克萨斯医学中心的多个研讨会。我的研究策略将决定威尔逊病动物模型（Atp7b-/- 小鼠）中核受体结合的整个基因组变化。威尔逊氏病是一种常染色体隐性遗传病，由 Cu- 功能缺失突变引起。转运 P 型 ATP 酶 ATP7b，导致多种症状，包括肝铜蓄积、胆汁淤积、肝硬化、肝功能衰竭和神经功能障碍。威尔逊氏病的治疗疾病仅限于螯合疗法、锌疗法或肝移植。螯合疗法已与多种副作用和患者依从性差有关，并且可能导致威尔逊氏病不受控制肝功能衰竭，需要肝移植才能使患者生存。尽管威尔逊氏病很严重，关于铜介导的代谢变化的见解是有限的。我的博士后研究建立了 Atp7b-/- 小鼠和威尔逊病患者的核受体活性缺陷。拟议的K01 实验继续这些研究以确定核受体启动子占据的更广泛的变化和靶基因 mRNA 表达，以及测试针对核受体是否会降低肝脏功能在 Atp7b-/- 小鼠中观察到的病理学。