THE ROLE OF HUMAN PXR IN ANTI-TUBERCULOSIS DRUG-INDUCED LIVER INJURY

人类 PXR 在抗结核药物引起的肝损伤中的作用

• 批准号: 8360787
• 负责人: Xiaochao Ma
• 金额: $ 21.17万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-02 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360787
• 关键词: Antitubercular Agents; Bile Acids; Disease; Funding; Genetically Engineered Mouse; Grant; Health; Human; Injury; Knockout Mice; Knowledge; Liver; Mediating; Mediator of activation protein; Metabolic Diseases; Metabolism; Mus; National Center for Research Resources; Nuclear Receptors; Pharmaceutical Preparations; Principal Investigator; Receptor Activation; Research; Research Infrastructure; Resources; Rifampin; Role; Safety; Source; Testing; Toxic effect; United States National Institutes of Health; Work; base; chemotherapy; cost; innovation; isoniazid; metabolomics; mouse model; novel strategies; pregnane X receptor; prevent; tuberculosis drugs

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Drug-induced liver injury is a major safety issue in anti-tuberculosis chemotherapy. The objective of this project is to investigate the mechanisms of liver injury associated with rifampicin and isoniazid co-therapy and to develop novel strategies to manage rifampicin and isoniazid induced liver injury. By using pregnane X receptor (PXR)-humanized mice, our preliminary studies identified that human PXR is essential in rifampicin and isoniazid induced liver injury. Our central hypothesis is that rifampicin-mediated human PXR activation disturbs the metabolism of isoniazid and bile acids, and these metabolic disorders result in the liver injury caused by rifampicin and isoniazid co-therapy. In order to test our hypothesis, we will utilize the genetically engineered mouse models (Pxr-null, PXR-humanized, and Cyp3a-null mice) and the LC-MS-based metabolomic approach to pursue the following specific aims: (1). Determine the importance of Cyp3a in rifampicin and isoniazid induced liver injury. (2). Define the effects of rifampicin-mediated PXR activation on isoniazid metabolism and disposition, and determine the mechanism of rifampicin-boosted isoniazid toxicity. (3). Define the effect of rifampicin and isoniazid co-treatment on bile acid metabolism, and determine its contribution in rifampicin and isoniazid induced cholestatic injury. This work is innovative in that human PXR is identified as an essential mediator of rifampicin and isoniazid induced liver injury. Successful completion of this project will greatly enhance our knowledge on rifampicin and isoniazid induced liver injury which will be applied towards predicting, preventing, and treating the liver injury caused by rifampicin and isoniazid co-therapy.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 药物性肝损伤是抗结核化疗的一个主要安全问题。 该项目的目的是研究利福平和异烟肼联合治疗相关的肝损伤机制，并制定治疗利福平和异烟肼引起的肝损伤的新策略。 通过使用孕烷X受体（PXR）人源化小鼠，我们的初步研究发现人PXR在利福平和异烟肼诱导的肝损伤中至关重要。 我们的中心假设是利福平介导的人体 PXR 激活扰乱了异烟肼和胆汁酸的代谢，这些代谢紊乱导致利福平和异烟肼联合治疗引起的肝损伤。 为了检验我们的假设，我们将利用基因工程小鼠模型（Pxr-null、PXR-人源化和 Cyp3a-null 小鼠）和基于 LC-MS 的代谢组学方法来实现以下具体目标：（1）。确定 Cyp3a 在利福平和异烟肼诱导的肝损伤中的重要性。 （2）。定义利福平介导的 PXR 激活对异烟肼代谢和处置的影响，并确定利福平增强异烟肼毒性的机制。 （3）。明确利福平和异烟肼联合治疗对胆汁酸代谢的影响，并确定其在利福平和异烟肼引起的胆汁淤积损伤中的作用。 这项工作的创新之处在于，人类 PXR 被确定为利福平和异烟肼诱导的肝损伤的重要介质。 该项目的成功完成将大大提高我们对利福平和异烟肼所致肝损伤的认识，并将其应用于利福平和异烟肼联合治疗引起的肝损伤的预测、预防和治疗。