Function and Evolution of the Pregnane X Receptor (PXR)

描述（由申请人提供）：候选人：我的目标是追求一个职业生涯进行基础和应用研究在学术上强大的病理学系。我的长期目标是了解决定和调节药物代谢和消除的因素，并应用这些知识来帮助患者的临床管理。我目前的计划是研究胆烷X受体（PXR）的功能和结构，PXR是一种孤儿核激素受体，是胆盐，类固醇激素和异生物质代谢和排泄的“主调节器”。指导临床科学家发展奖是至关重要的，继续我的进步，成为一个独立的医生，科学家，并将使我能够开发和扩大我的项目，以及获得更具体的和指导培训肝脏代谢和计算生物学，特别是基于结构的分子建模和生物信息学。工作环境：匹兹堡大学在肝脏生物学和代谢，计算生物学和药物遗传学方面拥有非常强大的研究团队。导师Stephen Strom博士在研究哺乳动物（包括人类）的原代肝细胞以及内源性化合物和外源性物质诱导代谢酶方面拥有丰富的经验。二级导师卡洛斯卡马乔博士在蛋白质和蛋白质-配体相互作用的基于结构的建模方面拥有丰富的经验。研究项目：PXR被结构多样的异生物质和内源性配体激活。PXR的配体选择性的潜在因素还不完全清楚，预测PXR配体的计算机模型也很有限。我们已经确定了118胆盐和类固醇化合物在人类和斑马鱼PXR的详细浓度响应数据。我们建议使用四维定量构效关系分析和分子建模来确定PXR介导配体选择性的结构特征，并开发更好地预测配体与PXR相互作用的分子模型。

DESCRIPTION (provided by applicant): Candidate: My goal is to pursue a career conducting basic and applied research in an academically strong pathology department. My long-term goal is to understand the factors that determine and regulate drug metabolism and elimination and to apply that knowledge to aid clinical management of patients. My current plan is to investigate the function and structure of the pregnane X receptor (PXR), an orphan nuclear hormone receptor that is a 'master regulator' of bile salt, steroid hormone, and xenobiotic metabolism and excretion. The Mentored Clinical Scientist Development Award is critical to continue my progress towards becoming an independent physician-scientist and will allow me to develop and expand my project as well as gain more specific and mentored training in liver metabolism and computational biology, particularly structure-based molecular modeling and bioinformatics. Environment: The University of Pittsburgh has very strong research groups in liver biology and metabolism, computational biology, and pharmacogenetics. The mentor, Dr. Stephen Strom, has extensive experience with studies of primary hepatocytes from mammals, including humans, and of induction of metabolizing enzymes by endogenous compounds and xenobiotics. The secondary mentor, Dr. Carlos Camacho, has extensive experience with structure-based modeling of proteins and protein-ligand interactions. Research project: PXR is activated by structurally diverse xenobiotic and endogenous ligands. The factors underlying ligand selectivity of PXR are incompletely understood and in silico models to predict PXR ligands are limited. We have determined detailed concentration-response data for 118 bile salt and steroid compounds at human and zebrafish PXR. We propose to use four-dimensional quantitative structure-activity relationship analysis and molecular modeling to determine the structural features of PXR that mediate ligand selectivity and develop molecular models that better predict ligand interactions with PXR.