Function and Evolution of the Pregnane X Receptor (PXR)

应聘者：我的目标是从事基础性和应用性研究，在一个学术水平很高的国家 病理科。我的长期目标是了解决定和规范药物的因素 新陈代谢和排泄，并应用这些知识来帮助患者的临床管理。我目前的情况 计划研究孤儿核孕烷X受体(PXR)的功能和结构 荷尔蒙受体是胆盐、类固醇激素和外源新陈代谢的主要调节器。 排泄物。导师临床科学家发展奖是我继续取得进展的关键 成为一名独立的内科科学家，这将使我能够发展和扩大我的项目以及 在肝脏代谢和计算生物学方面获得更具体和有指导的培训，特别是 基于结构的分子建模和生物信息学。 环境：匹兹堡大学在肝脏生物学和新陈代谢方面拥有非常强大的研究小组， 计算生物学和药物遗传学。导师斯蒂芬·斯特罗姆博士拥有丰富的经验 对包括人类在内的哺乳动物的原代肝细胞和诱导代谢的研究 内源化合物和外源化合物所致的酶。副导师卡洛斯·卡马乔博士 在基于结构的蛋白质建模和蛋白质-配体相互作用方面有丰富的经验。 研究项目：PXR被结构不同的外源和内源性配体激活。这个 PXR配体选择性的潜在因素还不完全清楚，并在计算机模型中预测PXR 配体是有限的。我们已经测定了118种胆盐和类固醇的详细浓度反应数据。 人类和斑马鱼PXR的化合物。我们建议使用四维定量结构-活性 用关系分析和分子模拟确定PXR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。

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.