Function and Evolution of the Pregnane X Receptor (PXR)

候选人：我的目标是在学术实力雄厚的大学从事基础和应用研究。 病理科。我的长期目标是了解决定和调节药物的因素， 代谢和消除，并应用这些知识来帮助患者的临床管理。我现在的 计划是研究一种孤儿核受体-烷X受体（PXR）的功能和结构， 激素受体，是胆盐、类固醇激素和异生物质代谢的“主调节剂”， 排泄指导临床科学家发展奖是至关重要的，继续我的进展， 成为一名独立的物理学家，科学家，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指导性的培训，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代谢方面拥有非常强大的研究团队， 计算生物学和药物遗传学。导师斯蒂芬·斯特罗姆博士有着丰富的经验 通过研究哺乳动物（包括人类）的原代肝细胞， 内源性化合物和外源性物质对酶的影响。第二导师，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。的 PXR的配体选择性的潜在因素还不完全清楚，也没有计算机模型来预测PXR 配体是有限的。我们测定了118种胆盐和甾体的详细浓度-效应数据 化合物在人类和斑马鱼的PXR。我们建议使用四维定量结构-活性 关系分析和分子建模，以确定介导配体的PXR的结构特征 选择性和开发分子模型，更好地预测配体与PXR的相互作用。

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.