Function and Evolution of the Pregnane X Receptor (PXR)

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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.