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. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Kurogi, Katsuhisa; Yoshihama, Maki; Horton, Austin et al. (2017) Identification and characterization of 5?-cyprinol-sulfating cytosolic sulfotransferases (Sults) in the zebrafish (Danio rerio). J Steroid Biochem Mol Biol 174:120-127
Steussy, B W; Capper, M; Krasowski, M D et al. (2016) Algorithms utilizing peripheral blood hematopoietic progenitor cell counts in lieu of some CD34+ cell counts predict successful peripheral blood stem cell collections with substantial time and cost savings. ISBT Sci Ser 11:153-162
Petrie, M; Lynch, K L; Ekins, S et al. (2013) Cross-reactivity studies and predictive modeling of ""Bath Salts"" and other amphetamine-type stimulants with amphetamine screening immunoassays. Clin Toxicol (Phila) 51:83-91
Fidler, Andrew E; Holland, Patrick T; Reschly, Erica J et al. (2012) Activation of a tunicate (Ciona intestinalis) xenobiotic receptor orthologue by both natural toxins and synthetic toxicants. Toxicon 59:365-72
Ekins, Sean; Williams, Antony J; Krasowski, Matthew D et al. (2011) In silico repositioning of approved drugs for rare and neglected diseases. Drug Discov Today 16:298-310
Krasowski, Matthew D; Ai, Ni; Hagey, Lee R et al. (2011) The evolution of farnesoid X, vitamin D, and pregnane X receptors: insights from the green-spotted pufferfish (Tetraodon nigriviridis) and other non-mammalian species. BMC Biochem 12:5
Kurogi, Katsuhisa; Krasowski, Matthew D; Injeti, Elisha et al. (2011) A comparative study of the sulfation of bile acids and a bile alcohol by the Zebra danio (Danio rerio) and human cytosolic sulfotransferases (SULTs). J Steroid Biochem Mol Biol 127:307-14
Ogawa, Shoujiro; Mitamura, Kuniko; Ikegawa, Shigeo et al. (2011) Chemical synthesis of the (25R)- and (25S)-epimers of 3ýý,7ýý,12ýý-trihydroxy-5ýý-cholestan-27-oic acid as well as their corresponding glycine and taurine conjugates. Chem Phys Lipids 164:368-77
Krasowski, Matthew D; Ni, Ai; Hagey, Lee R et al. (2011) Evolution of promiscuous nuclear hormone receptors: LXR, FXR, VDR, PXR, and CAR. Mol Cell Endocrinol 334:39-48
Hagey, Lee R; Lida, Takashi; Tamegai, Hideyuki et al. (2010) Major biliary bile acids of the medaka (Oryzias latipes): 25R- and 25S-epimers of 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid. Zoolog Sci 27:565-73

Showing the most recent 10 out of 40 publications