Medical Student Research Fellowship for Summer 2005

Mentor: Richard J. Auchus
Department: Internal Medicine/Endocrinology & Metabolism
Room number: Y9.308
Mail Code: 8857
Phone number: 8-6751
E-mail: richard.auchus@UTSouthwestern.edu
Project title: biochemistry, physiology, and genetics of human steroid biosynthesis

Human subjects IRB approved project number (where applicable): 0902-505, 1203-776, 1203-811

Animal subjects IRB approved project number (where applicable): N/A

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)

basic research and patient-based research

Brief Description of Project:

Basic:
We are interested in determining the biochemical principles and structural features that govern how hydroxysteroid dehydrogenases function in living cells as primarily oxidative or reductive enzymes. This project involves site-directed mutagenesis and modification of tissue culture conditions to alter the directional preference of these enzymes in vivo. We then perform detailed in vivo and in vitro enzymology studies of the altered enzymes to understand why these changes are observed. Other projects related to peripheral androgen metabolism, the genetics of steroid biosynthesis, and steroidogenic cytochrome P450 monooxygenases are also in progress, and students may participate in these projects as well.

Clinical:
We participate in ongoing clinical trials to study the genetics, biochemistry, and physiology of mineralocorticoid-dependent hypertension, particularly primary hyperaldosteronism and 17-hydroxylase deficiency in collaboration with Ronald Victor in the Hypertension Division. These studies include pharmacologic challenges, hormone profiling, and measurement of analytes in adrenal vein specimens in hypertensive subjects.

Previous Research Activities or Publications with Medical Students:
Tim C. Lee (now a pediatrics resident at UCLA) worked with me for a year after graduating college and during the summer after his first year in medical school (1996-1998). He and I developed our yeast system for studying enzymology of steroidogenic cytochromes P450 (Auchus et al 1998 J Biol Chem 273:3158-3165; Lee et al 1999 J Clin Endocrinol Metab 84:2104-2110). Tim received the Academic Pediatric Society/Society for Pediatric Research (APS/SPR) Student Research Award in 1999 for this work. Tim is now chief resident in pediatrics at UCLA.
Kavita Vyas, worked in my lab the summer of 2000, characterizing the biochemistry of fusion proteins to probe the mechanism of action of cytochrome b5 on CYP17. Kavita won the award for best poster at the 39th Medical Student Research Forum, which was presented at the Endocrine Society meeting in June 2001, and she is now a second-year medical student at Columbia.
Daniel Sherbet, MS3, worked in my lab for 2 summers (2001-2002, characterizing a mutation in CYP17 that causes isolated 17, 20-lyase deficiency by a novel mechanism. Daniel's oral presentation at the 40th Medical Student Research Forum was selected as the best talk of the day. The work was presented at the Endocrine Society meeting in June, 2002 and published (Sherbet et al J Biol Chem 278:48563-48569). Daniel is now a medical student research Fellow of the Howard Hughes Medical Institute for a year while he studies hydroxysteroid dehydrogenases.
Kristen Bruce, studied (-)-progesterone (the enantiomer of progesterone) as an inhibitor of CYP17 and CYP21 in 2001 and started our work on HSD directionality. Her work on (-)-progesterone was published (Auchus et al Arch Biochem Biophys 409:134-144). She is now in dental school.
David Stidd, MS3, worked here in 2003. He synthesized deuterium-labeled steroids to measure kinetic isotope effects for CYP17 and CYP21. David won an award for best basic science poster at the 42nd Medical Student Research Forum,
Andrew Brandmeier was a SURF student in 2003. He engineered mutations to change the directional preference of AKR1C9 (rat liver 3 -hydroxysteroid dehydrogenase). He is now an MD-PhD student at Indiana University.
Siareyah Rambally, MS2, identified a mutation in a patient with 17 -hydroxysteroid type 3 deficiency in 2003. She also demonstrated that the magnitude of the directional preference for human 17 -hydroxysteroid type 1 in transfected cells was not fixed but could be varied by changes in culture medium that alter intracellular nicotinamide cofactor concentrations.
We are preparing manuscripts for David, Andrew, and Siareyah's work this spring.

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