Request for Funding

Medical Student Research Fellowship for Summer 2004

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: physiology, genetics, and biochemistry of studies of human steroid biosynthesis and mineralocorticoid excess states

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 are also studying which of these enzymes contribute to peripheral androgen metabolism and lead to individual variations in androgen production. We study the genetics of steroid biosynthesis, mainly patients with mutations in CYP17 causing 17-hydroxylase deficiency or in subjects with 17 -hydroxysteroid type 3 deficiency. In addition, projects on steroidogenic cytochrome P450 monooxygenases are being performed by senior members of the laboratory, and students may be able to 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. 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.
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 first-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).
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).
David Stidd, MS2, 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, a senior at Duke University, was a SURF student in 2003. He engineered mutations to change the directional preference of AKR1C9 (rat liver 3 -hydroxysteroid dehydrogenase).
Siareyah Rambally, MS1, 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.

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