Loss of libido is a significant medical problem and results in a profound diminution of life and many patient visits to the urologist. In part, male sexual drive requires the synthesis of testosterone mediated by the steroidogenic acute regulatory (StAR) protein in testicular Leydig cells. Interestingly, the enzymes responsible for steroidogenesis in the Leydig cell are also present in neuronal and glial cell types of the brain. This leads to the intriguing possibility that steroids locally produced in the brain (neurosteroids) could be involved in the regulation of libido, as well. In fact, administration of neurosteroids in the brain has been shown to affect sexual behavior in rodents. Therefore, we plan to investigate whether hormone-regulated neurosteroids are critical for libido. Recently, mRNA encoding the hormone-regulated StAR protein, was detected in the brain. This gives us an exciting chance to more directly assess the functional role of neurosteroids by developing a model whereby we eliminate StAR protein expression and thus, steroid production in the brain, without affecting steroid synthesis in the gonads and the adrenal gland. Selectivity will be accomplished by using a Cre-lox tissue-specific knockout strategy. We propose to use this model to test the hypothesis that while gonadal steroids are permissive, StAR-dependent neurosteroid synthesis in the brain has an essential physiologic role in libido. Therefore, to test the hypothesis that StAR-mediated neurosteroid synthesis is essential for libido, I propose to both define the pathways involved in neurosteroid biosynthesis in the brain (especially in structures important for libido) and the regulation of StAR by immunohistochemisry, in vitro assays, and other biochemical techniques, and to generate a conditional StAR-knockout mouse model to examine effects on the brain and sexual behavior during and after development and in aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK061548-03
Application #
6781699
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2002-09-30
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$129,839
Indirect Cost
Name
Baylor College of Medicine
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
LaVoie, Holly A; Whitfield, Nicole E; Shi, Bo et al. (2014) STARD6 is expressed in steroidogenic cells of the ovary and can enhance de novo steroidogenesis. Exp Biol Med (Maywood) 239:430-5
King, Steven R (2008) Emerging roles for neurosteroids in sexual behavior and function. J Androl 29:524-33
Bhangoo, Amrit; Anhalt, Henry; Ten, Svetlana et al. (2006) Phenotypic variations in lipoid congenital adrenal hyperplasia. Pediatr Endocrinol Rev 3:258-71
Manna, Pulak R; Chandrala, Syam P; King, Steven R et al. (2006) Molecular mechanisms of insulin-like growth factor-I mediated regulation of the steroidogenic acute regulatory protein in mouse leydig cells. Mol Endocrinol 20:362-78
King, S R; Smith, A G A; Alpy, F et al. (2006) Characterization of the putative cholesterol transport protein metastatic lymph node 64 in the brain. Neuroscience 139:1031-8
Jo, Youngah; King, Steven R; Khan, Shafiq A et al. (2005) Involvement of protein kinase C and cyclic adenosine 3',5'-monophosphate-dependent kinase in steroidogenic acute regulatory protein expression and steroid biosynthesis in Leydig cells. Biol Reprod 73:244-55
Rommerts, F F G; Kuhne, L; van Cappellen, G W A et al. (2004) Specific dose-dependent effects of ethane 1,2-dimethanesulfonate in rat and mouse Leydig cells and non-steroidogenic cells on programmed cell death. J Endocrinol 181:169-78
King, S R; Matassa, A A; White, E K et al. (2004) Oxysterols regulate expression of the steroidogenic acute regulatory protein. J Mol Endocrinol 32:507-17
King, Steven R; Ginsberg, Stephen D; Ishii, Tomohiro et al. (2004) The steroidogenic acute regulatory protein is expressed in steroidogenic cells of the day-old brain. Endocrinology 145:4775-80