An essential event in regulated steroidogenesis is the acute response of steroidogenic cells to trophic hormones; this response predominantly reflects increased delivery of cholesterol substrate to the cholesterol side-chain cleavage enzyme (Cyp11a) in the inner mitochondrial membrane. The essential role of the Steroidogenic Acute Regulatory protein (STAR) in cholesterol translocation has been revealed by humans with congenital lipoid adrenal hyperplasia (lipoid CAH) and by StAR knockout (STAR KO) mice. There are two divergent models of StAR action: that it acts at the outer mitochondrial membrane, perhaps undergoing a conformational change that facilitates cholesterol translocation, or that it shuttles cholesterol between the outer mitochondrial membrane and the steroidogenic complex in the inner membrane. We believe that the former model--based largely on transfection studies in non-steroidogenic COS cells--reflects aberrant effects of StAR over-expression in non-steroidogenic cells. We further hypothesize that induction of steroidogenesis in bona fide steroidogenic cells will require mitochondrial targeting of STAR. To address this question, we will analyze StAR function in immortalized cell lines derived from StAR KO mice. These cell lines also will provide a unique system to explore other aspects of StAR structure and function within the context of steroidogenic cells. Results that provide novel insights into StAR function will be verified in vivo by transgenic rescue of StAR KO mice via BAC transgenesis. Finally, recent studies suggest that the vertebrate brain produces a series of steroid derivatives--termed neurosteroids--that play important roles in processes such as memory, stress response, seizure threshold, and anxiety; we propose to generate CNS-specific StAR KO mice, thereby providing a unique opportunity to define the role of StAR in neurosteroid production. Collectively, these studies will provide novel insights into the function of this essential component of regulated steroidogenesis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054028-06
Application #
6990489
Study Section
Endocrinology Study Section (END)
Program Officer
Margolis, Ronald N
Project Start
1998-06-25
Project End
2007-11-30
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
6
Fiscal Year
2006
Total Cost
$304,668
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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King, Steven R; Manna, Pulak R; Ishii, Tomohiro et al. (2002) An essential component in steroid synthesis, the steroidogenic acute regulatory protein, is expressed in discrete regions of the brain. J Neurosci 22:10613-20
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Stallings, Nancy R; Hanley, Neil A; Majdic, Gregor et al. (2002) Development of a transgenic green fluorescent protein lineage marker for steroidogenic factor 1. Mol Endocrinol 16:2360-70
Zhao, L; Bakke, M; Krimkevich, Y et al. (2001) Hypomorphic phenotype in mice with pituitary-specific knockout of steroidogenic factor 1. Genesis 30:65-9
Hasegawa, T; Zhao, L; Caron, K M et al. (2000) Developmental roles of the steroidogenic acute regulatory protein (StAR) as revealed by StAR knockout mice. Mol Endocrinol 14:1462-71
Dellovade, T L; Young, M; Ross, E P et al. (2000) Disruption of the gene encoding SF-1 alters the distribution of hypothalamic neuronal phenotypes. J Comp Neurol 423:579-89

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