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ROLE OF BENZODIAZEPINE RECEPTOR IN LEYDIG CELL FUNCTION

Award Number: R01ES007747
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/1995
PERIOD OF PERFORMANCE END DATE: 11/30/2011

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ROLE OF BENZODIAZEPINE RECEPTOR IN LEYDIG CELL FUNCTION - DESCRIPTION (provided by applicant): The precise mechanism by which LH accelerates the transport of the substrate cholesterol from the cytosol to the inner mitochondrial membrane, the rate-determining step in steroidogenesis, is unknown. The mitochondrial high affinity cholesterol binding protein peripheral-type benzodiazepine receptor (PBR) and the hormone-induced cytosolic steroidogenic acute regulatory protein (StAR) were found to function in a coordinated manner to transfer cholesterol into mitochondria. We recently demonstrated that in Leydig cells the StAR-induced cholesterol import into mitochondria is mediated by PBR. Based on these findings we hypothesize that changes in the structure and levels of PBR determine the amount of StAR-mobilized cholesterol available for testosterone synthesis. We will test this hypothesis with 3 Specific Aims. In Aim 1, we will determine how changes in PBR structure affect cholesterol transport. Using biophysical techniques coupled with studies of in vitro reconstituted wild-type and mutant PBR, we will investigate the sequence of molecular events involved in the transfer of cholesterol mobilized by StAR to the cytochrome P450scc via PBR. In Aim 2, we will investigate the impact of PBR and StAR inactivation on cholesterol transport and steroidogenesis. PBR and StAR structure-based drug design identified lead compounds that target the cholesterol-binding domains of these proteins and inhibit steroidogenesis. The specificity of these in vitro effects and the in vivo effect of these compounds on steroid synthesis will be investigated. In Aim 3, we will test the hypothesis that the steroidogenic potential of Leydig cells is dictated by PBR protein levels, which in turn, are primarily regulated by PBR gene transcription. In search of molecules inhibiting PBR gene expression and steroidogenesis, we identified peroxisome proliferators (PPs), environmental agents known to exert testis-specific toxic effects. In vitro gene transcription and in vivo studies using transgenic mice showing restricted Leydig cell expression of the PBR gene promoter will be used to understand PBR expression and steroidogenesis in normal testes and testes exposed to the toxic effects of PPs. These studies should provide detailed understanding of the role of PBR and PBR-StAR interaction in cholesterol transport and steroidogenesis, and lead to better understanding of how environmental toxicants might function to elicit male reproductive pathologies as well as to therapies for such pathologies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2011 ( Subtotal = $233,401 )
2011	2011	RESEARCH INSTITUTE OF THE MCGILL UNIVERSITY HEALTH CTR	tgnih07.05	MONTREAL				CAN	Environmental Health	000	16	12/1/2010	NON-COMPETING CONTINUATION	$212,183
2011	2011	RESEARCH INSTITUTE OF THE MCGILL UNIVERSITY HEALTH CTR	tgnih07.05	MONTREAL				CAN	Environmental Health	001	16	6/3/2011	NON-COMPETING CONTINUATION	$21,218
														Subtotal = $233,401

Issue Date FY: 2010 ( Subtotal = $235,759 )
2010	2010	MC GILL UNIVERSITY HEALTH CTR RES INST	tgnih07.05	MONTREAL				CAN	Environmental Health	001	15	5/17/2010	NON-COMPETING CONTINUATION	$21,433
2010	2010	MC GILL UNIVERSITY HEALTH CTR RES INST	tgnih07.05	MONTREAL				CAN	Environmental Health	000	15	12/1/2009	NON-COMPETING CONTINUATION	$214,326
														Subtotal = $235,759

Issue Date FY: 2009 ( Subtotal = $238,140 )
2009	2009	MC GILL UNIVERSITY HEALTH CTR RES INST	tgnih07.05	MONTREAL				CAN	Environmental Health	001	14	3/20/2009	NON-COMPETING CONTINUATION	$23,814
2009	2009	MC GILL UNIVERSITY HEALTH CTR RES INST	tgnih07.05	MONTREAL				CAN	Environmental Health	000	14	12/2/2008	NON-COMPETING CONTINUATION	$214,326
														Subtotal = $238,140

Issue Date FY: 2007 ( Subtotal = $349,200 )
2007	2007	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Environmental Health	000	12	12/1/2006	COMPETING CONTINUATION	$349,200
														Subtotal = $349,200

Issue Date FY: 2005 ( Subtotal = $388,000 )
2005	2005	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Environmental Health	000	11	3/23/2005	NON-COMPETING CONTINUATION	$388,000
														Subtotal = $388,000

Issue Date FY: 2004 ( Subtotal = $388,000 )
2004	2004	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Environmental Health	000	10	2/17/2004	NON-COMPETING CONTINUATION	$388,000
														Subtotal = $388,000

Issue Date FY: 2003 ( Subtotal = $388,000 )
2003	2003	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Environmental Health	000	9		NON-COMPETING CONTINUATION	$388,000
														Subtotal = $388,000

Issue Date FY: 2002 ( Subtotal = $385,240 )
2002	2002	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Environmental Health	000	8	3/28/2002	COMPETING CONTINUATION	$385,240
														Subtotal = $385,240

Issue Date FY: 2001 ( Subtotal = $311,274 )
2001	2001	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Environmental Health	000	7	3/19/2001	NON-COMPETING CONTINUATION	$311,274
														Subtotal = $311,274

Issue Date FY: 2000 ( Subtotal = $358,599 )
2000	2000	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Environmental Health	000	6	3/24/2000	NON-COMPETING CONTINUATION	$358,599
														Subtotal = $358,599

Issue Date FY: 1999 ( Subtotal = $352,120 )
1999	1999	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Environmental Health	000	5	5/13/1999	NON-COMPETING CONTINUATION	$352,120
														Subtotal = $352,120

Issue Date FY: 1998 ( Subtotal = $275,182 )
1998	1998	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Environmental Health	000	4	4/16/1998	COMPETING CONTINUATION	$275,182
														Subtotal = $275,182

Grand Total All Awards = $3,902,915

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ROLE OF BENZODIAZEPINE RECEPTOR IN LEYDIG CELL FUNCTION

Award Number: R01ES007747

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/1995

PERIOD OF PERFORMANCE END DATE: 11/30/2011

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