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REGULATION OF CYTOCHROME P450 BIOSYNTHESIS

Award Number: R01GM039360
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/1996
PERIOD OF PERFORMANCE END DATE: 04/30/2010

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REGULATION OF CYTOCHROME P450 BIOSYNTHESIS - DESCRIPTION (provided by applicant): The overall goal of this project is to understand the molecular mechanisms by which phenobarbital (PB) induces cytochrome P450 gene (CYP) expression. P450s catalyze the activation or inactivation of a wide variety of endogenous and exogenous compounds. Clinically, induction of P450s underlies many drug interactions, and the balance between inactivation and activation, which is influenced by induction, determines the ultimate therapeutic or toxic effect of ingested compounds. PB treatment induces the nuclear translocation of the constitutive androstane receptor (CAR). CAR binds to three nuclear receptor (NR) binding sites in a PB responsive enhancer (PBRU) as a heterodimer with RXR and recruits p160 coactivators and other unknown proteins resulting in changes in chromatin structure and gene activation. The specific aims are to identify the regulatory complex recruited by CAR to the PBRU, to determine changes in chromatin structure at the PBRU correlated with activation of the CYP genes, and to determine the import and export signals of CAR necessary for its nucleocytoplasmic shuttling. To facilitate the isolation of CAR and its protein complexes from mouse liver, a transgenic mouse expressing flag-tagged CAR will be constructed. Nuclear CAR protein complexes in PB-treated animals will be enriched by flag immunoaffinity isolation and proteins in the complex will be identified by mass spectrometry. The relative importance of the three p160 coactivators and the three NR binding sites will be determined. Proteins recruited to the PBRU after PB treatment will be identified by chromatin immunoprecipitation assays and chromatin structure will be probed by sensitivity to cleavage by nucleases and hydroxyl radicals. The functional significance of proteins detected at the PBRU or in CAR complexes will be determined by transient transfections in cultured cells and in hepatocytes in vivo. Nuclear import and export signals and receptors for CAR will be identified by examining the distribution of chimera of CAR fragments and fluorescent proteins in hepatocytes transfected in vivo. These studies, emphasizing in vivo approaches, should provide a description of the regulatory complex at the PBRU, which will provide insight into the mechanism of PB induction of CYP genes, and determine transport signals for nucleocytoplasmic shuttling, which is a key process regulated by PB treatment.


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: 2009 ( Subtotal = $278,540 )
2009	2009	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Biomedical Research and Research Training	000	21	4/15/2009	NON-COMPETING CONTINUATION	$278,540
														Subtotal = $278,540

Issue Date FY: 2008 ( Subtotal = $276,356 )
2008	2008	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Biomedical Research and Research Training	000	20	4/18/2008	NON-COMPETING CONTINUATION	$276,356
														Subtotal = $276,356

Issue Date FY: 2007 ( Subtotal = $276,672 )
2007	2007	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Biomedical Research and Research Training	000	19	5/10/2007	NON-COMPETING CONTINUATION	$276,672
														Subtotal = $276,672

Issue Date FY: 2006 ( Subtotal = $285,251 )
2006	2006	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Biomedical Research and Research Training	000	18	4/28/2006	COMPETING CONTINUATION	$285,251
														Subtotal = $285,251

Issue Date FY: 2004 ( Subtotal = $357,429 )
2004	2004	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Biomedical Research and Research Training	000	17	3/19/2004	NON-COMPETING CONTINUATION	$280,929
2004	2004	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Biomedical Research and Research Training	001	16	1/26/2004	SUPPLEMENT FOR EXPANSION	$76,500
														Subtotal = $357,429

Issue Date FY: 2003 ( Subtotal = $202,121 )
2003	2003	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Cell Biology and Biophysics Research	000	16		NON-COMPETING CONTINUATION	$202,121
														Subtotal = $202,121

Issue Date FY: 2002 ( Subtotal = $199,679 )
2002	2002	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Cell Biology and Biophysics Research	000	15	3/20/2002	NON-COMPETING CONTINUATION	$199,679
														Subtotal = $199,679

Issue Date FY: 2001 ( Subtotal = $197,794 )
2001	2001	UNIVERSITY OF ILLINOIS URBANA CAMPUS	809 SOUTH WRIGHT STREET	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Cell Biology and Biophysics Research	000	14	3/5/2001	COMPETING CONTINUATION	$197,794
														Subtotal = $197,794

Issue Date FY: 2000 ( Subtotal = $210,567 )
2000	2000	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Biomedical Research and Research Training	000	13	5/10/2000	NON-COMPETING CONTINUATION	$210,567
														Subtotal = $210,567

Issue Date FY: 1999 ( Subtotal = $203,383 )
1999	1999	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Biomedical Research and Research Training	000	12	3/31/1999	NON-COMPETING CONTINUATION	$203,383
														Subtotal = $203,383

Issue Date FY: 1998 ( Subtotal = $196,032 )
1998	1998	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Biomedical Research and Research Training	001	11	9/19/1998	SUPPLEMENT FOR EXPANSION	$33,167
1998	1998	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Biomedical Research and Research Training	000	11	3/27/1998	NON-COMPETING CONTINUATION	$162,865
														Subtotal = $196,032

Grand Total All Awards = $2,683,824

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REGULATION OF CYTOCHROME P450 BIOSYNTHESIS

Award Number: R01GM039360

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/1996

PERIOD OF PERFORMANCE END DATE: 04/30/2010

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