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CHROMIUM GENOTOXICITY: RESPONSE AND REPAIR MECHANISMS

Award Number: R01ES005304
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: 01/01/1990
PERIOD OF PERFORMANCE END DATE: 04/30/2008

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CHROMIUM GENOTOXICITY: RESPONSE AND REPAIR MECHANISMS - DESCRIPTION (provided by applicant): Certain chromium compounds are environmentally and occupationally important human respiratory carcinogens that are mutagenic and carcinogenic at exposure levels which induce some growth arrest and apoptotic cell death. A growing body of evidence indicates that interference with DNA replication is not only a proximal stimulus for carcinogen-induced terminal growth arrest and apoptotic cell death, but may also instigate genomic changes which contribute to the early stages of neoplasia in the progeny of cells which have escaped cell death, We made the initial discovery that chromium-induced DNA-DNA interstrand crosslinks (Cr-DDC) are present in chromate-exposed cells and cause guanine-specific polymerase arrest (PAL) in in vitro replication systems. In the last grant period we made significant progress in studying the formation of this lesion and some of its biological consequences. Based on those studies we have formulated the following over-riding hypothesis: Cr-DDC are polymerase-stalling lesions that activate DNA repair pathways, which generate double-strand break (DSB) intermediates and induce key cellular survival pathways including recombination. Thus, the major objective of this research is to investigate the formation, repair, and biological and molecular consequences of chromium-induced polymerase arresting lesions, in yeast and human cellular/genetic paradigms that allow us to understand the contribution of these lesions to cellular stress and survival responses, The aims for the next period are (i) to conduct further biochemical analysis of Cr-induced polymerase arresting lesions, and to test the hypothesis that direct Cr-DNA binding and/or base oxidation is critical or sufficient for the formation of this base-specific lesion, (ii) to test the hypothesis that Cr-DDC (polymerase arresting lesions) and/or repair intermediates have a critical role in cellular toxicity and/or triggering survival responses. (iii) to mechanistically apply Differential Expression Profiling (DNA MicroArray Gene Chip technology) to decipher survival and repair pathways that are activated when key DNA repair genes are missing, and (iv) to test the hypothesis that recombination is activated by Cr-DDC/PAL (in both cellular and in vitro recombination systems), and is critical to the survival of genetically damaged cells. This research will help elucidate the molecular mechanisms of chromium toxicity and carcinogenesis and will have practical value in contributing to the evaluation of risk to humans in contact with chromates.


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: 2007 ( Subtotal = $342,293 )
2007	2007	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Environmental Health	000	17	4/27/2007	NON-COMPETING CONTINUATION	$342,293
														Subtotal = $342,293

Issue Date FY: 2006 ( Subtotal = $352,517 )
2006	2006	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Environmental Health	000	16	5/3/2006	NON-COMPETING CONTINUATION	$352,517
														Subtotal = $352,517

Issue Date FY: 2005 ( Subtotal = $357,542 )
2005	2005	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Environmental Health	000	15	5/2/2005	NON-COMPETING CONTINUATION	$357,542
														Subtotal = $357,542

Issue Date FY: 2004 ( Subtotal = $354,703 )
2004	2004	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Environmental Health	000	14	4/30/2004	NON-COMPETING CONTINUATION	$354,703
														Subtotal = $354,703

Issue Date FY: 2003 ( Subtotal = $353,764 )
2003	2003	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Environmental Health	000	13	8/1/2003	COMPETING CONTINUATION	$353,764
														Subtotal = $353,764

Issue Date FY: 2002 ( Subtotal = $275,362 )
2002	2002	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Environmental Health	000	12	4/19/2002	NON-COMPETING CONTINUATION	$275,362
														Subtotal = $275,362

Issue Date FY: 2001 ( Subtotal = $279,228 )
2001	2001	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Environmental Health	000	11	5/1/2001	NON-COMPETING CONTINUATION	$279,228
														Subtotal = $279,228

Issue Date FY: 2000 ( Subtotal = $312,222 )
2000	2000	GEORGE WASHINGTON UNIVERSITY	44983 KNOLL SQUARE	ASHBURN	VA	20147	LOUDOUN	USA	Environmental Health	000	10	4/21/2000	NON-COMPETING CONTINUATION	$312,222
														Subtotal = $312,222

Issue Date FY: 1999 ( Subtotal = $375,810 )
1999	1999	GEORGE WASHINGTON UNIVERSITY	44983 KNOLL SQUARE	ASHBURN	VA	20147	LOUDOUN	USA	Environmental Health	000	9	4/9/1999	COMPETING CONTINUATION	$375,810
														Subtotal = $375,810

Issue Date FY: 1998 ( Subtotal = $243,943 )
1998	1998	GEORGE WASHINGTON UNIVERSITY	44983 KNOLL SQUARE	ASHBURN	VA	20147	LOUDOUN	USA	Environmental Health	000	8	11/18/1997	NON-COMPETING CONTINUATION	$243,943
														Subtotal = $243,943

Grand Total All Awards = $3,247,384

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CHROMIUM GENOTOXICITY: RESPONSE AND REPAIR MECHANISMS

Award Number: R01ES005304

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: 01/01/1990

PERIOD OF PERFORMANCE END DATE: 04/30/2008

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