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ROLE OF OXIDATIVE MECHANISMS IN THE TOXICITY OF METALS

Award Number: R01GM057945
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: 05/01/1999
PERIOD OF PERFORMANCE END DATE: 06/30/2008

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ROLE OF OXIDATIVE MECHANISMS IN THE TOXICITY OF METALS - DESCRIPTION (provided by applicant): Metals are associated with a range of degenerative conditions and they pose a serious threat to human health. Considerable evidence indicates that reactive oxygen species (ROS) may play a key role in causing the deleterious biological effects of metals. However, this evidence remains inconclusive and the principal cellular and molecular mechanism(s) underlying metal toxicology have yet to be clearly resolved. This work exploits the experimental advantages of the yeast model Saccharomyces cerevisiae to elucidate cellular metal toxicity, so avoiding the limitations imposed on studies of this nature in animal models. Recent advances in functional genomics technologies that are unique to yeast, in conjunction with results leading up to this proposal from our laboratory, underscore S. cerevisiae as the eukaryotic model of choice here. The objective is to test the hypothesis that oxidative mechanisms are the primary cause of metal toxicity in cells. This will be achieved using two principal strategies developed in our laboratory, each highly distinct from previous approaches to this problem. The work will focus on copper, chromium and cadmium as examples of model redox-active and - inactive toxic metals. First, we will explore in greater depth an entirely novel question that is giving us major new insight to metal toxicity: do proteins that protect against oxidative damage determine the differing metal resistances of individual cells within isogenic populations? We have already discovered that the mechanisms underlying this heterogeneous metal resistance are distinct from those giving rise to culture-averaged resistance (the focus of past studies). Moreover, specific antioxidant functions appear to underpin the heterogeneity, and this key issue will be resolved directly in this project. In addition, an innovative genome-wide search will be carried out to find new determinants of heterogeneity. These heterogeneity studies are vital because, for the first time, they allow true evaluation of the roles of genes-of-interest in situ, i.e., pertaining to intact cells in which expression is not manipulated artificially. Second, we will build on our recent successful use of specific oxidative-damage repair enzymes applied to the problem of metal toxicity. Alongside such approaches, this project will introduce powerful new functional-genomics tools to identify the essential molecular-target(s) of metal action in cells. We will determine directly whether oxidative mechanisms cause the inactivation of these targets, and whole-cell toxicity. By testing the hypothesis in the manners described, the proposed studies should advance significantly our understanding of metal toxicology at the cellular level, and concurrently provide greater insight into the impact of ROS on biological systems.


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 = $204,807 )
2007	2007	UNIVERSITY OF NOTTINGHAM	**	NOTTINGHAM		00000		GBR	Biomedical Research and Research Training	000	9	6/26/2007	NON-COMPETING CONTINUATION	$204,807
														Subtotal = $204,807

Issue Date FY: 2006 ( Subtotal = $210,924 )
2006	2006	UNIVERSITY OF NOTTINGHAM	**	NOTTINGHAM		00000		GBR	Biomedical Research and Research Training	000	8	6/23/2006	NON-COMPETING CONTINUATION	$210,924
														Subtotal = $210,924

Issue Date FY: 2005 ( Subtotal = $215,424 )
2005	2005	UNIVERSITY OF NOTTINGHAM	**	NOTTINGHAM		00000		GBR	Biomedical Research and Research Training	000	7	6/30/2005	NON-COMPETING CONTINUATION	$215,424
														Subtotal = $215,424

Issue Date FY: 2004 ( Subtotal = $216,000 )
2004	2004	UNIVERSITY OF NOTTINGHAM	**	NOTTINGHAM		00000		GBR	Biomedical Research and Research Training	000	6	6/28/2004	COMPETING CONTINUATION	$216,000
														Subtotal = $216,000

Issue Date FY: 2003 ( Subtotal = $148,339 )
2003	2003	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	PO BOX 4030	ATLANTA	GA	30302	FULTON	USA	Biomedical Research and Research Training	000	5		NON-COMPETING CONTINUATION	$148,339
														Subtotal = $148,339

Issue Date FY: 2002 ( Subtotal = $144,059 )
2002	2002	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	PO BOX 4030	ATLANTA	GA	30302	FULTON	USA	Biomedical Research and Research Training	000	4	5/27/2002	NON-COMPETING CONTINUATION	$144,059
														Subtotal = $144,059

Issue Date FY: 2001 ( Subtotal = $139,903 )
2001	2001	GEORGIA STATE UNIVERSITY	PO BOX 4030	ATLANTA	GA	30302	FULTON	USA	Biomedical Research and Research Training	000	3	5/11/2001	NON-COMPETING CONTINUATION	$139,903
														Subtotal = $139,903

Issue Date FY: 2000 ( Subtotal = $135,870 )
2000	2000	GEORGIA STATE UNIVERSITY	PO BOX 4030	ATLANTA	GA	30302	FULTON	USA	Biomedical Research and Research Training	000	2	9/25/2000	NON-COMPETING CONTINUATION	$135,870
														Subtotal = $135,870

Issue Date FY: 1999 ( Subtotal = $140,954 )
1999	1999	GEORGIA STATE UNIVERSITY	PO BOX 4030	ATLANTA	GA	30302	FULTON	USA	Biomedical Research and Research Training	000	1	4/19/1999	NEW	$140,954
														Subtotal = $140,954

Grand Total All Awards = $1,556,280

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ROLE OF OXIDATIVE MECHANISMS IN THE TOXICITY OF METALS

Award Number: R01GM057945

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: 05/01/1999

PERIOD OF PERFORMANCE END DATE: 06/30/2008

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