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CYANIDE-INDUCED NEUROTOXICITY: MOLECULAR DEATH SIGNALING

Award Number: R01ES004140
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: 06/01/1986
PERIOD OF PERFORMANCE END DATE: 04/30/2009

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CYANIDE-INDUCED NEUROTOXICITY: MOLECULAR DEATH SIGNALING - DESCRIPTION (provided by applicant): Cyanide (CN), a prototype mitochondrial toxicant, produces progressive degeneration in select brain areas. This selective vulnerability to cyanide is characterized in vivo by apoptotic cell death in cortex and necrotic degeneration in substantia nigra. In primary cultured cells, cyanide produces a unique, cytotoxic response in which cortical cells (CX) undergo apoptosis and mesencephalic cells (MC) undergo necrosis, paralleling the regio-specific responses observed in animals. A rapid rise in cytosolic free Ca2+ and generation of reactive oxygen species are initiators of both modes of cell death. Preliminary studies show that two mitochondrial proteins (BNIP3 and UCP-2) are sensors of the initiation signals and function as co-regulators of cell death to determine which cell death pathway is executed. Proposed studies will characterize the role of BNIP3 and UCP-2 as sensors/regulators of cyanide-induced apoptosis and necrosis using primary cultured rat CX and MC cells as comparative models. To examine BNIP3 and UCP-2 as regulators of cyanide-induced cell death, changes in their expression will be produced, followed by monitoring subsequent changes in apoptotic and necrotic markers. Transient transfection with cDNA will be used to increase expression and RNA interference will produce knock down. For characterizing the link between BNIP3 and UCP-2 as functional co-regulators, cells will be co-transfected (cDNA or RNA interference) to concurrently increase or decrease expression of these proteins to determine if the mode of death can be modified temporally or switched. Upstream and downstream signaling cascades that initiate and execute BNIP3/UCP-2-mediated apoptosis and necrosis will be compared in the CX and MC expression models. Signals that activate BNIP3/UCP-2 will be characterized and then linked to recruitment of execution pathways. This will include determining how BNIP3/UCP-2 activation executes cell death by monitoring cellular redistribution/activity of apoptotic and necrotic signaling factors, including Bcl-2 proteins, cytochrome c, caspases, ATP levels and mitochondrial membrane pore transition. The long-term goal of this project is to identify mechanisms underlying cyanide-induced cell death and understand why brain areas are selectively vulnerable to cyanide. This study will provide valuable insight into neurotoxicant-induced neurodegeneration and fundamental information on regulation of cell death in the CNS.


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: 2008 ( Subtotal = $332,381 )
2008	2008	PURDUE UNIVERSITY	610 PURDUE HALL	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Environmental Health	000	22	4/7/2008	NON-COMPETING CONTINUATION	$332,381
														Subtotal = $332,381

Issue Date FY: 2007 ( Subtotal = $382,900 )
2007	2007	PURDUE UNIVERSITY	610 PURDUE HALL	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Environmental Health	000	21	4/20/2007	NON-COMPETING CONTINUATION	$382,900
														Subtotal = $382,900

Issue Date FY: 2006 ( Subtotal = $422,478 )
2006	2006	PURDUE UNIVERSITY	610 PURDUE HALL	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Environmental Health	000	20	5/9/2006	NON-COMPETING CONTINUATION	$393,391
2006	2006	PURDUE UNIVERSITY	610 PURDUE HALL	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Environmental Health	001	19	12/19/2005	SUPPLEMENT FOR EXPANSION	$29,087
														Subtotal = $422,478

Issue Date FY: 2005 ( Subtotal = $358,284 )
2005	2005	PURDUE UNIVERSITY	SPONS PROGRAMS-1063 HOVDE HALL	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Environmental Health	000	19	5/12/2005	NON-COMPETING CONTINUATION	$358,284
														Subtotal = $358,284

Issue Date FY: 2004 ( Subtotal = $430,767 )
2004	2004	PURDUE RESEARCH FOUNDATION	SPONS PROGRAMS-1063 HOVDE HALL	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Environmental Health	000	18	6/30/2004	COMPETING CONTINUATION	$354,767
2004	2004	PURDUE RESEARCH FOUNDATION	SPONS PROGRAMS-1063 HOVDE HALL	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Environmental Health	001	17	1/26/2004	SUPPLEMENT FOR EXPANSION	$76,000
														Subtotal = $430,767

Issue Date FY: 2003 ( Subtotal = $234,025 )
2003	2003	PURDUE RESEARCH FOUNDATION	SPONS PROGRAMS-1063 HOVDE HALL	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Environmental Health	000	17		NON-COMPETING CONTINUATION	$234,025
														Subtotal = $234,025

Issue Date FY: 2002 ( Subtotal = $227,212 )
2002	2002	PURDUE RESEARCH FOUNDATION	SPONS PROGRAMS-1063 HOVDE HALL	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Environmental Health	000	16	2/4/2002	NON-COMPETING CONTINUATION	$227,212
														Subtotal = $227,212

Issue Date FY: 2001 ( Subtotal = $220,593 )
2001	2001	PURDUE RESEARCH FOUNDATION	SPONS PROGRAMS-1063 HOVDE HALL	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Environmental Health	000	15	1/10/2001	NON-COMPETING CONTINUATION	$220,593
														Subtotal = $220,593

Issue Date FY: 2000 ( Subtotal = $213,868 )
2000	2000	PURDUE RESEARCH FOUNDATION	610 PURDUE HALL	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Environmental Health	000	14	1/24/2000	NON-COMPETING CONTINUATION	$213,868
														Subtotal = $213,868

Issue Date FY: 1999 ( Subtotal = $218,371 )
1999	1999	PURDUE RESEARCH FOUNDATION	610 PURDUE HALL	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Environmental Health	000	13	1/28/1999	COMPETING CONTINUATION	$218,371
														Subtotal = $218,371

Grand Total All Awards = $3,040,879

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CYANIDE-INDUCED NEUROTOXICITY: MOLECULAR DEATH SIGNALING

Award Number: R01ES004140

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: 06/01/1986

PERIOD OF PERFORMANCE END DATE: 04/30/2009

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