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NEUROTROPHIN BLOOD/BRAIN BARRIER DELIVERY IN ISCHEMIA

Award Number: R01NS034698
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: HEALTH SERVICES
PERIOD OF PERFORMANCE START DATE: 03/01/1996
PERIOD OF PERFORMANCE END DATE: 04/30/2007

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NEUROTROPHIN BLOOD/BRAIN BARRIER DELIVERY IN ISCHEMIA - DESCRIPTION (provided by applicant): Neurotrophins are powerful neuroprotective agents in global or regional brain ischemia when the protein is injected directly into the ischemic brain. Intra-cerebral administration is necessary, because the neurotrophins do not cross the brain capillary endothelial wall, which forms the blood-brain barrier (BBB) in vivo, in the absence of BBB disruption. Presently, there is no neuroprotective agent available to stroke patients, because of the BBB problem. The present work develops neurotrophin chimeric peptides, which are enabled to cross the BBB and cause neuroprotection in the brain following delayed intravenous administration. A neurotrophin chimeric peptide is formed when the neurotrophin is conjugated or fused to a BBB transport vector. The latter is an endogenous peptide or peptidomimetic monoclonal antibody (MAb), which cross the BBB via receptor-mediated transcytosis (RMT) on endogenous BBB peptide transport systems. The model neurotrophins studied are brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF). The model BBB transport vector used for rats is the murine OX26 MAb to the rat transferrin receptor (TfR). The neurotrophin is conjugated to the transport vector with avidin-biotin technology. The proposed work involves 3 Specific Aims. First, the BDNF and bFGF chimeric peptides will be engineered using hybridoma technology, chemical coupling reactions, and avidin-biotin systems. Second, the infarction volume in rats subjected to reversible middle cerebral artery occlusion (MCAO) and treated with varying combinations of the BDNF and bFGF chimeric peptides will be measured. The goal of this Aim is to prolong the therapeutic window beyond the present window of 1-2 hours during which neuroprotection is possible after a 1 hour MCAO. Infarction volumes will be measured at both 1 and 7 days after ischemia. Third, the effects of chronic treatment with BDNF or bFGF chimeric peptides on neurogenesis in the infarcted region will be investigated. Both BDNF and bFGF have been recently shown to induce the formation of new neurons within the adult brain following direct injection into the brain. This work will attempt to show that neurogenesis in the adult brain subjected to ischemia can be induced with the intravenous administration of BDNF and/or bFGF, providing the neurotrophin is enabled to cross the intact BBB in vivo.


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: 2006 ( Subtotal = $247,573 )
2006	2006	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	4/13/2006	NON-COMPETING CONTINUATION	$247,573
														Subtotal = $247,573

Issue Date FY: 2005 ( Subtotal = $253,531 )
2005	2005	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	5/5/2005	NON-COMPETING CONTINUATION	$253,531
														Subtotal = $253,531

Issue Date FY: 2004 ( Subtotal = $253,531 )
2004	2004	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	5/14/2004	NON-COMPETING CONTINUATION	$253,531
														Subtotal = $253,531

Issue Date FY: 2003 ( Subtotal = $253,531 )
2003	2003	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8		COMPETING CONTINUATION	$253,531
														Subtotal = $253,531

Issue Date FY: 2002 ( Subtotal = $226,111 )
2002	2002	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	2/27/2002	NON-COMPETING CONTINUATION	$226,111
														Subtotal = $226,111

Issue Date FY: 2001 ( Subtotal = $270,848 )
2001	2001	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	6/12/2001	SUPPLEMENT FOR EXPANSION	$50,000
2001	2001	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	10920 WILSHIRE BLVD, 5TH FLOOR	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	3/21/2001	NON-COMPETING CONTINUATION	$220,848
														Subtotal = $270,848

Issue Date FY: 2000 ( Subtotal = $214,445 )
2000	2000	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biological Basis Research in the Neurosciences	000	5	2/25/2000	NON-COMPETING CONTINUATION	$214,445
														Subtotal = $214,445

Issue Date FY: 1999 ( Subtotal = $207,973 )
1999	1999	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Biological Basis Research in the Neurosciences	000	4	4/30/1999	COMPETING CONTINUATION	$207,973
														Subtotal = $207,973

Issue Date FY: 1998 ( Subtotal = $161,215 )
1998	1998	UNIVERSITY OF CALIFORNIA-LOS ANGELES, SCH OF MEDICINE	405 HILGARD AVENUE	LOS ANGELES	CA	90024	LOS ANGELES	USA	Biological Basis Research in the Neurosciences	000	3	3/4/1998	NON-COMPETING CONTINUATION	$161,215
														Subtotal = $161,215

Grand Total All Awards = $2,088,758

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NEUROTROPHIN BLOOD/BRAIN BARRIER DELIVERY IN ISCHEMIA

Award Number: R01NS034698

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: HEALTH SERVICES

PERIOD OF PERFORMANCE START DATE: 03/01/1996

PERIOD OF PERFORMANCE END DATE: 04/30/2007

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