This Competing Renewal of an R01 application will further evaluate how biochemical changes along with modification of brain capillaries will lead to alterations in blood-brain barrier (BBB) and blood-tumor barrier (BTB) permeability. These barriers can be selectively opened for brief periods of time and if the mechanism of such modulation can be identified, it may be possible to target drugs to specific injured or tumor bearing brain regions. Previous results by the principal investigator suggest that it may be possible to selectively open the BBB or BTB through modulation of bradykinin 2 (B2) receptors, nitric oxide (NO), cyclic GMP (cGMP) and calcium-dependent potassium (KCa) channels. The bradykinin mediated opening of these barriers occurs via a sequential modulation of these mechanisms. However, the precise cellular location of such modulation is unknown. The current proposal will evaluate the role of individual cell types that mediate differential permeability responses in different endothelial cell populations. These will be evaluated in vivo using rat models of brain tumors and injury.
The Specific Aims will: (1) evaluate binding sites for bradykinin and evaluate transfer coefficient (Ki) values for various sized molecules in relation to B2 receptor density and function, (2) assess the role of NO, soluble guanylate cyclase (sGC), cGMP-dependent protein kinase and KCa channels in permeability, and (3) determine if molecules of differing size or viral particles cross normal or compromised BBB by tight junctions or trans endothelial vesicle routes and if infusion of vasoactive substances may initiate such permeability changes. The results of the proposed work have implications in enhanced and potentially targeted drug delivery to the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37NS032103-06
Application #
6199738
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Jacobs, Tom P
Project Start
1993-08-01
Project End
2004-06-30
Budget Start
2000-09-01
Budget End
2001-06-30
Support Year
6
Fiscal Year
2000
Total Cost
$382,500
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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Hu, Jinwei; Yuan, Xiangpeng; Ko, MinHee K et al. (2007) Calcium-activated potassium channels mediated blood-brain tumor barrier opening in a rat metastatic brain tumor model. Mol Cancer 6:22
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