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.
