Grant: Operating Grant - PA: Regional Partnership Program : Manitoba

The treatment of brain related disorders is often hampered by the inability to achieve sufficient concentrations of the drug within the brain. This is due in large part to the restrictive nature of the brain microvessel endothelial cells that form the blood-brain barrier (BBB). My laboratory is interested in ways to modulate BBB permeability to more effectively delivery therapeutic agents to the brain. One method we are pursuing involves the activation of varoius phospholipid receptors expressed on the brain endothelial cells to temporarily enhance BBB permeability to a wide variety of compounds. Our preliminary work using the naturally occurring activators of these receptors, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P)has proven the utility of this approach. We propose the creation and refinement of this drug delivery platform through (1) identification of the crucial phospholipid receptors responsible for the permeability responses to LPA and S1P. (2) Selection of more specific and "drugable" activators of these receptors by screening for responses in a series of LPA and S1P analog compounds. (3)Proof-of-principle for brain drug delivery platform using a mouse brain tumor model. Together these studies will establish a foundation for use of this approach to improve for the treatment of various CNS disorders.