Brain recovery from injury secondary to stroke or trauma or brain tumors is a function of the cellular regeneration that follows injury. An important component of this regeneration involves the biology of the brain microvasculature, which makes up the blood=brain barrier (BBB) in vivo. The molecular and cellular biology of the brain capillary endothelium and its contiguous cells, such as pericytes, is the focus of this Program Project, which will investigate 5 different aspects of the BBB. The Project by W.M. Pardridge and R.J. Boado will investigate the molecular regulation of the blood-brain barrier GLUT1 glucose transporter, and will emphasize post-transcriptional mechanisms of regulation, and the isolation of putative brain factors that induce GLUT1 gene expression at the BBB. Project by E.M. Wright will perform studies on the molecular cloning of blood-brain barrier nutrient transporters using the frog oocyte expression system, and poly A+ mRNA derived from isolated brain capillaries. Project by E.M. Cornford investigates the modulation of blood-brain nutrient transport, focusing on blood-brain barrier glucose transport, and utilizes in vivo physiologic techniques, in vivo biochemical manipulation of the BBB glucose transporter, and immunogold electron microscopic techniques to identify the subcellular localization of the BBB GLUT1 glucose transporter in pathologic states such as anoxia or ischemia. Project by K.L. Black investigates leukotrienes and the blood-brain barrier, and the role these signal transduction molecules play in opening the BBB in experimental and human brain tumors; studies in this area will also include in situ hybridization investigations on the gene expression of the enzyme, 5- lipoxygenase, which is rate-limiting for leukotriene synthesis. Project by D.E. Bredesen involves the study of a novel cloning procedure to identify Beta-amyloid precursor protein processing enzymes in brain capillary microvascular cells such as pericytes; Alzheimer's Disease leads to perivascular amyloid deposition, which predisposes individuals to hemorrhagic stroke. All five projects will utilize a Cell Isolation/Morphology Core which will provide cultured cells, morphologic techniques at the light microscopic and ultrastructural level, as well as purified preparations of biologically intact poly A+mRNA derived from isolated brain capillaries. Extensive utilization of this Core will provide a common vehicle for interaction amongst the five projects, as well as for extension of blood-brain barrier research to the biochemical and molecular biological level.
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