Project Summary In a variety of neurological conditions brain abnormalities have been observed in specific brain areas using MRI and immunohistological methods. These include patients suffering from stroke, small vessel disease, multiple sclerosis and infectious diseases, such as cerebral malaria (CM). Many neurological conditions contain an underlying vascular component. Brain vascular pathologies appear to differ according to vessel size and specific brain area the vessels reside in, including differences in vessels residing in gray matter (GM) versus white matter (WM). These differing pathologies are especially clear in CM: hemorrhagic punctae in WM but not in GM. Little is known of exactly what these differences are, the underlying causes of these vascular differences in GM versus WM and how these differences could relate to divergent neuropathological responses. We hypothesize that, cerebral microvessels derived from various GM and WM brain regions, exhibit differing properties, including different expression of transporters, receptors, junctional molecules and cell adhesion molecules. These differences are due to differences in the metabolic and functional needs of the direct physiological environment of these cerebral microvessel, including presence of astrocyte-neuronal versus pericyte-oligodendrocytes. These differences may be responsible for the varying inflammatory- and hemorrhagic- responses to stimuli, such as microbial stimulation, oxygen deprivation in stroke, or responses to therapeutics. In this proposal we intend to study the underlying differences of the brain’s vasculature using a comprehensive approach using human brain samples of different brain areas in combination with in-vitro BBB modeling. We propose to compare A) the global expression differences of the brain micro-vasculature. Thereafter, distinctive vascular markers that are specific for certain brain areas will be selected and their expression confirmed in different brain areas. B) Functional responses of brain endothelium will be tested using in vitro BBB models that have properties reflecting these vascular differences, e.g. WM and GM brain endothelium. We anticipate that this proposal will lead to clarification of vascular differences in the different brain areas and will offer an explanation for differing pathologies observed in neurological conditions. A better understanding of the vascular heterogeneity may lead to future development of novel targeted therapeutics.