Molecular & functional aspects of vascular permeability

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The main function of vascular endothelium is the mediation and control of transendothelial exchanges of water and solutes (both small and large molecules) between blood plasma and the interstitial fluid. This function IS OBVIOUSLY "vital", judged on the dependency on it of all the cells from all tissues and organs. While the morphological structures involved in transendothelial exchanges have been identified (i.e. caveolae, transendothelial channels, fenestrae and intercellular junctions), there is very little to no biochemical evidence on the molecular composition of the structures involved, their biogenesis and regulation. The major goals of this research proposal are to elucidate the specific chemical composition and function of the endothelial differentiations such as fenestrae and caveolae and their stomatal diaphragms. The finding will also document a novel aspect of the transendothelial transport namely the possibility and ways of its modulation (in rate and components transported). Besides their impact on the understanding of the normal physiological process of the transendothelial transport, the data could be used further in the study of the pathophysiology of several human diseases (e.g. tumor angiogenesis, diabetes, retinopathy, psoriasis, pulmonary, fibrosis, thrombocytopenia, allergic encephalomyelitis, arterial hypertension) where such transport modulations have been shown to occur. These studies could also provide novel transport related endothelial specific molecular markers that could be used in designing strategies for drugs and gene targeting to selected microvascular beds. The techniques employed are cell fractionation, cell free-assays, in-vivo screening methods, two- dimensional electrophoresis, cell culture, transfections, light and electron microscopy.