The long term objective of this research is to determine the role of cellular adhesion systems in the development and maintenance of brain microvessel structure and blood-brain barrier function, a property unique to the central nervous system capillary. Clinically, brain microvessel formation and function is important in brain ontogenesis, neuronal homeostasis and in considerations of drug delivery to brain: its dysfunction is important in the pathogenesis of inflammatory states, tumors and cerebrovascular disease. Despite extensive study, the factors that regulate brain microvessel structure and function in normal and disease states are poorly understood. The elucidation of such factors will aid in the development of therapeutic modalities that manipulate capillary function to clinical advantage. The requirement of an intimate association between endothelta, astrocytes and pericytes for normal brain microvessel function and the presence of altered associations in certain disease states suggests that cell-cell and cell-extracellular matrix adhesions determine brain microvessel structure and to some degree function. The biochemistry of cell-cell and cell-matrix adhesion within the CNS capillary is poorly understood.
The specific aims of this proposal are: (1) To identify cell- substratum adhesive interactions of brain microvessel cells and to characterize the endogenously synthesized cell-substratum adhesion molecules that mediate such interactions, (2) To identify cell-cell adhesive interactions between brain microvessel cells and to characterize the cell-cell adhesion molecules that mediate them and (3) To characterize glycosaminoglycans synthesized by brain microvessels that may function in these cell adhesion systems.
