The long-term objective of this Program Project Grant is to clarify basic mechanisms that regulate cerebral circulation and the choroid plexus. The Program represents an interactive, cohesive group of investigators who propose to address both physiological and pathophysiological mechanisms. The Program has four themes: First, studies are proposed to examine influence of endothelium on cerebral vascular muscle and choroid plexus. Experiments are planned in cell culture and in vivo to examine effects of vasoactive factors that are released by endothelium. The factors include eicosanoids and endothelium- derived relaxing and contracting factors. Second, responses to neurohumoral stimuli will be examined. Studies are planned to examine effects of neurotransmitters, neural stimuli, and vasoactive amines and peptides on cerebral endothelium, vascular muscle, and astrocytes in cell culture, and on blood flow to brain and choroid plexus in vivo. Studies also are proposed to examine second messengers that mediate these responses in vitro and in vivo. Third, mediators of vascular injury will be studied. Effects of eicosanoids, leukocytes, and inflammatory mediators on cerebral endothelium and blood vessels will be studied in vitro and in vivo. Fourth, effects of chronic hypertension will be studied. Experiments are proposed to examine hemodynamic determinants and consequences of cerebral vascular hypertrophy and remodeling during chronic hypertension. Effects of hypertension on cerebral endothelium, astrocytes, and choroid plexus will be studied in vitro and in vivo. The first three projects in the Program use primarily cell biology approaches to study cerebral endothelium, vascular muscle, and astrocytes. The last four projects use primarily in vivo approaches to study cerebral circulation and the choroid plexus. The seven research projects are: Adhesion molecules of the blood-brain barrier, Eicosanoids in brain microvessel/astrocyte interactions, Astrocyte modulation of vascular cell function, Regulation of choroid plexus function, Effects of chronic hypertension on cerebral blood vessels, Neurohumoral regulation of cerebral blood vessels, and Cerebral circulation in chronic hypertension. The projects are supported by three core facilities: Administrative/Biostatistics, Morphology, and Stroke-prone animal core. This integrated, multidisciplinary approach is intended to facilitate rapid progress, and more penetrating insight, in cerebral vascular research.
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