Our objective is to develop an in vitro model of the blood brain barrier through which major hypotheses of vasogenic cerebral edema may be tested. Cerebral edema accompanies many different pathological insults to the CNS and is a prime determining factor of the ultimate morbidity or mortality associated with many of these insults. Several hypotheses have been proposed to explain the disruption of the blood brain barrier which precedes the formation of vasogenic cerebral edema. Arachidonic acid metabolism is a central issue in most of these hypotheses, but precise characterization of the metabolites involved, their sites of origin and/or action, and the mechanisms of their actions remains largely undetermined. Uniquely, mouse cerebral endothelium and vascular smooth muscle and rat C6 glioma cells are available in the laboratory for in vitro exploration of these hypotheses. Preliminary studies suggest that some cerebral endothelial properties are maintained in culture (i.e, impermeability to certain macromolecules), while others require co-culture of cerebral endothelium with C6 glioma cells for their expression (i.e., Gamma-GTP activity and polarity to amino acid transport). Further studies to characterize this in vitro blood brain barrier model will include: 1) permeability studies with small versus large M.W. and low versus high octanol/water partition co-efficient solutes, 2) ultrastructural probes for analysis of vesicular transport, 3) measurement of transendothelial electrical resistance, and 4) more extensive co-culture studies to assess intercellular interactions required for blood brain barrier differentiation and maintenance. Cell type specific studies of arachidonic acid metabolism utilizing primarily thin layer chromatography, high performance liquid chromatography, and radioimmunoassay will characterize sites of specific eicosanoid metabolism. Preliminary studies reveal differences between endothelium and smooth muscle. Knowledge of cerebrovascular eicosanoid metabolism will then be utilized to assess its effects on the in vitro model of the blood brain barrier developed earlier.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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Neurological Disorders Program Project Review B Committee (NSPB)
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University of Iowa
Schools of Medicine
Iowa City
United States
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Moore, S A (2001) Polyunsaturated fatty acid synthesis and release by brain-derived cells in vitro. J Mol Neurosci 16:195-200; discussion 215-21
Moore, S A; Hurt, E; Yoder, E et al. (1995) Docosahexaenoic acid synthesis in human skin fibroblasts involves peroxisomal retroconversion of tetracosahexaenoic acid. J Lipid Res 36:2433-43
Moore, S A (1994) Local synthesis and targeting of essential fatty acids at the cellular interface between blood and brain: a role for cerebral endothelium and astrocytes in the accretion of CNS docosahexaenoic acid. World Rev Nutr Diet 75:128-33
Spector, A A; Gordon, J A; Moore, S A (1994) Beta-oxidation of hydroxyeicosatetraenoic acids: a peroxisomal process. World Rev Nutr Diet 75:8-15
Moore, S A (1993) Cerebral endothelium and astrocytes cooperate in supplying docosahexaenoic acid to neurons. Adv Exp Med Biol 331:229-33
Xu, J; Qu, Z X; Moore, S A et al. (1992) Receptor-linked hydrolysis of phosphoinositides and production of prostacyclin in cerebral endothelial cells. J Neurochem 58:1930-5
Giordano, M J; Mathur, S N; Moore, S A (1992) Differential metabolism of hydroxyeicosatetraenoic acid isomers by mouse cerebromicrovascular endothelium. J Neurochem 58:374-82
Moore, S A; Yoder, E; Murphy, S et al. (1991) Astrocytes, not neurons, produce docosahexaenoic acid (22:6 omega-3) and arachidonic acid (20:4 omega-6). J Neurochem 56:518-24
Yorek, M A; Stefani, M R; Moore, S A (1991) Acute and chronic exposure of mouse cerebral microvessel endothelial cells to increased concentrations of glucose and galactose: effect on myo-inositol metabolism, PGE2 synthesis, and Na+/K(+)-ATPase transport activity. Metabolism 40:347-58
Moore, S A; Giordano, M J; Kim, H Y et al. (1991) Brain microvessel 12-hydroxyeicosatetraenoic acid is the (S) enantiomer and is lipoxygenase derived. J Neurochem 57:922-9

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