The strictly regulated microenvironment of the brain is in part maintained by the blood-brain (BBB) and blood-CSF (BCSFB) barriers. These barriers are made up of the endothelial cells of the cerebral microvasculature (BBB) and the epithelial cells of the choroid plexus (BCSFB). Both the BBB and the BCSFB control passage of ions and larger molecules into the brain by virtue of specialized transport systems, and very tight cell-to-cell connections mediated by adherens and tight junctions. It is well established that ischemic insults, such as stroke, cause a breakdown of the BBB, leading to brain edema, and this breakdown is mediated in part by alterations in tight junction and adherens junction structures. However, little is known about the cellular effects of ischemia on the BCSFB, although choroid plexus epithelial cells do express tight junction and adherens junction proteins. The hypothesis of this proposal is that the integrity of the BBB and BCFB after hypothesis and aglycemia is compromised, and that this compromise is mediated in part by the signaling effects of a rise in intracellular calcium. Calcium signaling may potentially alter the expression of tight junction, adherens junction and cytoskeletal proteins, providing a molecular mechanism for the increase in barrier permeability seen in vivo and in vitro. These studies will provide new information about the role of calcium in regulating barrier system permeability, and may provide targets for future pharmacological and therapeutic treatments of stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32NS043052-02
Application #
6622355
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Jacobs, Tom P
Project Start
2002-01-01
Project End
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
2
Fiscal Year
2003
Total Cost
$46,420
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Biology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
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Brown, Rachel C; Egleton, Richard D; Davis, Thomas P (2004) Mannitol opening of the blood-brain barrier: regional variation in the permeability of sucrose, but not 86Rb+ or albumin. Brain Res 1014:221-7
Hawkins, Brian T; Abbruscato, Thomas J; Egleton, Richard D et al. (2004) Nicotine increases in vivo blood-brain barrier permeability and alters cerebral microvascular tight junction protein distribution. Brain Res 1027:48-58
Brown, Rachel C; Mark, Karen S; Egleton, Richard D et al. (2004) Protection against hypoxia-induced blood-brain barrier disruption: changes in intracellular calcium. Am J Physiol Cell Physiol 286:C1045-52
Brown, Rachel C; Mark, Karen S; Egleton, Richard D et al. (2003) Protection against hypoxia-induced increase in blood-brain barrier permeability: role of tight junction proteins and NFkappaB. J Cell Sci 116:693-700
O'Neil, Roger G; Brown, Rachel C (2003) The vanilloid receptor family of calcium-permeable channels: molecular integrators of microenvironmental stimuli. News Physiol Sci 18:226-31
Brown, Rachel C; Davis, Thomas P (2002) Calcium modulation of adherens and tight junction function: a potential mechanism for blood-brain barrier disruption after stroke. Stroke 33:1706-11