Blood-Brain Barrier in Neuroinflammation

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Increased blood-brain barrier (BBB) permeability represents a classic hallmark of central nervous system inflammation that occurs in a variety of neuropathological conditions. In generally the range of increase of BBB permeability goes from intensive remodeling of the brain interendothelial cell junction, (vascular endothelial cell contraction, altered distribution of endothelial intercellular junction proteins) which lead to wid opening of paracellular route - BBB breakdown to BBB leakage, a selective permeability for small molecular size compounds without visible remodeling of TJ complex. BBB leaking is seen in many disease states like Alzheimer and Parkinson disease, vascular dementia, and epilepsy but also in the process of BBB recovery after ischemic episodes or inflammation. Insofar as the accumulating evidences define the morphological alteration and underlying mechanism of the TJ alteration in BBB breakdown, very little is know about type of alteration and mechanism of BBB leaking. In order to elucidate cause and mechanism of persistent BBB leakage develop after postischemic inflammatory response we propose a research plan directed at testing of the following hypothesis: The persistent leakage of BBB after brain ischemic/reperfusion injury is caused by structural alteration of transmembrane TJ proteins that develops in chronic post-stroke inflammatory conditions. The present study will determine; a) the characteristics of TJ complex and BBB functionality after brain I/R injury, b) the type of claudins protein-protein interactions essential for the tightness and stability of TJ complex in brain endothelial cells, c) the signal transduction pathways involved in regulation of prolonged leakage of BBB after brain I/R injury and d) the pathways that improve the brain endothelial barrier after stroke onset. Collectively, these studies will provide new information related to the mechanisms of BBB paracelluar permeability that is relevant to multiple disease states and will, hopefully, elucidate methods for controlling this event.