This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. West Nile virus (WNV), which is transmitted by mosquitoes, usually causes a mild disease in humans. In approximately 2% of infected people, however, WNV causes a fatal brain disease, called meningoencephalitis. Currently, there are no drugs to treat WNV or vaccines to prevent WNV infection in humans. Our preliminary studies indicate that WNV gains entry into the brain by crossing the blood-brain barrier (BBB) and produces mediators, such as enzymatic proteins called matrix metalloproteinases (MMPs), that degrade the BBB. Our central hypothesis is that the increased production of MMPs by WNV-infected blood and brain cells, via the cyclooxygenase-2 (COX-2) signaling pathway, mediates BBB breakdown by degrading specific tight junction proteins (TJP). We will pursue three specific aims:
Aim 1 will analyze the role of COX-2 enzyme and its product, Prostaglandin E2, in regulating the levels of MMPs.
In Aim 2, we will assess the ability of WNV-infected monocytes to degrade TJP and its transmigration across a well-established in vitro BBB model.
Aim 3 will employ a mouse model to characterize WNV-induced alterations in TJP. Further, we will also determine the potential of MMP inhibitors to prevent BBB disruption and eventual entry of WNV into the CNS. Our comprehensive study using cell culture and animal model will highlight the role of MMPs-induced BBB disruption in WNV disease pathogenesis. The discovery of new insights into the function(s) of MMPs and TJP in BBB disruption and ability of MMP inhibitors to improve WNV disease outcome would have considerable therapeutic relevance.
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