AbstractBlood brain barrier (BBB) disruption is an integral feature of neurological diseases as diverse asmultiple sclerosis, acute hemorrhagic leukoencephalitis (AHLE), traumatic brain injury, stroke,cerebral malaria, viral hemorrhagic fevers, epilepsy, glioblastoma, alzheimer?s disease, and HIVdementia. A fundamental question in these diseases is the extent inflammatory immune cellscontribute to CNS vascular permeability. This lack of understanding currently underminestherapeutic approaches to treat neurological disease in which uncontrolled BBB disruptioncontributes to pathology. My research program was the first to demonstrate that CD8 T cellshave the capacity to disrupt BBB tight junctions using a novel murine model. Using this model,we have developed a tractable approach to dissect immune-mediated mechanisms of vascularendothelial growth factor (VEGF) mediated BBB disruption using a variation of Theiler?s MurineEncephalomyelitis Virus (TMEV) and the Plasmodium berghei ANKA (PbA) model systems.Our central hypothesis is CD8 T cells promote neuronal expression of VEGF whichresults in disruption of cerebral endothelial cell tight junctions and vascular permeability.We will test our central hypothesis through the following aims:Specific Aim #1 ? Determine the extent direct engagement of antigen specific CD8 T cells withneurons promotes VEGF expression and ensuing vascular changes.Specific Aim #2 ? Determine the extent neuronal expression of VEGF and its receptorscontribute to CD8 T cell-initiated BBB disruption.Specific Aim #3 ? Evaluate the contribution of neuronal VEGF to CD8 T cell-mediated BBBdisruption in the Plasmodium berghei ANKA (PbA) model of experimental cerebral malaria.To our knowledge, no other laboratories have a similar mouse as PIFS that capitalizes onreadily inducible acute CNS vascular permeability mediated by a well-defined immune cell type.Confirming the existence of homologous inflammatory mechanisms in humans would be the firststep toward therapeutic intervention of neurological diseases in which neuroinflammationinduced CNS vascular permeability plays a significant part. To accomplish these aims, we willemploy: (a) flow cytometry, (b) behavioral studies, (c) high resolution confocal microscopy andimmunohistochemistry, (d) 2-photon intravital microscopy (e) protein biochemistry, and (f) smallmammal MRI.
|Effective start/end date||7/1/16 → 6/30/17|
- National Institutes of Health: $397,500.00