This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Blood-brain barrier (BBB) disruption is a hallmark of nervous system diseases associated with vascular permeability and leakage of blood proteins into the CNS, such as stroke, multiple sclerosis (MS), Alzheimers Disease (AD), brain glioblastomas and spinal cord injury. Even though vascular abnormalities and persistent BBB disruption represent one of the early histopathological alterations of demyelinating lesions in MS and areas of neurodegeneration in AD and stroke, the molecular basis of how vascular permeability impairs brain function remains largely unknown. Our previous studies identified blood factors that when deposited in the nervous system after BBB disruption, they inhibit peripheral nerve regeneration and exacerbate inflammatory demyelination in the central nervous system in an animal model for MS. The specific hypothesis in this proposal is that BBB disruption that leads to leakage of blood in the CNS is responsible for microglia activation. Our hypothesis is based on the observations that: 1. Using two-photon microscopy, microglia respond very rapidly by process extension and isolation of the traumatized sites to blood vessel damage in the brain; 2. Microglia can get activated in vitro in response to blood factors, resulting in a dynamic rearrangement of the actin cytoskeleton, membrane ruffling, and increased phagocytosis. Based on these observations, the experimental focus of this proposal is on the direct demonstration of microglial activation by BBB disruption and blood leakage using live imaging in the mouse brain. Since several molecular pathways of microglial activation in response to blood factors have being elucidated, we plan to test the involvement of these pathways by pharmacologic and genetic manipulations in combination to our in vivo imaging approach. By doing so, we expect our work to provide a state-of-the-art demonstration of the molecular link between blood factors and brain parenchyma as it relates to glial cell activation, a hallmark of several cerebrovascular and neurodegenerative pathologies.
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