Role of the BBB and Choroid Plexus in VP-mediated Edema

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. Cerebral edema is a major clinical problem in the management of patients with various forms of brain injury, such as traumatic brain injury (TBI), ischemic stroke, and intracerebral hemorrhage. Yet, in the past decades, very limited progress has been made in identifying new potential targets for the treatment of this condition. Although several factors have been found to mediate disruption of the blood-brain barrier (BBB) and promote the formation of edema in an injured brain, therapeutic targeting of these factors may frequently have undesirable side effects or be difficult to accomplish. Increasing evidence, supported by a number of animal studies and clinical findings, indicates that vasopressin(VP) critically contributes to the opening of the BBB and the formation of edema after brain injury. However,an understanding of the cellular and molecular mechanisms underlying these VP actions is incomplete. Based on new data obtained in this laboratory, it is hypothesized that VP exacerbates brain edema both by increasing astrocyte synthesis of a potent vascular permeability factor, vascular endothelial growth factor (VEGF), and by facilitating neutrophil invasion of the CNS. To test the above hypothesis, the following specific aims are proposed: Aim 1 - Define the signaling cascade mediating the VP-dependent increase in astrocyte VEGF expression, and assess the therapeutic efficacy of interfering with VP signaling in a rat model of TBI; Aim 2 - Investigate the VP-mediated up- regulation of chemokine synthesis in the choroid plexus and astroglia, and determine its role in promoting neutrophil invasion after TBI; Aim 3 - Characterize the transcriptional regulation of the vasopressinV-ia receptor, whose expression is highly increased after TBI. In these experiments, we will use a combination of in vivo and in vitro approaches, such as the rat model of TBI, as well as astrocyte and choroid plexus cell cultures. Several methodologies, including molecular and biochemical techniques, will also beemployed. The long-term objective of this proposal is to define the cellular and molecular mechanisms underlying the VP-dependent formation of cerebral edema. The results obtained may have important implications for designing novel therapeutic strategies for intervening in such CNS disorders as TBI, ischemic stroke, and intracerebral hemorrhage.