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 upregulation 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 vasopressin V-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 be employed. 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.
| Szmydynger-Chodobska, Joanna; Gandy, Jessica R; Varone, Andrew et al. (2013) Synergistic interactions between cytokines and AVP at the blood-CSF barrier result in increased chemokine production and augmented influx of leukocytes after brain injury. PLoS One 8:e79328 |
| Szmydynger-Chodobska, Joanna; Strazielle, Nathalie; Gandy, Jessica R et al. (2012) Posttraumatic invasion of monocytes across the blood-cerebrospinal fluid barrier. J Cereb Blood Flow Metab 32:93-104 |
| Szmydynger-Chodobska, Joanna; Zink, Brian J; Chodobski, Adam (2011) Multiple sites of vasopressin synthesis in the injured brain. J Cereb Blood Flow Metab 31:47-51 |
| Chodobski, Adam; Zink, Brian J; Szmydynger-Chodobska, Joanna (2011) Blood-brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res 2:492-516 |
| Szmydynger-Chodobska, Joanna; Fox, Leora M; Lynch, Kirsten M et al. (2010) Vasopressin amplifies the production of proinflammatory mediators in traumatic brain injury. J Neurotrauma 27:1449-61 |
| Szmydynger-Chodobska, Joanna; Strazielle, Nathalie; Zink, Brian J et al. (2009) The role of the choroid plexus in neutrophil invasion after traumatic brain injury. J Cereb Blood Flow Metab 29:1503-16 |
| Pickering, Chris; Hagglund, Maria; Szmydynger-Chodobska, Joanna et al. (2008) The Adhesion GPCR GPR125 is specifically expressed in the choroid plexus and is upregulated following brain injury. BMC Neurosci 9:97 |
| Pascale, C L; Szmydynger-Chodobska, J; Sarri, J E et al. (2006) Traumatic brain injury results in a concomitant increase in neocortical expression of vasopressin and its V1a receptor. J Physiol Pharmacol 57 Suppl 11:161-7 |
| Szmydynger-Chodobska, Joanna; Chung, Insung; Chodobski, Adam (2006) Chronic hypernatremia increases the expression of vasopressin and voltage-gated Na channels in the rat choroid plexus. Neuroendocrinology 84:339-45 |
| Redzic, Zoran B; Preston, Jane E; Duncan, John A et al. (2005) The choroid plexus-cerebrospinal fluid system: from development to aging. Curr Top Dev Biol 71:1-52 |
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