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

。 脑水肿是治疗各种形式脑损伤患者的一个主要临床问题。 损伤，如创伤性脑损伤(TBI)、缺血性中风和脑出血。然而，在过去， 几十年来，在确定治疗这种疾病的新的潜在靶点方面取得的进展非常有限 条件。虽然已经发现有几个因素可以调节血脑屏障(BBB)的破坏。 并促进损伤脑内水肿的形成，这些因素的治疗靶向可能经常 有不良的副作用或难以实现。越来越多的证据，得到了一些支持 动物研究和临床结果表明，血管加压素(VP)对心脏的开放起关键作用。 血脑屏障与脑损伤后水肿的形成。然而，对细胞和分子的理解 这些VP行动背后的机制是不完整的。根据这个实验室获得的新数据， 推测VP通过增加星形胶质细胞合成α-氨基丁酸来加重脑水肿。 强大的血管通透性因子，血管内皮生长因子(VEGF)，并通过促进 中性粒细胞侵入中枢神经系统。 为了验证上述假设，提出了以下具体目标：目标1-定义信令 级联介导VP依赖的星形胶质细胞血管内皮生长因子表达增加，并评价其治疗效果 干预VP信号通路在大鼠脑损伤模型中的作用目的2-探讨VP介导的UP-1信号转导途径 脉络丛和星形胶质细胞中趋化因子合成的调节及其促进作用 颅脑损伤后中性粒细胞的侵袭；目的3-表征加压素V-ia的转录调控 受体，其在颅脑损伤后的表达显著增加。在这些实验中，我们将结合使用 体内和体外方法，如大鼠脑外伤模型，以及星形胶质细胞和脉络丛细胞 文化。还将采用包括分子和生化技术在内的几种方法。 这项提议的长期目标是定义潜在的细胞和分子机制 VP依赖性脑水肿的形成。所获得的结果可能对 设计新的治疗策略来干预诸如脑外伤、缺血性中风和 脑内出血。

. 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.