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

BBB 和脉络丛在 VP 介导的水肿中的作用

• 批准号: 6985899
• 负责人: ADAM CHODOBSKI
• 金额: $ 38.79万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985899
• 关键词: astrocytes; biological signal transduction; blood brain barrier; brain edema; brain injury; cell differentiation; cellular pathology; chemokine; choroid plexus; disease /disorder model; enzyme linked immunosorbent assay; hormone receptor; hormone regulation /control mechanism; laboratory rat; mitogen activated protein kinase; molecular pathology; neutrophil; nuclear factor kappa beta; polymerase chain reaction; protein biosynthesis; receptor expression; tissue /cell culture; vascular endothelial growth factors; vasopressins

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：脑水肿是治疗各种形式的脑损伤患者的主要临床问题，如创伤性脑损伤(TBI)、缺血性中风和脑内出血。然而，在过去的几十年里，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。尽管已发现多种因素可以破坏血脑屏障(BBB)并促进脑损伤后脑水肿的形成，但针对这些因素的治疗往往会产生不良的副作用或难以实现。越来越多的证据表明，血管加压素(VP)在脑损伤后血脑屏障的开放和水肿的形成中起关键作用，并得到了许多动物研究和临床研究的支持。然而，对这些VP作用背后的细胞和分子机制的了解是不完整的。根据本实验室获得的新数据，推测VP通过增加星形胶质细胞合成强大的血管通透性因子血管内皮生长因子(VEGF)和促进中性粒细胞对中枢神经系统的侵袭来加剧脑水肿。 为了验证上述假说，提出了以下具体目标：目的1-明确介导VP依赖的星形胶质细胞血管内皮生长因子表达增加的信号级联反应，并评估干预VP信号在大鼠脑损伤模型中的治疗效果； 目的：研究VP对脑外伤后脉络丛和星形胶质细胞趋化因子合成的上调作用，并探讨其在促进中性粒细胞侵袭中的作用； 目的3-研究脑创伤后血管加压素V-ia受体的转录调控。在这些实验中，我们将使用体内和体外相结合的方法，例如脑外伤大鼠模型，以及星形胶质细胞和脉络丛细胞培养。还将采用包括分子和生化技术在内的几种方法。 这项建议的长期目标是确定依赖VP的脑水肿形成的细胞和分子机制。这些结果可能对设计新的治疗策略以干预脑损伤、缺血性中风和脑出血等中枢神经系统疾病具有重要意义。