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: 7489257
• 负责人: ADAM CHODOBSKI
• 金额: $ 1.5万
• 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/7489257
• 关键词: Adverse effects; Animals; Apical; Astrocytes; Binding Sites; Biochemical; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Edema; Brain Injuries; Brattleboro Rats; Cell Line; Central Nervous System Diseases; Cerebral Edema; Cerebral hemisphere hemorrhage; Chemotactic Factors; Clinical; Condition; Consensus; Cultured Cells; DNA Binding; Data; Disruption; Edema; End Point; Enhancers; Epidermal Growth Factor Receptor; Epithelial Cells; Extracellular Signal Regulated Kinases; Genes; Growth Factor; In Vitro; Ischemic Stroke; Knowledge; Laboratories; Lesion; MAPK14 gene; Mediating; Membrane; Methodology; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mutate; Nuclear Translocation; Numbers; Parents; Pathologic; Patients; Peptide Fragments; Permeability; Phosphotransferases; Play; Promoter Regions; Radioactive; Rattus; Research Personnel; Role; Signal Transduction; Structure of choroid plexus; TNFRSF5 gene; Techniques; Testing; Transcriptional Activation; Transcriptional Regulation; Traumatic Brain Injury; Treatment Efficacy; Up-Regulation; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vasopressin Receptor; Vasopressins; Water; Western Blotting; base; cerebrovascular; chemokine; clinically relevant; cytokine; design; in vivo; inhibitor/antagonist; injured; kinase inhibitor; neutrophil; novel therapeutics; programs; promoter; receptor; research study; size; small molecule; stress-activated protein kinase 1; therapeutic target; transcription factor

. 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.

. 脑水肿是一个主要的临床问题，在管理病人的各种形式的脑 损伤，如创伤性脑损伤（TBI）、缺血性中风和脑内出血。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。 条件虽然已经发现几种因素介导血脑屏障（BBB）的破坏， 并促进损伤脑中水肿的形成，这些因子的治疗靶点可能经常 具有不希望的副作用或难以实现。越来越多的证据支持， 动物研究和临床结果表明，加压素（VP）对开放的关键性作用， 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行为的潜在机制是不完整的。根据本实验室获得的新数据， 假设VP通过增加星形胶质细胞合成 有效的血管通透性因子，血管内皮生长因子（VEGF），并通过促进 中性粒细胞侵入CNS。 为了检验上述假设，提出了以下具体目标：目标1 -定义信令 级联介导的星形胶质细胞VEGF表达的VP依赖性增加，并评估治疗 在TBI大鼠模型中干扰VP信号传导的功效;目的2 -研究VP介导的上调- 调节脉络丛和星形胶质细胞中趋化因子的合成，并确定其在促进 创伤性脑损伤后中性粒细胞侵袭;目的3 -表征加压素V-ia的转录调节 受体，其表达在TBI后高度增加。在这些实验中，我们将结合使用 体内和体外方法，如TBI大鼠模型，以及星形胶质细胞和脉络丛细胞， cultures.几种方法，包括分子和生物化学技术，也将被采用。 这项建议的长期目标是确定细胞和分子机制， VP依赖性脑水肿的形成。所获得的结果可能对以下方面具有重要意义： 设计新的治疗策略，用于干预诸如TBI、缺血性中风和 脑内出血