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: 7433719
• 负责人: ADAM CHODOBSKI
• 金额: $ 35.64万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7433719
• 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

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（由申请人提供）：脑水肿是治疗各种形式脑损伤（如创伤性脑损伤（TBI）、缺血性卒中和脑出血）患者的主要临床问题。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了非常有限的进展。尽管已经发现几种因素介导血脑屏障（BBB）的破坏并促进受伤脑中水肿的形成，但这些因素的治疗靶向可能经常具有不期望的副作用或难以实现。越来越多的证据表明，加压素（VP）在脑损伤后血脑屏障开放和水肿形成中起重要作用。然而，这些VP行动的细胞和分子机制的理解是不完整的。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强效血管通透性因子血管内皮生长因子（VEGF）和促进中性粒细胞侵入CNS而加重脑水肿。 目的1 -确定介导星形胶质细胞VEGF表达的VP依赖性增加的信号级联，并评估在TBI大鼠模型中干扰VP信号的治疗功效; 目的2 -研究VP介导的脉络丛和星形胶质细胞趋化因子合成的上调，并确定其在TBI后促进中性粒细胞侵袭中的作用; 目的3 -表征加压素V-Ia受体的转录调节，其表达在TBI后高度增加。在这些实验中，我们将使用体内和体外方法的组合，例如TBI的大鼠模型，以及星形胶质细胞和脉络丛细胞培养物。还将采用几种方法，包括分子和生物化学技术。 这项建议的长期目标是确定VP依赖性脑水肿形成的细胞和分子机制。所获得的结果可能具有重要的意义，设计新的治疗策略干预等中枢神经系统疾病，如创伤性脑损伤，缺血性中风，脑出血。