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: 7244230
• 负责人: ADAM CHODOBSKI
• 金额: $ 35.63万
• 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/7244230
• 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（申请人提供）：脑水肿是创伤性脑损伤（TBI）、缺血性脑卒中、脑出血等各种形式脑损伤患者治疗的主要临床问题。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的进展非常有限。虽然已经发现有几个因素可以介导血脑屏障（BBB）的破坏并促进损伤脑水肿的形成，但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。越来越多的动物研究和临床结果支持的证据表明，抗利尿激素（VP）对脑损伤后血脑屏障的开放和水肿的形成至关重要。然而，对这些VP作用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一种有效的血管通透性因子，血管内皮生长因子（VEGF），并促进中性粒细胞侵袭中枢神经系统，从而加剧脑水肿。