TUMOR-DERIVED VASCULAR FERMEABILITY FACTOR & BRAIN EDEMA

肿瘤源性血管通透性因子

• 批准号: 3460221
• 负责人: GREGORY R CRISCUOLO
• 金额: $ 10.73万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3460221
• 关键词: antiinflammatory agents; benzodiazepines; blood brain barrier; brain edema; brain metabolism; brain neoplasms; calcium channel blockers; calcium flux; corticosteroids; dexamethasone; dihydropyridines; dyes; fluorescence spectrometry; glioma; human tissue; laboratory rat; phenylalkylamine; radiotracer; retina; tissue /cell culture; vascular endothelium permeability

The long-term objective of this research program is to advance the current knowledge of blood-brain barrier disruption in the setting of tumor-associated brain edema. This will be accomplished by studying a vascular permeability factor (VPF), that is expressed by malignant glial tumors grown in tissue culture. In addition to promoting microvascular permeability, partially purified VPF is known to induce transient changes in endothelial cytosolic calcium. Of particular interest is how the VPF-induced intracellular calcium ion flux, alterations in the F-actin content, and changes in endothelial cytoarchitecture, may relate to impaired blood-brain barrier integrity in the setting of intracerebral tumor. Furthermore, the mechanism of glucocorticosteroid-induced inhibition of VPF activity, and its relevance to the known clinical efficacy of dexamethasone in the setting of neoplastic brain edema will be studied. This research seeks to supplement the current understanding of neoplastic blood-brain barrier disruption in hopes of proposing novel and more effective therapeutic alternatives. Specifically, to test the hypothesis that: VPF plays an integral role in the genesis of neoplastic brain edema. The following specific aims have been devised to support or test this hypothesis. To determine if: (1) VPF is capable of inducing cytosolic calcium changes in cultured brain and retinal endothelial cells, (2) VPF is capable of altering the cytoarchitecture of brain and retinal endothelial cells grown in monolayer cultures, (3) VPF is capable of altering the physiological barrier integrity of brain and retinal endothelial cells grown in monolayer cultures, (4) VPF activity may be inhibited in vitro and in vivo is; and to propose that effective inhibitory agents (VPF antagonists) may be applicable to the treatment of tumor-induced vasogenic brain edema. The methodology will include standard tissue culture techniques, use of a biological assay for quantifying VPF induced microvascular permeability, determination of endothelial cytosolic calcium changes in response to VPF exposure using a fluorescent intracellular calcium ion probe (fura-2/AM), monitoring endothelial cells for evidence of VPF-induced cytoarchitectural changes. by assaying for F-actin and by using electron microscopy, and using radiolabeled albumin to study the barrier integrity of endothelial cells grown in monolayers. The health-relatedness of this project derives from the substantial morbidity associated with peritumoral brain edema. Improvements in therapeutic intervention will result from a more complete understanding of this process. Ultimately, effective treatment of neoplastic brain edema will reduce the risk of surgically-induced neurological deficits, and improve patient tolerance of adjunctive radiotherapy, chemotherapy, and immunotherapy.

这项研究计划的长期目标是推动目前的 了解血脑屏障破坏的背景下， 肿瘤相关的脑水肿 这将通过研究一个 血管通透性因子（VPF），由恶性胶质细胞表达， 在组织培养中生长的肿瘤。 除了促进微血管 部分纯化的VPF已知可诱导瞬时变化 在内皮细胞胞浆钙中。 特别令人感兴趣的是 VPF诱导的细胞内钙离子流，F-肌动蛋白的改变 内容物和内皮细胞结构的变化可能与 在脑内出血的情况下血脑屏障完整性受损 肿瘤 此外，糖皮质激素诱导的 VPF活性的抑制，及其与已知临床 地塞米松在肿瘤性脑水肿的情况下的疗效将是 研究了 这项研究旨在补充目前对 肿瘤性血脑屏障破坏，希望提出新的， 更有效的治疗方法。 具体来说，为了测试 假设：VPF在肿瘤的发生中起着不可或缺的作用 脑水肿 制定了以下具体目标， 测试这个假设。 确定：（1）VPF是否能够诱导 培养的脑和视网膜内皮细胞中的胞质钙变化， (2)VPF能够改变脑和视网膜的细胞结构， 单层培养的内皮细胞，（3）VPF能够 改变脑和视网膜的生理屏障完整性 单层培养的内皮细胞，（4）VPF活性可能是 抑制在体外和体内;并提出有效的抑制， 药物（VPF拮抗剂）可用于治疗 肿瘤引起的血管源性脑水肿 该方法将包括标准 组织培养技术，使用生物测定法定量VPF 诱导微血管通透性，内皮细胞胞浆 钙变化响应VPF暴露使用荧光 细胞内钙离子探针（fura-2/AM），监测内皮细胞 VPF诱导的细胞结构变化的证据。通过测定 肌动蛋白和使用电子显微镜，并使用放射性标记的白蛋白， 研究单层内皮细胞的屏障完整性。 的 该项目的健康相关性来自于 与瘤周脑水肿有关 改善治疗 更全面地了解这一点， 过程 最终，肿瘤性脑水肿的有效治疗将 降低神经系统损伤的风险， 患者对连续放疗、化疗的耐受性， 免疫疗法。