BIOCHEMISTRY OF BRAIN TUMOR MICROVESSEL DEVELOPMENT

脑肿瘤微血管发育的生物化学

• 批准号: 2332982
• 负责人: John J Laterra
• 金额: $ 20.62万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 1998-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2332982
• 关键词: angiogenesis; brain neoplasms; cell differentiation; cell growth regulation; human tissue; laboratory rat; mucopolysaccharides; neoplastic growth; plasminogen activator; protease inhibitor; proteoglycan; tissue /cell culture; vascular endothelium; vascular endothelium permeability; western blottings

Primary brain tumors cause over 12,000 deaths each year in the United States alone. Existing therapies are largely ineffective. Vessel- targeted therapies have substantial therapeutic potential since angiogenesis is required for solid tumor growth. In addition, blood- brain barrier dysfunction is a major cause of morbidity in patients with brain tumors. Because of the relationship between perivascular glia and microvessels within normal brain and gliomas, we have developed in vivo and in vitro methodologies to determine mechanisms by which these cells influence endothelial behavior. We have established that perivascular plasminogen activation regulates glioma angiogenesis and growth, and survival of glioma-bearing animals. The objectives of this application are to determine mechanisms by which glioma cells alter CNS microvessel growth and differentiation and to develop strategies for improving patient survival by targeting the plasminogen activation pathway. In vitro and in vivo experimental rat and human glioma models will be used to determine mechanisms by which glioma cells influence angiogenesis and endothelial differentiation. In aim #1 we will determine how astrocytes and glioma cells alter periendothelial plasminogen activation and microvessel morphogenesis. Plasminogen activators (PA) and PA inhibitors will be quantitated and localized in endothelial, glioma, and mixed glioma endothelial cultures. The effects of purified components of the P6 pathway will be determined. Findings will reveal mechanisms by which PAs regulate glioma-induced microvessel formation. In aim #2 we will establish roles of other glioma cell products during angiogenic cell interactions in vitro. Immunocytological and biochemical methods will be used to determine the functions of cell adhesion and de-adhesion molecules, collagen, collagenases, and proteoglycans during angiogenic glioma-endothelial interactions. In aim #3 we will use immunohistochemical and biochemical techniques to determine if specific PAs, PAIs, adhesion molecules, and extracellular matrix regulate microvessel growth and differentiation in normal brain and brain tumors in vivo. In aim #4 we will use systemic and interstitial drug delivery strategies to optimize the therapeutic response of intracranial gliomas to plasminogen activation inhibitors and to determine if responses are due to effects on tumor microvessel growth and endothelial barrier expression. Our findings will identify mechanisms by which glioma cells induce pathological microvessel responses and test novel vessel-targeted approaches to treating primary brain tumors.

在美国，原发性脑肿瘤每年导致超过12，000人死亡。 只有国家。 现有的治疗方法大多无效。 船只─ 靶向疗法具有显著的治疗潜力， 血管生成是实体瘤生长所必需的。 另外，血- 脑屏障功能障碍是脑血管病患者发病的主要原因。 脑瘤 由于血管周围神经胶质细胞与 在正常脑和神经胶质瘤内的微血管，我们已经在体内开发了 和体外方法来确定这些细胞 影响内皮细胞行为。 我们已经确定血管周围 纤溶酶原激活调节神经胶质瘤血管生成和生长，和 神经胶质瘤动物的存活率。 本申请的目的 是为了确定神经胶质瘤细胞改变CNS微血管的机制， 增长和差异化，并制定战略， 通过靶向纤溶酶原激活途径来提高患者存活率。 将在体外和体内实验大鼠和人类胶质瘤模型， 用于确定神经胶质瘤细胞影响血管生成的机制 和内皮分化。 在目标#1中，我们将确定如何 星形胶质细胞和胶质瘤细胞改变内皮细胞周围纤溶酶原激活 和微血管形态发生。 纤溶酶原激活剂（PA）和PA 抑制剂将被定量并定位在内皮细胞、神经胶质瘤和 混合胶质瘤内皮培养物。 纯化成分的效果 P6通道将被确定。 研究结果将揭示机制 PA通过其调节胶质瘤诱导的微血管形成。 目标#2 我们将确定其他胶质瘤细胞产物在血管生成过程中的作用 体外细胞相互作用。 免疫细胞学和生物化学方法 将用于确定细胞粘附和去粘附的功能 分子、胶原蛋白、胶原酶和蛋白聚糖 胶质瘤-内皮细胞相互作用。 在目标#3中，我们将使用 免疫组织化学和生物化学技术，以确定是否特异性 PA、PAI、粘附分子和细胞外基质调节 正常脑和脑肿瘤中的微血管生长和分化 in vivo. 在目标#4中，我们将使用全身和间质药物递送 优化颅内胶质瘤治疗反应的策略 纤溶酶原激活抑制剂，并确定反应是否 由于对肿瘤微血管生长和内皮屏障的影响 表情 我们的发现将确定神经胶质瘤细胞 诱导病理性微血管反应并测试新血管靶向 治疗原发性脑肿瘤的方法。