BIOCHEMISTRY OF BRAIN TUMOR MICROVESSEL DEVELOPMENT

在美国，每年有超过12,000人死于原发性脑瘤 只有一个州。现有的治疗方法在很大程度上无效。船只- 靶向治疗有很大的治疗潜力，因为 血管生成是实体瘤生长所必需的。另外，血液- 脑屏障功能障碍是脑血管疾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 正常大脑和胶质瘤中的微血管，我们已经在体内形成了 以及体外方法来确定这些细胞的机制 影响内皮细胞的行为。我们已经确定血管周围 纤溶酶原激活调节胶质瘤血管生成和生长 荷脑胶质瘤动物的存活。本应用程序的目标是 是为了确定胶质瘤细胞改变中枢神经系统微血管的机制 增长和差异化，并制定改进策略 通过靶向纤溶酶原激活途径使患者存活。 在体外和体内实验大鼠和人脑胶质瘤模型 用于确定胶质瘤细胞影响血管生成的机制 血管内皮细胞分化。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周纤溶酶原激活 和微血管形态发生。纤溶酶原激活物(PA)和PA 抑制物将在内皮细胞、胶质瘤和 混合神经胶质瘤内皮细胞培养。提纯成分的作用 P6通路的作用将被确定。研究结果将揭示机制 通过PAS调节胶质瘤诱导的微血管形成。在目标#2中 我们将确定其他胶质瘤细胞产品在血管生成过程中的作用 细胞在体外的相互作用。免疫细胞学和生化方法 将用于确定细胞黏附和去黏附的功能 血管生成过程中的分子、胶原、胶原酶和蛋白多糖 胶质瘤与内皮细胞的相互作用。在目标#3中，我们将使用 免疫组织化学和生化技术确定特异性 PAS、PAIS、黏附分子和细胞外基质调节 正常脑组织和脑肿瘤中微血管的生长和分化 在活体内。在目标4中，我们将使用全身给药和间质给药 优化颅内胶质瘤治疗反应的策略 以确定对纤溶酶原激活抑制剂的反应是否 由于对肿瘤微血管生长和内皮屏障的影响 表情。我们的发现将确定胶质瘤细胞 诱导病理性微血管反应并测试新的血管靶向 治疗原发脑肿瘤的方法。

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.