BIOLOGY OF THE VASCULATURE OF HUMAN PRIMARY BRAIN TUMORS

这是一项脑瘤研究的可行性拨款申请 来自西北大学及其附属医院的研究中心。 尽管对生物行为的认识有了实质性的提高 恶性原发脑肿瘤的早期显著改善 经诊断，脑肿瘤患者的存活率并没有提高。 这是一组调查人员首次提出申请 精心组装，将临床和基础研究优势带到 西北大学脑肿瘤的研究和治疗。 目前正在进行更多的教师招聘工作，并计划招聘更多的教师 在这项可行性拨款的三年期间，当 完成后，将带来团队的研究和临床补充 在某种程度上，它可以进行广泛的基础和临床协作 研究并能成功竞争全计划项目资助 三年后申请。这个应用程序的中心主题是 血管生成及其功能后果。血管生成是一种 原发脑瘤生长的必然后果，但其功能 可能是近乎正常的或极度异常的，尤其是 关于对脑肿瘤影响最大的血管属性 治疗，即渗透性。此应用程序中的四个项目将 关注血管生成的两个两极方面，即控制因素 启动，以及在另一极，船舶行为和响应 完全发展的肿瘤的治疗。这些项目将试图带来 这些非常基础和实用的杆子放在一起。项目1将重点放在 通过测量血液来改变脑瘤血管的特性- 恶性胶质瘤、少突胶质细胞瘤和 髓母细胞瘤和对普通治疗的反应。这是一个主题 在人类身上几乎没有关于它的定量信息，但 这最终必须成为理解交付任何 脑肿瘤的诊断或治疗物质。项目2是 旨在探索血管生成抑制的机制，聚焦 铜依赖酶在生长因子蛋白水解酶中的作用 互动。项目3打算开发新的体内方法来治疗 测量血管生成的发展和治疗效果。 这些新方法将增加我们关于血管系统的知识基础 脑瘤，让我们可以预测脑瘤的行为 血管，并作为药物脑内给药模型的基础 肿瘤。项目4假设蛋白质水解酶的产生 胶质瘤可能与原癌基因的异常表达有关， 并将研究原癌基因产物，次级细胞信使， 和蛋白水解酶，并确定这些是否与 血管生成和毛细血管功能。没有治疗性的研究是 包括在本申请中，但血管生成的治疗性试验 目前正在设计抑制剂，并将成为不可或缺的一部分 在第一年内完成这个项目。

This is a Feasibility Grant application for a Brain Tumor Research Center from Northwestern University and its affiliated hospitals. Despite substantially increased knowledge about the biological behavior of malignant primary brain tumors and significant improvements in early diagnosis, survival of patients with brain tumors has not improved. This is the first application from a team of investigators that has been carefully assembled to bring clinical and basic research strengths to the study and treatment of brain tumors at Northwestern University. Additional faculty recruitments are now occurring and more are planned over the three year period of this feasibility grant, which, when completed, will bring the research and clinical complement of the team to a point it can conduct extensive collaborative basic and clinical research and can successfully compete for a full Program Project Grant application in three years. The central theme of this application is angiogenesis and its functional consequences. Angiogenesis is an obligate consequence of primary brain tumor growth, and yet the function of the new vessels may be nearly normal or wildly abnormal, particularly with regard to the one vessel property that most affects brain tumor therapy, i.e., permeability. The four projects in this application will focus on the two polar aspects of angiogenesis, the factors controlling initiation, and, at the other pole, vessel behavior and responses to therapy in fully developed tumors. These projects will attempt to bring these very basic and applied poles together. Project 1 will focus on the altered properties of brain tumor blood vessels by measuring blood- to-tissue transport in malignant gliomas, oligodendrogliomas, and medulloblastomas, and responses to common therapy. This is a topic about which almost no quantitative information exists in humans, and yet which must ultimately form the basis for understanding delivery of any diagnostic or therapeutic substance to brain tumors. Project 2 is designed to explore the mechanisms of angiogenesis inhibition, focusing on the role of copper dependent enzymes in growth factor-protease interactions. Project 3 intends to develop novel in vivo methods for measuring the development of angiogenesis and the effects of therapy. These new methods will add to our knowledge base about the vasculature of brain tumors, allow us to predict the behavior of brain tumor vessels, and serve as the basis for modeling drug delivery to brain tumors. Project 4 hypothesizes that proteolytic enzyme production in gliomas can be related to the aberrant expression of proto-oncogenes, and will study proto-oncogene products, secondary cellular messengers, and proteolytic enzymes, and determine if these can be related to angiogenesis and capillary function. No therapeutic studies are included in this application, but therapeutic trials of angiogenesis inhibitors are currently being designed and will become an integral part of this program within the first year.