PRECLINICAL MOUSE: CENTRAL NERVOUS SYSTEM CANCERS

四名调查人员组成了这项提议的核心，每一人都为财团带来了特殊的专业知识。私家侦探特里·范戴克博士利用鼠标操纵策略研究癌症已有16年之久。在分析肿瘤抑制基因p53和pRb的过程中，她的实验室使用转基因和基因敲除策略建立了几个肿瘤模型。埃里克·霍兰德博士是一名神经外科医生，也是一名新成立的调查员。当他在Varmus实验室担任研究助理时，他开发了一种新的方法，用于对小鼠的癌症基因进行短期体细胞分析。他在确定生长因子在胶质细胞生长和迁移中的作用方面取得了重大进展。大卫·路易斯博士是一位神经病理学家，对人类胶质瘤的基因损伤很感兴趣。最近，他在19号染色体上定位了一个新的胶质瘤特异性肿瘤抑制基因(TSG)。基因治疗领域的领先者R Jude Samulski(UNC)博士开发出了具有在体内传递体细胞基因的巨大潜力的病毒载体。这项提议的主要实验目标是开发准确反映人类胶质瘤分期和类别的小鼠模型。这里开发和利用的许多策略也可以更广泛地应用于其他中枢神经系统癌症模型。范戴克博士的实验室已经开发出一种脉络丛(CP)肿瘤模型，该模型在组织学上与人类疾病相似。它描述了CP模型及其推导方法。霍兰德博士的工作将通过将体细胞基因导入小鼠大脑来定义细胞对人类胶质瘤中观察到的遗传变化的反应。范戴克实验室将利用生殖系修改策略来产生具有类似变化的小鼠品系。范戴克和霍兰德之间的密切互动将有助于快速识别将被工程改造成生殖系的基因变化。这些实验室的初步结果表明，在小鼠身上产生胶质瘤样病理方面取得了重大进展。项目4将建立一种针对胶质细胞的PTEN基因的靶向失活，这是人类胶质瘤中常见的一种失活。这只小鼠将用于模型推导，路易斯博士将评估在小鼠身上诱导的病理与在人类中观察到的相似程度。将继续对人类和小鼠样本进行组织学和遗传学研究。Louis实验室将完成对胶质瘤特异性TSG的分离，Van Dyke实验室将使用基因靶向策略来评估其肿瘤抑制功能。最后，我们将在现有和开发中的小鼠模型中检查有限数量的治疗策略，包括Holland博士的EGFR靶向策略，以及Samulski和Van Dyke博士的抗血管生成基因疗法。

Four investigators, each of who bring special expertise to the consortium, comprise the core of this proposal. The PI, Dr. Terry Van Dyke, has utilized mouse manipulation strategies to study cancer for 16 years. In the course of analyzing the tumor suppressors p53 and pRb, her lab has established several tumor models using transgenic and knock-out strategies. Dr. Eric Holland is a Neurosurgeon and newly established investigator. While a research associate in the Varmus lab, he developed a novel approach for short term somatic analysis of cancer genes in the mouse. He has made significant progress in defining growth factor roles in glial cell growth and migration. Dr David Louis is a Neuropathologist interested in the genetic lesions of human glioma. Most recently he mapped a new glioma specific tumor suppressor gene (TSG) on chromosome 19. Dr R Jude Samulski (UNC), a leader in genetic therapy, has developed viral vectors that show great potential for somatic gene delivery in vivo. The major experimental goal of this proposal is to develop mouse models that accurately reflect stages and classes of human glioma. Many strategies developed and utilized here can also be applied more broadly to other CNS cancer models. Dr Van Dyke's laboratory has already developed a choroid plexus (CP) tumor model that is histologically similar to the human disease. It describes the CP model and the approaches used for its derivation. Dr Holland's work will define the cellular responses to genetic changes observed in human glioma by somatic gene introduction into the mouse brain. The Van Dyke lab will utilize germline modification strategies to generate mouse strains with similar alterations. Close interaction between Van Dyke and Holland will facilitate rapid identification of genetic changes to be engineered into the germline. Preliminary results from these labs indicate significant progress toward producing glioma- like pathologies in the mouse. Project 4 will establish a glial- specific targeted inactivation of the pTEN gene, a common inactivation in human glioma. This mouse will be used in model derivation, and Dr Louis will assess the extent to which pathologies induced in the mouse resemble those observed in humans. Histological and genetic studies in human and mouse samples will be pursued. The Louis lab will complete their isolation of the glioma-specific TSG, and the Van Dyke lab will use gene-targeting strategies to assess its tumor suppressor function. Finally, we will examine a limited number of therapeutic strategies in existing and developing mouse models, including EGFR-targeted strategies by Dr Holland and anti- angiogenesis gene therapy by Drs. Samulski and Van Dyke.