PRECLINICAL MOUSE: CENTRAL NERVOUS SYSTEM CANCERS

临床前小鼠：中枢神经系统癌症

• 批准号: 6377688
• 负责人: TERRY A VAN DYKE
• 金额: $ 90.61万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377688
• 关键词: angiogenesis inhibitors; biological models; cooperative study; disease /disorder model; epidermal growth factor; gene targeting; gene therapy; genetic strain; genetically modified animals; glioma; growth factor receptors; inbreeding; laboratory mouse; model design /development; mutant; neoplasm /cancer classification /staging; neoplasm /cancer genetics; neoplastic process; neuropathology; nonhuman therapy evaluation; transfection /expression vector; tumor suppressor genes

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.

四名研究人员构成了该提案的核心，每一位研究人员都为该联盟带来了特殊的专业知识。 PI Terry Van Dyke 博士利用小鼠操作策略研究癌症已有 16 年之久。 在分析抑癌基因p53和pRb的过程中，她的实验室利用转基因和敲除策略建立了多种肿瘤模型。 Eric Holland 博士是一位神经外科医生和新成立的研究者。作为 Varmus 实验室的研究员，他开发了一种对小鼠癌症基因进行短期体细胞分析的新方法。 他在定义生长因子在神经胶质细胞生长和迁移中的作用方面取得了重大进展。 David Louis 博士是一位神经病理学家，对人类神经胶质瘤的遗传病变感兴趣。 最近，他在 19 号染色体上绘制了一个新的神经胶质瘤特异性肿瘤抑制基因 (TSG)。R Jude Samulski 博士 (UNC) 是基因治疗领域的领导者，他开发了病毒载体，该载体在体内体细胞基因传递方面显示出巨大的潜力。 该提案的主要实验目标是开发能够准确反映人类神经胶质瘤阶段和类别的小鼠模型。 这里开发和使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。 Van Dyke 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 模型及其推导所使用的方法。 Holland 博士的工作将通过将体细胞基因引入小鼠大脑来定义细胞对人类神经胶质瘤中观察到的遗传变化的反应。 范戴克实验室将利用种系修饰策略来产生具有类似改变的小鼠品系。 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化到种系中的基因变化。 这些实验室的初步结果表明，在小鼠中产生神经胶质瘤样病理学方面取得了重大进展。 项目 4 将建立 pTEN 基因的神经胶质特异性靶向失活，这是人类神经胶质瘤中常见的失活。 该小鼠将用于模型推导，路易斯博士将评估小鼠中诱导的病理与人类中观察到的病理的相似程度。 将在人类和小鼠样本中进行组织学和遗传学研究。 Louis 实验室将完成神经胶质瘤特异性 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，我们将在现有和正在开发的小鼠模型中检查有限数量的治疗策略，包括 Holland 博士的 EGFR 靶向策略和 Drs. 的抗血管生成基因疗法。萨穆尔斯基和范戴克。