GENETIC PATHWAYS TOWARD GLIOMAGENESIS

描述（申请人描述）： 新发胶质母细胞瘤患者 多形性的中位生存期为9个月， 可用的治疗。 尽管低级别星形细胞瘤的预后 在至少50%的病例中，这些肿瘤会 进展为中级（间变性）星形细胞瘤，最后 多形性胶质母细胞瘤肝纤维化发病机制的研究进展 这些致命的脑肿瘤由于缺乏真正的动物而受到阻碍 这个模型概括了这种疾病的遗传学和生物学。细胞遗传 对临床胶质瘤标本的分析已经确定了多种遗传病变， 已知参与致癌/肿瘤抑制途径。 申请人的工作假设是，不同的遗传途径 控制胶质母细胞瘤的两种临床亚型的发展。那些 从低或中等级别星形细胞瘤发展而来的肿瘤累积突变 随着时间的推移，参与生长、分化、凋亡和 血管生成，逐渐产生更具侵略性的表型。与此相反， 新生胶质母细胞瘤是以下因素的关键组合的结果： 其中初始表型是最高级别肿瘤的突变。的 DePinho实验室已经设计并广泛表征了 有几个基因缺失的小鼠，这些基因可能参与 这些不同疾病实体的发病机制。网站或资源的可用性 再加上实验室在转基因和基因敲除方面的专业知识， 技术，为申请人提供了一个独特的机会，以探讨 胶质瘤形成的遗传机制，建立自发的小鼠模型 胶质母细胞瘤，并获得在这些领域的概念和技术经验。 目的1：建立转基因小鼠，表达荧光标记的 中间丝，GFAP和巢蛋白，用作特异性标记物， 星形胶质细胞和干细胞。目标2：评估 癌基因EGFR的过度表达在乳腺癌发病机制中的作用 胶质母细胞瘤目的3：研究关键基因突变的生物学效应。 肿瘤抑制途径控制的生长，分化和生存 神经胶质细胞以及这些突变如何在功能上与活化的EGFR相互作用。 目的4：寻找与已知癌基因协同作用的基因， 抑制剂在恶性神经胶质瘤的发展和/或进展中的应用 完善的逆转录病毒插入方法。

DESCRIPTION (Applicant's Description): Patients with de novo glioblastoma multiforme have a median survival of nine months when treated with currently available therapy. Although the prognosis for low-grade astrocytomas is significantly better, in at least 50 percent of cases, these tumors will progress to intermediate-grade (anaplastic) astrocytomas and finally to glioblastoma multiforme. Progress in the understanding of the pathogenesis of these deadly brain tumors has been hampered by the lack of a bonafide animal model that recapitulates the genetics and biology of this disease. Cytogenetic analysis of clinical glioma specimens has identified multiple genetic lesions known to be involved in oncogenic/tumor suppressor pathways. The working hypothesis of the applicant is that distinct genetic pathways govern the development of the two clinical subtypes of glioblastoma. Those that develop from low- or intermediate-grade astrocytomas accumulate mutations over time in key pathways involved in growth, differentiation, apoptosis and angiogenesis, producing progressively more aggressive phenotypes. In contrast, de novo glioblastomas arise as a consequence of a critical combination of mutations in which the initial phenotype is the highest grade tumor. The DePinho laboratory has engineered and extensively characterized strains of mice with deletions of several of the genes which likely participate in the pathogenesis of these distinct disease entities. The availability of these mice coupled with the laboratory's expertise in transgenic and knockout technology, provides the applicant with a unique opportunity to probe the genetic mechanisms of gliomagenesis, develop a spontaneous mouse model of glioblastoma, and gain conceptual and technical experience in these areas. Aim 1: To generate a transgenic mouse that expresses fluorescently-labeled intermediate filaments, GFAP and nestin, to be used as specific markers of astrocytes and stem cells, respectively, in all experiments. Aim 2: To assess the role of overexpression of the oncogene, EGFR, in the pathogenesis of glioblastoma. Aim 3: To study the biological effects of known mutations in key tumor suppressor pathways governing growth, differentiation and survival of glial cells and how such mutations functionally interact with activated EGFR. Aim 4: To identify genes that cooperate with known oncogenes and tumor suppressors in the development and/or progression of malignant gliomas using a well-established retroviral insertional approach.