An Investigation of the Cell of Origin in Gliomagenesis

胶质瘤发生中起源细胞的研究

• 批准号: 6620729
• 负责人: Robert M. Bachoo
• 金额: $ 17.12万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620729
• 关键词: SCID mouse; astrocytes; astrocytoma; biological signal transduction; cell differentiation; cell growth regulation; cell migration; cell proliferation; epidermal growth factor; gene expression; genetic promoter element; genetically modified animals; glia; glial fibrillary acidic protein; glioma; growth factor receptors; histogenesis; in situ hybridization; laboratory mouse; microarray technology; neoplasm /cancer genetics; neoplastic process; nerve stem cell; northern blottings; protein structure function; tissue /cell culture

DESCRIPTION (provided by applicant): Prominent biological features of normal astrocyte development include proliferation, migration and differentiation, all features recapitulated in the malignant progression of gliomas. The regulation of these processes is largely unknown although there is good evidence that Epidermal Growth Factor Receptor (EGFR) signaling may play a role in the growth and differentiation of the glial lineage. Correspondingly, EGFR also appears to be a major target in gliomagenesis where mutational activation of EGFR is associated with acquisition of the aggressive hallmarks of glioblastoma. Available evidence suggests that an immature differentiation state and INK4a deficiency act in concert to provide a permissive environment for the transforming actions of activated EGFR. My longterm goal is to understand how interactions between cellular differentiation, EGFR activation and INK4a deficiency effect the transformation of glia. My working hypothesis is that EGFR activation cooperates with INK4a deficiency in gliomagenesis and that the biological phenotype resulting from this interaction may be modulated by the cellular state of differentiation. Specific Aim 1: To generate and characterize a transgenic mouse that directs the expression of the tetracycline activator, rtTA, under the control of the astrocyte-specific GFAJP promoter. Specific Aim 2: To compare the impact of EGFR* activation on normal and INK4a deficient neural stem cells and mature astrocyte in cell culture. Specific Aim 3: To compare the EGFR* transcriptome in neural stem cells and mature astrocytes both wild-type or deficient for INK4a by cDNA microarray expression profiling. Specific Aim 4: To initiate a functional analysis of genes (identified in Specific Aim 3) whose expression is altered as a result of the state of cellular differentiation and INK4a status.

描述（由申请人提供）：正常人的突出生物学特征 星形胶质细胞的发育包括增殖、迁移和分化，所有这些 神经胶质瘤恶性进展的特点。法规 尽管有充分的证据表明，这些过程的具体过程在很大程度上是未知的 表皮生长因子受体 (EGFR) 信号传导可能在生长中发挥作用 和神经胶质谱系的分化。相应地，EGFR 似乎也 是神经胶质瘤发生的主要靶标，其中 EGFR 的突变激活是 与胶质母细胞瘤侵袭性特征的获得有关。 现有证据表明，未成熟的分化状态和 INK4a 协调行动，为缺陷提供宽松的环境 激活的 EGFR 的转化作用。我的长期目标是了解如何 细胞分化、EGFR 激活和 INK4a 之间的相互作用 缺乏会影响神经胶质细胞的转化。我的工作假设是 EGFR 激活与神经胶质瘤发生中的 INK4a 缺陷协同作用，并且 这种相互作用产生的生物表型可能受到以下因素的调节 细胞的分化状态。具体目标 1：生成并表征 指导四环素激活剂表达的转基因小鼠， rtTA，在星形胶质细胞特异性 GFAJP 启动子的控制下。具体目标 2：比较 EGFR* 激活对正常和 INK4a 缺陷的影响 细胞培养中的神经干细胞和成熟星形胶质细胞。具体目标 3： 比较神经干细胞和成熟星形胶质细胞中的 EGFR* 转录组 通过 cDNA 微阵列表达谱分析发现 INK4a 为野生型或缺陷型。 具体目标 4：启动基因功能分析（在 具体目标 3) 其表达因以下状态而改变 细胞分化和 INK4a 状态。