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: 6421333
• 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/6421333
• 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）：正常的突出生物学特征 星形胶质细胞的发展包括增殖，迁移和分化，所有这些 在神经胶质瘤的恶性进展中概括的特征。法规 尽管有充分的证据表明 表皮生长因子受体（EGFR）信号传导可能在生长中起作用 和神经胶质谱系的分化。相应地，EGFR似乎也 成为胶质激素的主要靶点，其中EGFR的突变激活 与获得胶质母细胞瘤的积极标志有关。 可用证据表明，未成熟的差异化状态和Ink4a 不足行为协同为提供一个宽松的环境 转换激活的EGFR的动作。我的长期目标是了解如何 细胞分化，EGFR激活与Ink4a之间的相互作用 缺乏影响神经胶质的转化。我的工作假设是 eGFR激活与胶质作用中的Ink4a缺乏合作，并且 这种相互作用引起的生物表型可能由 细胞分化状态。特定目的1：生成和表征 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不足的影响 神经干细胞和细胞培养中成熟的星形胶质细胞。特定目标3： 比较神经干细胞和成熟星形胶质细胞中的EGFR*转录组 野生型或因cDNA微阵列表达分析而缺乏Ink4a。 特定目的4：启动基因的功能分析（在 特定目标3）由于状态而改变其表达 细胞分化和Ink4a状态。