An Investigation of the Cell of Origin in Gliomagenesis

描述（由申请人提供）：正常人的突出生物学特征 星形胶质细胞发育包括增殖、迁移和分化，所有 胶质瘤恶性进展的特征。调控 这些过程在很大程度上是未知的，尽管有很好的证据表明， 表皮生长因子受体（EGFR）信号传导可能在生长中发挥作用， 和胶质细胞谱系的分化。相应地，EGFR似乎也 是胶质瘤形成的主要靶点，其中EGFR的突变激活是 与胶质母细胞瘤的侵袭性标志的获得有关。 现有的证据表明，不成熟的分化状态和INK4a 缺乏一致行动，以提供一个宽松的环境， 活化EGFR的转化作用。我的长期目标是了解 细胞分化、EGFR活化和INK4a之间的相互作用 缺乏影响胶质细胞的转化。我的假设是 EGFR活化与INK4a缺陷在胶质瘤形成中协同作用， 由这种相互作用产生的生物表型可以通过 细胞的分化状态。具体目标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* 活化对正常和INK4a缺陷型的影响 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， 野生型或INK4a缺陷型。 具体目标4：启动基因的功能分析（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。

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.