Revealing new regulators of EGFR-P13K driven glioma proliferation and migration

揭示 EGFR-P13K 驱动神经胶质瘤增殖和迁移的新调节因子

基本信息

批准号：
8504550
负责人：
Renee D Read
金额：
$ 24.03万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8504550
关键词：
1-Phosphatidylinositol 3-Kinase Apoptosis Astrocytes Bioinformatics Biological Assay Biological Models Brain Candidate Disease Gene Cell Communication Cells Chromosome Deletion Drosophila genus Epidermal Growth Factor Receptor Genes Genetic Genetic Screening Genetic Techniques Genome Glioblastoma Glioma Growth Human Instruction Integral Membrane Protein Laboratories Malignant Neoplasms Mammalian Genetics Modeling Molecular Neoplasm Metastasis Neoplasms Nervous system structure Neuroglia Neurons Orthologous Gene Output Pathogenesis Pathway interactions Pattern Phenotype Phosphotransferases Proliferating Property Proteins RNA Interference Regulation Role Signal Pathway Signal Transduction System Therapeutic Training Translating Tumor Cell Invasion base cell transformation cell type fly follow-up human disease insight loss of function migration mouse model neoplastic novel overexpression response therapeutic target tumor

项目摘要

Glioblastoma (GBM) is the most common and deadly malignant tumor of the centrail nervous system. GBM cells proliferate rapidly and diffusely infiltrate the brain, properties which render these tumors largely incurable. To effectively control GBM, the mechanisms underlying tumor cell invasion and proliferation must be understood and targeted with novei therapies. Constitutive activation of the EGFR-Ras and PI-3 kinase (PI3K) signaling pathways is a common feature in human GBM and is sufficient to cause glioblastoma-like phenotypes in mouse models. How these signaling pathways specifically control glial pathogenesis is unclear. A novel Drosophila model was created to understand the molecular basis df EGFR and PI3K driven GBM. When targeted to glia and glial precursors using genetic techniques, co-activation of EGFR and PI3K in Drosophila gives rise to neoplastic, invasive glial cells that create transplantable tumor-like growths^ mimicking the human disease. This mode! has been used to identify new regulators of glial neoplasia through genetic screens and phenotypic analyses. Human orthologs of novel genes identified in these screens were assessed for their involvement in human GBM because they represent excellent candidates for genes directly involved in the pathogenesis. My results reveal atypical kinases that are necessary forthe proliferation and survival of GBM cells, and that one of these kinases sufficient for transformation of irnmortalized astrocytes. My results suggest that overexpression of these kinases creates a feedforward loop that promotes and maintains GBM cell transformation, and disruption of this loop triggers apoptosis of GBM cells. Proposed iStudies of these kinases are aimed,at elucidating their specific roles in transformation and EGFR-PI3K signaling in both Drosophila and mammalian systems.

胶质母细胞瘤（GBM）是中枢神经系统最常见和致命的恶性肿瘤。胶质母细胞瘤细胞迅速增殖并广泛浸润大脑，这些特性使得这些肿瘤在很大程度上无法治愈的。为了有效控制GBM，必须研究肿瘤细胞侵袭和增殖的机制被理解并被新疗法瞄准。 EGFR-Ras 和 PI-3 激酶的组成型激活 (PI3K) 信号通路是人类 GBM 的常见特征，足以引起胶质母细胞瘤样小鼠模型中的表型。这些信号通路如何特异性控制神经胶质细胞的发病机制不清楚。创建了一种新的果蝇模型来了解 EGFR 和 PI3K 驱动的分子基础 GBM。当使用遗传技术靶向神经胶质细胞和神经胶质前体细胞时，EGFR 和 PI3K 的共激活在果蝇中产生肿瘤性、侵袭性神经胶质细胞，从而产生可移植的肿瘤样生长^ 模仿人类疾病。这个模式！已被用于识别神经胶质瘤形成的新调节因子通过遗传筛选和表型分析。在这些中鉴定出的新基因的人类直系同源物评估屏幕对人类 GBM 的参与程度，因为它们代表了优秀的候选者直接参与发病机制的基因。我的结果揭示了非典型激酶，这是 GBM 细胞的增殖和存活，并且这些激酶之一足以转化永生化星形胶质细胞。我的结果表明这些激酶的过度表达会产生前馈循环促进和维持 GBM 细胞转化，破坏该循环会触发 GBM 细胞凋亡细胞。对这些激酶的拟议研究旨在阐明它们在转化和果蝇和哺乳动物系统中的 EGFR-PI3K 信号传导。