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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：
8668168
负责人：
Renee D Read
金额：
$ 24.65万
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8668168
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、最致命的恶性肿瘤。“绿带运动”