Characterization of GEFT AS a Novel Glioblastoma Oncogene

GEFT 作为一种新型胶质母细胞瘤癌基因的表征

基本信息

批准号：
8266544
负责人：
Milan Girish Chheda
金额：
$ 17.09万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8266544
关键词：
1-Phosphatidylinositol 3-Kinase Affect Astrocytes Automobile Driving Biochemical Candidate Disease Gene Cell Count Cell Line Cell Proliferation Cell Survival Cells Central Nervous System Neoplasms Collection Development Epidermal Growth Factor Receptor Gene Targeting Genes Genetic Genomics Glioblastoma Glioma Goals Guanine Nucleotide Exchange Factors Human In Vitro Instruction Life Maintenance Malignant Glioma Maps Mus Mutation Oncogenes Pathogenesis Pathway interactions Play Primary Brain Neoplasms Principal Investigator Process Proteins RNA Interference Recurrence Role Signal Pathway Signal Transduction Testing Tumor Suppressor Genes Tumorigenicity Xenograft procedure aggressive therapy cancer genome cell growth neoplastic cell novel oncogene addiction protein protein interaction research study response rho GTP-Binding Proteins small hairpin RNA tumor tumor growth tumorigenesis

项目摘要

Glioblastomas (GBM) are the most common and lethal primary central nervous system tumors. With the most aggressive therapy, median survival is 14.6 months. To date, there has not been a systematic approach to validate the function of candidate genes that are somatically amplified, for their role in glioma pathogenesis. These genes might play direct roles driving tumorigenesis, or tumor cells might depend on them for their survival and proliferation, a process known as "oncogene addiction." Therefore, these pathways are attractive targets for therapy. I performed an RNA interference screen targeting genes on regions commonly amplified in GBM and identified GEFT, a guanine nucleotide exchange factor (GEF), as essential for GBM cell proliferation and/or viability. Using genetic and biochemical approaches, I propose to characterize GEFT and its protein- protein interactions. I will test how suppression of GEFT regulates cell growrth and/or survival, and test if over- expression is sufficient to transform genetically well defined, immortalized astrocytes into a malignant glioma state. Additionally, I will determine the effector(s) of GEFT for cell proliferation and/or survival. RELEVANCE (See instructions): Glioblastomas (GBM) are the most common and lethal primary brain tumors. With the most aggressive therapy, median survival is 14.6 months. I propose to characterize a gene, GEFT, that might play a role in formation and maintenance of these tumors.

胶质母细胞瘤（GBM）是最常见和致命的原发性中枢神经系统肿瘤。与最积极治疗，中位生存期为14.6个月。迄今为止，还没有一个系统的方法验证体细胞扩增的候选基因的功能，了解它们在神经胶质瘤发病机制中的作用。这些基因可能在驱动肿瘤发生方面发挥直接作用，或者肿瘤细胞可能依赖它们来发挥作用生存和增殖，这个过程被称为“癌基因成瘾”。因此，这些途径很有吸引力治疗的目标。我针对通常扩增的区域的基因进行了 RNA 干扰筛选 GBM 并确定 GEFT（一种鸟嘌呤核苷酸交换因子 (GEF)）对于 GBM 细胞增殖至关重要和/或生存能力。我建议使用遗传和生化方法来表征 GEFT 及其蛋白质- 蛋白质相互作用。我将测试 GEFT 的抑制如何调节细胞生长和/或存活，并测试是否过度- 表达足以将遗传明确的永生化星形胶质细胞转化为恶性神经胶质瘤状态。此外，我将确定 GEFT 对细胞增殖和/或存活的效应器。相关性（参见说明）：胶质母细胞瘤（GBM）是最常见和致命的原发性脑肿瘤。以最激进的方式治疗后，中位生存期为14.6个月。我建议描述一个基因 GEFT，它可能在这些肿瘤的形成和维持。