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

• 批准号: 8130382
• 负责人: Milan Girish Chheda
• 金额: $ 11.56万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8130382
• 关键词: Characterization; GEFT; Novel; Glioblastoma; Oncogene

DESCRIPTION (provided by applicant): Project Summary: 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. Public Health Relevance: 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, which might play a role in formation and maintenance of these tumors.

描述（由申请人提供）： 项目摘要：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。采用最积极的治疗，中位生存期为 14.6 个月。迄今为止，还没有一种系统的方法来验证体细胞扩增的候选基因的功能及其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生存和增殖，这一过程被称为“癌基因成瘾”。因此，这些途径是有吸引力的治疗靶点。我针对 GBM 中常见扩增区域的基因进行了 RNA 干扰筛选，并鉴定出 GEFT（一种鸟嘌呤核苷酸交换因子 (GEF)）对于 GBM 细胞增殖和/或活力至关重要。我建议使用遗传和生化方法来描述 GEFT 及其蛋白质-蛋白质相互作用的特征。我将测试 GEFT 的抑制如何调节细胞生长和/或存活，并测试过度表达是否足以将基因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。 公共卫生相关性：胶质母细胞瘤 (GBM) 是最常见和致命的原发性脑肿瘤。采用最积极的治疗，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中发挥作用。