EGFR MEDIATED APOPTOSIS IN GLIOMAS

EGFR 介导的胶质瘤细胞凋亡

• 批准号: 6633249
• 负责人: AMYN HABIB
• 金额: $ 6.2万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-22 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6633249
• 关键词: apoptosis; athymic mouse; biological signal transduction; cell line; cell proliferation; disease /disorder model; epidermal growth factor; glioma; growth factor receptors; receptor expression; tissue /cell culture; transfection

Glioblastoma Multiforme is the most common malignant tumor of the central nervous system. It is resistant to current methods of treatment and is associated with a poor prognosis. The elucidation of novel strategies to kill glial tumor cells is thus an urgent need. The epidermal growth factor receptor (EGFR) gene is amplified and over- expressed in about half of these tumors. Epidermal growth factor acts as a mitogen and over-expression of its receptor may contribute to the excessive proliferation seen in cancer. However, ligand stimulation of cells over-expressing the EGFR also has been shown to induce apoptosis. Thus a key answered question in tumor biology is: what are the factors which determine whether excessive activation of growth factor receptors leads to mitogenesis versus apoptosis? An improved understanding of mechanisms involved in the preferential activation of apoptosis may lead to more effective treatment. Our first approach will e to use inducible transfection systems to determine the threshold of receptor expression in glioma cells whereby a mitogenic signal changes to a death signal. Our preliminary data suggests that over-expression of the EGFR results in the aberrant activation of cell death pathways and leads to the recruitment of key proteins involved in apoptosis such as RIP and Caspase-8 to the EGFR mediated apoptosis in glioma cells in vitro as well as in animal models of glial tumors. The applicant is a board-certified neurologist who has taken care of patients with nervous system tumors and is committed to a career in academic neuro-oncology. The program outlined in this application provides a rigorous and intensive didactic and research experience, which will enable the applicant to pursue a career as an independent researcher. The mentor is the Director of Cancer Biology at Beth Israel Deaconess Medical Center (BIDMC), and has extensive experience in signal transduction mediated by receptor tyrosine kinases. The clinical mentor is a neuro-oncologist who is the Co-Director of the Brain Tumor Center at BIDMC. The academic environment at Harvard Medical School at BIDMC is well suited to pursue the goals outlined in this application.

多形胶质母细胞瘤是中枢神经系统中最常见的恶性肿瘤。它抗当前的治疗方法，与预后不良有关。因此，阐明杀死神经胶质肿瘤细胞的新型策略是迫切需要的。表皮生长因子受体（EGFR）基因在这些肿瘤的大约一半中被扩增并过度表达。表皮生长因子充当有丝分裂原，其受体的过表达可能导致癌症中看到的过度增殖。然而，过表达EGFR的细胞的配体刺激也已被证明会诱导凋亡。因此，肿瘤生物学中的一个关键回答问题是：确定生长因子受体过度激活是否导致有丝分裂而不是凋亡的因素是什么？对凋亡的优先激活涉及的机制有了改进的理解，可能会导致更有效的治疗方法。我们的第一种方法将使用可诱导的转染系统来确定神经胶质瘤细胞中受体表达的阈值，从而将有丝分裂信号变为死亡信号。我们的初步数据表明，EGFR的过表达导致细胞死亡途径的异常激活，并导致募集参与凋亡的关键蛋白，例如RIP和CASPASE-8，以EGFR介导的胶质瘤细胞中的EGFR介导的凋亡以及在胶质性肿瘤模型中的胶质瘤细胞中的凋亡。申请人是一名经过董事会认证的神经科医生，他已经照顾了神经系统肿瘤的患者，并致力于从事学术神经肿瘤学的职业。本申请中概述的计划提供了严格而密集的教学和研究经验，这将使申请人能够从事独立研究人员的职业。这位导师是贝丝以色列执事医疗中心（BIDMC）的癌症生物学主任，并且在受体酪氨酸激酶介导的信号转导方面具有丰富的经验。临床导师是一位神经肿瘤学家，是BIDMC脑肿瘤中心的联合导演。 BIDMC哈佛医学院的学术环境非常适合追求本申请中概述的目标。