EGFR MEDIATED APOPTOSIS IN GLIOMAS

多形性胶质母细胞瘤是中枢神经系统最常见的恶性肿瘤。它对目前的治疗方法有抗性，并且与预后不良有关。因此，迫切需要阐明杀死神经胶质肿瘤细胞的新策略。表皮生长因子受体（EGFR）基因在这些肿瘤中的大约一半中扩增和过表达。表皮生长因子作为有丝分裂原，其受体的过度表达可能导致癌症中的过度增殖。然而，过表达EGFR的细胞的配体刺激也已显示诱导细胞凋亡。因此，肿瘤生物学中一个关键的问题是：是什么因素决定了生长因子受体的过度激活是否导致有丝分裂还是凋亡？对细胞凋亡优先激活机制的进一步理解可能会导致更有效的治疗。我们的第一个方法将使用诱导型转染系统来确定神经胶质瘤细胞中受体表达的阈值，从而使促有丝分裂信号变为死亡信号。我们的初步数据表明，EGFR的过度表达导致细胞死亡途径的异常激活，并导致参与细胞凋亡的关键蛋白如RIP和Caspase-8在体外胶质瘤细胞以及胶质瘤动物模型中的EGFR介导的细胞凋亡的募集。申请人是一名经过委员会认证的神经科医生，曾照顾过神经系统肿瘤患者，并致力于学术神经肿瘤学的职业生涯。在此应用程序中概述的程序提供了一个严格和密集的教学和研究经验，这将使申请人追求作为一个独立的研究人员的职业生涯。导师是贝斯以色列女执事医疗中心（BIDMC）的癌症生物学主任，在受体酪氨酸激酶介导的信号转导方面拥有丰富的经验。临床导师是一位神经肿瘤学家，他是BIDMC脑肿瘤中心的联合主任。BIDMC的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。

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.