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具有耐药性，并伴有预后不良。因此，迫切需要阐明新的杀伤胶质肿瘤细胞的策略。表皮生长因子受体（EGFR）基因在大约一半的肿瘤中被扩增和过度表达。表皮生长因子作为一种有丝分裂原，其受体的过度表达可能导致癌症的过度增殖。然而，配体刺激过表达EGFR的细胞也可诱导细胞凋亡。因此，肿瘤生物学中的一个关键问题是：哪些因素决定了生长因子受体的过度激活是否导致有丝分裂发生或细胞凋亡？对细胞凋亡优先激活机制的进一步了解可能会导致更有效的治疗。我们的第一种方法是使用诱导转染系统来确定神经胶质瘤细胞中受体表达的阈值，从而使有丝分裂信号转变为死亡信号。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，并导致参与凋亡的关键蛋白（如RIP和Caspase-8）在体外和胶质肿瘤动物模型中募集到EGFR介导的胶质瘤细胞凋亡。申请人是一名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。本申请中概述的课程提供了严格而密集的教学和研究经验，这将使申请人能够追求独立研究人员的职业生涯。导师是Beth Israel Deaconess Medical Center （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。临床导师是一名神经肿瘤学家，也是BIDMC脑肿瘤中心的联合主任。哈佛医学院BIDMC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.