Analysis of CD95L and TRAIL apoptotic pathways in glioma.

胶质瘤中CD95L和TRAIL凋亡途径的分析。

• 批准号: nhmrc : 145689
• 负责人: A/Pr Christine Hawkins
• 金额: $ 28.21万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2001
• 资助国家: 澳大利亚
• 起止时间: 2001-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/analysis-cd95l-trail-pathways-glioma/96886
• 关键词: Analysis; CD95L; TRAIL; apoptotic; pathways

Most patients with the brain cancer malignant glioma die within two years of diagnosis, thus innovative approaches to treatment are desperately needed. Mutations which prevent the precancerous cells from responding to suicide (apoptotic) signals can contribute to tumourigenesis. As standard treatment regimes act by inducing this cellular suicide machinery, tumour cells with apoptotic pathway alterations can be resistant to conventional therapies. Malignant gliomas are typically resistant to chemo- and radiotherapy, and therefore may have altered apoptotic pathways. By identifying the components of apoptotic pathways in glioma cells, rational design of either novel drugs, or treatments which will restore-enable susceptibility of the tumour cells to currently available therapies will be feasible. Here we will focus on the suicide pathways triggered by the molecules CD95L and TRAIL. We will characterise the sensitivity of glioma cells to CD95L and TRAIL, chemotherapeutic drugs and irradiation. We will then systematically survey the molecules implicated in CD95L and TRAIL-mediated cell death, based on studies in other cell types, to determine the relevant components of the molecular pathways which lead to apoptosis following CD95L-TRAIL exposure. We will also assess the roles played by known inhibitors, in determining resistance to CD95L and-or TRAIL, and will perform screens for novel inhibitors of these pathways. This study will elucidate the molecules responsible for the CD95L-TRAIL-mediated apoptosis seen in some glioma cells, and the molecules which confer resistance to these treatments in others. We will also learn whether the typical resistance to chemo- and radiotherapy observed in gliomas is mechanistically linked to resistance to CD95 and-or TRAIL resistance. This knowledge will be valuable for the rational design of diagnostic and therapeutic agents for glioma, and potentially for other diseases.

大多数患有脑癌恶性胶质瘤的患者在诊断后两年内死亡，因此迫切需要创新的治疗方法。阻止癌前细胞对自杀（凋亡）信号作出反应的突变可能有助于肿瘤发生。由于标准治疗方案通过诱导这种细胞自杀机制起作用，具有凋亡途径改变的肿瘤细胞可能对常规疗法具有抗性。恶性神经胶质瘤通常对化疗和放疗具有抗性，因此可能改变了凋亡途径。通过鉴定神经胶质瘤细胞中凋亡途径的成分，合理设计新药或治疗方法将是可行的，这些药物或治疗方法将恢复肿瘤细胞对目前可用疗法的易感性。在这里，我们将重点关注由分子CD 95 L和TRAIL触发的自杀途径。本研究将探讨胶质瘤细胞对CD 95 L、TRAIL、化疗药物及放疗的敏感性。然后，我们将系统地调查参与CD 95 L和TRAIL介导的细胞死亡的分子，在其他细胞类型的研究的基础上，以确定导致CD 95 L-TRAIL暴露后细胞凋亡的分子途径的相关组成部分。我们还将评估已知抑制剂在确定对CD 95 L和/或TRAIL的抗性中所起的作用，并将筛选这些途径的新型抑制剂。这项研究将阐明在一些胶质瘤细胞中观察到的负责CD 95 L-TRAIL介导的凋亡的分子，以及在其他细胞中赋予对这些治疗的抗性的分子。我们还将了解在神经胶质瘤中观察到的对化疗和放疗的典型抵抗是否与对CD 95和/或TRAIL的抵抗机制有关。这些知识将是有价值的诊断和治疗药物的合理设计胶质瘤，并可能为其他疾病。