The influence of ionising radiation on intracellular pathways of the mitogen activated protein kinase (MAPK) family

电离辐射对丝裂原激活蛋白激酶（MAPK）家族细胞内通路的影响

• 批准号: 16668126
• 负责人: Dr. Melanie Wergin
• 金额: --
• 依托单位: Klinik für Bildgebende Diagnostik
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2005
• 资助国家: 德国
• 起止时间: 2004-12-31 至 2007-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/16668126?language=en
• 关键词: influence; ionising; radiation; intracellular; pathways

For radiotherapists, it is well known that different tumour types have different radiosensitivities. It is believed that a cross talk between tumour and endothelial cells have an impact on the radiosensitivity of solid tumours. Ionising radiation modulates signaling pathways in tumour cells. In this context, the mitogen activated protein kinase (MAPK) pathways play a major role. There are two key players of MAPK pathways in tumour cells that are activated by ionising radiation known to influence survival or apoptosis of tumour cells. In addition, the activation of these pathways can lead to overexpression of the vascular endothelial growth factor (VEGF). VEGF is then released from tumour cells and it protects endothelial cells from radiation induced apoptosis. The aim of this study is to first investigate the influence of ionising radiation on VEGF release from tumour cells, second, to analyse the influence of VEGF on intracellular MAPK signalling pathways in endothelial cells and third, to evaluate the direct influence of ionising radiation on MAPK pathways by blocking the signal transduction of VEGF with a specific VEGF receptor tyrosin kinase inhibitor (PTK787). Cell line studies are already under investigation. Part of this study will be a tumour xenograft model. The mice will be treated with fractionated radiation therapy alone or in combination with PTK787. At the same time canine patients with spontaneous oral SCC, FSA will be included in the study. For detection of active and inactive signalling proteins immunofluorescence and immunoblotting will be used. This study will give more insights in the mechanisms of radioresistance in tumours by showing a ratio between active and inactive MAPK signalling pathways in vitro and in vivo. This study will prove the efficacy of combined treatment of radiation therapy and specific blockage of survival pathways.

对于放射治疗师来说，众所周知，不同类型的肿瘤具有不同的放射敏感性。人们认为，肿瘤和内皮细胞之间的串扰对实体肿瘤的放射敏感性有影响。电离辐射调节肿瘤细胞中的信号通路。在此背景下，丝裂原活化蛋白激酶(MAPK)途径发挥了重要作用。在肿瘤细胞中有两个关键的MAPK通路，它们被电离辐射激活，从而影响肿瘤细胞的存活或凋亡。此外，这些通路的激活可导致血管内皮生长因子(VEGF)的过度表达。然后，血管内皮生长因子从肿瘤细胞中释放出来，保护内皮细胞免受辐射诱导的细胞凋亡。本研究旨在研究电离辐射对肿瘤细胞释放血管内皮生长因子的影响，分析电离辐射对内皮细胞内MAPK信号转导通路的影响，探讨电离辐射对血管内皮细胞MAPK信号转导通路的直接影响。细胞系的研究已经在调查中。这项研究的一部分将是肿瘤异种移植模型。这些小鼠将接受单独或与PTK787联合治疗的分次放射治疗。同时将犬自发性口腔鳞癌患者的FSA纳入研究范围。对于活性和非活性信号蛋白的检测，将使用免疫荧光和免疫印迹。这项研究将通过显示体外和体内活跃和不活跃的MAPK信号通路的比率，对肿瘤的辐射抗性机制提供更多的见解。本研究将证明放射治疗与特异性阻断生存通路相结合的治疗效果。