MNU诱导P53+/-小鼠模型中T细胞淋巴瘤早期发生关键基因筛查

T细胞淋巴瘤是一种恶性血液系统肿瘤，占每年确诊淋巴瘤的15%-25%，目前也缺乏对其特异性治疗方案，治疗所致副作用强而病人预后较差。临床样本的稀缺性以及异质性限制了对其机制的研究。因此，寻找T细胞淋巴瘤早期发生的关键基因，有利于为进一步深入研究T细胞淋巴瘤发生机制，寻找特异性药物靶点提供基础。本研究拟使用N-甲基亚硝基脲（MNU）诱导p53+/-小鼠建立T细胞淋巴瘤模型，通过转录组测序，得到T细胞淋巴瘤发生早期出现改变的基因及通路，通过体外进行多角度筛选验证，以及构建转基因及基因敲除小鼠模型以确认其生理功能，并最终应用于临床病人样本的筛查。找到新的T细胞淋巴瘤发生的关键基因，加深对于T细胞淋巴瘤发生机制的理解，为未来T细胞淋巴瘤的早期诊断，以及确定新的药物靶点提供基础。

T cell lymphoma is aggressive hematologic tumor which accounts for 15%-25% of the newly diagnosed cases each year. Due to a lack of tumor-specific therapy, the intensive chemotherapy causes significant side effect and the outcome of T cell lymphoma patients remains poor. The scarcity and genetic heterozygosity retards the elucidation of mechanisms. Identify key factors in T cell lymphoma development will provide foundation for further mechanism studies as well as searching for molecular drug targets. In present study, we propose a program using MNU induced p53 heterozygous knockout mice to generate T cell lymphoma mouse model. Transcriptome sequencing is generated to identify changes of gene expression level and pathways during T cell lymphoma development. These genes are further verified in vitro and in vivo by generating transgenic and gene knockout mouse models to prove its role in T cell lymphoma development. The genes are then screened in clinical samples. New genes crucial for T cell lymphoma might be found in present study to improve the understanding of mechanism and provide powerful tool of early diagnosis and tumour-specific therapy.