p53基因突变促进Wilms 肿瘤发展转移的小鼠动物模型研究

项目名称： p53基因突变促进Wilms 肿瘤发展转移的小鼠动物模型研究

项目编号： No.81472715

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 胡强华

作者单位： 大连医科大学

项目金额： 75万元

中文摘要： Wilms 肿瘤（WT）是严重危害儿童健康的肾脏癌，其远位转移的原因不明，且缺乏有效的治疗方法。申请人前期发现Wt1基因剔除会诱导WT生成，而上调Igf2具促进作用，这首次为WT的治疗研究提供了小鼠模型（JCI, 2011）。预实验表明存在其他机制加速WT生成，转移；而模拟人p53突变的小鼠p53R172H模型多生成转移性肿瘤。据此本项目提出（1）通过杂交Wt1和 p53R172H的小鼠模型，研究p53 突变对肿瘤发展转移的影响，建立WT转移的模型。（2）通过RNA-seq, miRNA-seq 和 Reverse Phase Protein Array分析，比较转移与非转移肿瘤之间差异表达基因和蛋白。（3）在小鼠转移瘤及人WT转移肿瘤细胞WiT49中核实差异表达分子功能，确定转移标志分子。本项目将揭示WT肿瘤发生转移的机制，并提出针对性治疗方法。

中文关键词： Wilms；肿瘤；肿瘤发展；肿瘤转移；小鼠模型；p53；突变

英文摘要： Wilms tumor as a pediatric renal cancer raises serious health risk to children. The mechanism of WT metastasis is unclear, no effective therapies are available for these patients. We recently discovered that somatic Wt1 knockout induced WT tumorigenesis ，and constitutive Igf2 upregulation accelerates tumorigenesis. It is the first WT mouse model for therapuetic study (JCI 2011). Preliminary data indicated that other mechanisms contribute to WT tumorigenesis and metastasis. A p53R172H mouse model corresponding to human mutation is demonstrated to often cause metastatic tumors. Thus, we propose to (1) cross the our previuosly generated WT mice with the mice carrying p53R172H (equivalent to human p53R175H) mutation to investigate the role of p53 mutation in WT genesis and metastasis. (2) identify gene/protein expression alterations between the non-metastaic and metastaic tumors via high-throughput RNA-seq, miRNA-seq and Reverse Phase Protein Array analyses. (3) develop a molecular signature for metastasis after validating the top prioritized molecular changes in mouse xenograft model and human metastatic WT cell line WiT49 with various assays. This study will reveal the mechanism of WT metastasis, and help to develop more effective and personalized therapy.

英文关键词： Wilms Tumor;tumor progression;tumor metastasis;mouse model;p53 mutation