Characterization of the Wilms tumor suppressor gene X (WTX) in tumorigenesis and normal kidney development of the mouse

Wilms 肿瘤抑制基因 X (WTX) 在小鼠肿瘤发生和正常肾脏发育中的表征

• 批准号: 84743245
• 负责人: Dr. Alexa Burger
• 金额: --
• 依托单位: Mass General Cancer Center
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/84743245?language=en
• 关键词: Characterization; Wilms; tumor; suppressor; gene

Wilms tumor is the most common pediatric kidney cancer and closely associated with renal organogenesis. Various genes associated with kidney development are found inappropriately inactivated in Wilms tumor, e.g. WT1, while others appear activated, such as CTNNB1, encoding a component of the Wnt signaling pathway; however, for the majority of Wilms tumor, no consistently specific aberrations have been detected. Recently, this obstacle could be overcome through the discovery of a novel inactivated gene in 30% of Wilms tumor, which is located on the X chromosome and named WTX. The aim of this project is to study inactivated WTX in the mouse to identify and characterize its influence during nephrogenesis. For this purpose, I will use a conditional WTX knockout mouse, which allows temporal and tissue-specific expression of WTX, and also will allow me to establish an in vivo Wilms tumor model based on WTX loss-of-function. I will use this genetic tool to show the significant relevance of WTX in this pediatric cancer as well as in normal nephrogenesis. In summary, the analysis of WTX will allow conclusions about its biological function, involved molecular mechanisms and pathways, as well as its contribution to tumorigenic events in renal precursor cells.

肾母细胞瘤是最常见的儿童肾癌，与肾脏器官发生密切相关。在肾母细胞瘤中发现了与肾脏发育相关的各种基因的异常失活，例如WT1，而其他基因似乎被激活，例如编码Wnt信号通路的一个组成部分的CTNNB1；然而，对于大多数肾母细胞瘤，没有检测到一致的特异性异常。最近，在30%的Wilms肿瘤中发现了一种新的失活基因，该基因位于X染色体上，命名为WTX，从而克服了这一障碍。本项目的目的是研究灭活的WTX在小鼠中的作用，以确定和表征其在肾脏形成过程中的影响。为此，我将使用条件WTX基因敲除小鼠，它允许WTX的时间和组织特异性表达，也将使我能够建立基于WTX功能丧失的体内Wilms肿瘤模型。我将使用这个遗传工具来证明WTX在这种儿科癌症以及正常肾发生中的重要相关性。综上所述，WTX的分析将使我们能够得出关于它的生物学功能、涉及的分子机制和途径以及它在肾前体细胞肿瘤形成事件中的作用的结论。