Further Genetic Analysis of PPARg in Min Tumorigenesis

描述(由申请人提供)： 结直肠癌(CRC)是美国的主要恶性肿瘤之一，每年新增病例13万例，死亡人数超过5万人。值得注意的是，尽管在早期发现和治疗方面取得了进展，但在过去30年中，结直肠癌的发病率和死亡率保持相当稳定。为了开发有效的结直肠癌预防和治疗方法，癌症研究人员面临的一个紧迫挑战是识别和表征导致结直肠癌易感性的遗传因素。关键的研究工具是遗传定义的老鼠模型，如ApcMin/+鼠标。我们之前已经使用致敏的Min小鼠定位并功能克隆了Min诱导的肿瘤发生的主要修饰物，分泌型磷脂酶Pla2g2a。这一建议通过使用Min小鼠来检查核受体PPARg的条件性敲除的表型，从而扩展了我们之前的工作。携带PPARg等位基因的小鼠、由肠道特异性绒毛蛋白启动子驱动的表达Cre重组酶的小鼠和Min小鼠之间的杂交将提供肠道中完全缺乏PPARg的Min试验小鼠。本实验将明确阐述PPARg在APC介导的小鼠结肠肿瘤形成中的作用。将野生型Pla2g2a转基因导入该测试杂交组合将检验Pla2g2a和PPARg之间潜在的遗传互作。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is one of the major malignancies in the United States, accounting for 130,000 new cases and more than 50,000 deaths each year. Notably, the incidence and mortality rates from CRC have remained fairly constant over the past three decades despite advances in early detection and therapy. To develop effective prevention and therapeutic modalities for CRC an emergent challenge for cancer investigators is to identify and characterize the constellation of genetic factors that underlie CRC susceptibility. Key research tools are genetically defined mouse models such as the ApcMin/+ mouse. We have previously used the sensitized Min mouse to map and functionally clone a major modifier of Min-induced tumorigenesis, the secretory phospholipase Pla2g2a. This proposal extends our previous work by using the Min mouse to examine the phenotype of a conditional knockout of the nuclear receptor PPARg. Intercrosses between mice carrying floxxed alleles of PPARg, mice expressing the Cre recombinase driven by the intestine-specific villin promoter, and Min mice will provide Min test mice completely deficient for PPARg in the intestine. This experiment will unequivocally address the role of PPARg in Apc-mediated mouse colon tumorigenesis. Introduction of a wildtype Pla2g2a transgene into this test cross will examine potential genetic interactions between Pla2g2a and PPARg.