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，每年有13万新发病例和5万多例死亡。值得注意的是，尽管在早期检测和治疗方面取得了进展，但在过去三十年中，CRC的发病率和死亡率仍然相当稳定。为了开发有效的CRC预防和治疗模式，癌症研究人员面临的一个紧急挑战是识别和表征CRC易感性的遗传因素。关键的研究工具是基因定义的小鼠模型，如ApcMin/+小鼠。我们以前使用的致敏小鼠的地图和功能性克隆的一个主要的改性剂敏诱导的肿瘤发生，分泌型磷脂酶Pla 2g 2a。该建议扩展了我们以前的工作，通过使用Min小鼠来检查核受体PPARg的条件性敲除的表型。携带PPARg的双杂交等位基因的小鼠、表达由精氨酸特异性绒毛蛋白启动子驱动的Cre重组酶的小鼠和Min小鼠之间的杂交将提供肠中完全缺乏PPARg的Min试验小鼠。该实验将明确地阐明PPARg在APC介导的小鼠结肠肿瘤发生中的作用。将野生型Pla 2g 2a转基因引入该测试杂交将检查Pla 2g 2a和PPARg之间的潜在遗传相互作用。

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.