Conditional Deletion of DPC4 in Pancreatic Tumorigenesis

描述(由申请人提供) 胰腺癌是这个国家第五大癌症死亡原因。 而且几乎都是致命的。生存状况不佳可以归因于 缺乏早期发现和有效治疗。改善这些方面的努力 由于缺乏良好的动物模型，两个方面都受到了阻碍 胰腺癌。迫切需要一个可靠的小鼠模型。巨大的 在理解人类的分子遗传学方面取得了进展 过去十年内发生的胰腺癌。现在很明显， 胰腺癌是一种遗传性疾病，抑癌基因最多。 常见的失活基因包括p16INK4a和DPC4。这一有价值的信息 可以用来创建直接反映人类胰腺的小鼠模型 腺癌。这个试点项目的主要目标是创造一种鼠标 导管型胰腺癌模型。第一个目标是有条件地 在小鼠的选择性组织中删除肿瘤抑制基因DPC4。DPC4 不仅是胰腺肿瘤发生中重要的抑癌基因，它 是胚胎发生过程中内胚层分化所必需的。有条件的 删除DPC4有望绕过这一发展要求，并 允许DPC4的失活只影响肿瘤的发生。其他内容 突变可能是肿瘤发生所必需的条件性缺失 DPC4小鼠。因此，该项目的第二个目标将探讨其影响 在有条件删除的DPC4背景中p16INK4a失活。 P16INK4a是另一个重要的抑癌基因，在近100个基因中失活 人胰腺癌及其失活的百分比发生得更早 DPC4突变在人胰腺肿瘤发生中的作用。复合突变体 小鼠可能表现出更具侵袭性的肿瘤表型，并表现出 序列突变在肿瘤发生中的重要性。一旦开发出来，一只老鼠 胰腺癌模型将成为治疗胰腺癌的宝贵工具 早期的新疗法和新方法的开发和测试 胰腺癌的检测。

DESCRIPTION (provided by applicant) Pancreatic cancer is the fifth leading cause of cancer death in this country and it is almost uniformly fatal. The poor survival can be attributed to the lack of early detection and effective treatments. Efforts to improve these two aspects have been hampered by the absence of a good animal model of pancreatic cancer. A reliable mouse model is urgently needed. Tremendous progress has been made in understanding the molecular genetics of human pancreatic adenocarcinoma within the last decade. It is now clear that pancreatic cancer is a genetic disease and the tumor suppressor genes most frequently inactivated include p16INK4a and DPC4. This valuable information can be utilized to create mouse models that directly mirror human pancreatic adenocarcinoma. The main objective of this pilot project is to create a mouse model of ductal pancreatic adenocarcinoma. The first aim is to conditionally delete a tumor suppressor gene, DPC4, in selective tissues of the mouse. DPC4 is not only an important tumor suppressor gene in pancreatic tumorigenesis, it is required for endoderm differentiation during embryogenesis. Conditional deletion of DPC4 will hopefully bypass this developmental requirement and allow the inactivation of DPC4 to affect only tumorigenesis. Additional mutations may be required for tumor development in the conditionally deleted DPC4 mouse. The second aim of the project will therefore explore the effects of P16INK4a inactivation in the conditionally deleted DPC4 background. P16INK4a is another important tumor suppressor gene inactivated in almost 100 percent of human pancreatic adenocarcinoma and its inactivation occurs earlier than DPC4 mutation in human pancreatic tumorigenesis. The compound mutant mouse may exhibit more aggressive tumor phenotypes and demonstrate the importance of sequential mutation in tumorigenesis. Once developed, a mouse model of pancreatic adenocarcinoma will serve as an invaluable tool for the development and testing of new treatments and new methods for the early detection of pancreatic cancer.