Conditional Deletion of DPC4 in Pancreatic Tumorigenesis

描述（由申请人提供） 胰腺癌是这个国家癌症死亡的第五大原因 几乎都是致命的 生存率低可归因于 缺乏早期发现和有效治疗。 努力改善这些 由于缺乏良好的动物模型， 胰腺癌 迫切需要一种可靠的小鼠模型。 巨大 人类遗传学的分子遗传学研究取得了进展， 胰腺癌的病例 现在已经清楚 胰腺癌是一种遗传性疾病，肿瘤抑制基因最多 经常失活的包括p16INK4a和DPC 4。 这些有价值的信息 可用于创建直接反映人类胰腺的小鼠模型， 腺癌 这个试验项目的主要目标是创造一个鼠标 胰腺导管腺癌模型。 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DPC 4。 DPC4 不仅是胰腺肿瘤发生中重要的抑癌基因， 是胚胎发生过程中内胚层分化所必需的。 条件 DPC4的缺失有望绕过这一发育要求， 允许DPC 4的失活仅影响肿瘤发生。 额外 突变可能是肿瘤发展所必需的条件性缺失 DPC 4小鼠。 因此，该项目的第二个目标将探讨 P16INK4a在条件性缺失的DPC4背景下失活的可能性。 P16INK4a是另一个重要的肿瘤抑制基因，在近100 %的人胰腺癌，其失活发生较早 DPC4突变在胰腺癌发生中的作用。 复合突变体 小鼠可能表现出更具侵袭性的肿瘤表型， 顺序突变在肿瘤发生中重要性。 一旦发育成熟， 胰腺癌的模型将作为一个宝贵的工具， 开发和测试新的治疗方法和新的方法， 胰腺癌的诊断

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.