Mouse Model for Human Pancreatic Ductal Adenocarcinoma

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，它几乎是致命的。胰腺癌患者预后差的原因是缺乏早期发现和有效的治疗。由于缺乏良好的胰腺癌动物模型，抗击胰腺癌的努力一直受到阻碍。迫切需要一种可靠的小鼠模型。近十年来，在了解人类胰腺腺癌的分子遗传学方面取得了巨大进展。现在很清楚，胰腺癌是一种遗传性疾病；最常失活的肿瘤抑制基因包括pl6/INK4a和SMAD4/DPC4，而致癌基因HER-2/neu/ERBB2在人胰腺腺癌中经常过表达。这一有价值的信息可用于创建直接反映人类胰腺腺癌的小鼠模型。该项目的主要目标是建立胰腺导管腺癌的小鼠模型。在此，我们提出三个互补的策略来实现这一目标。第一个目标是创建一个有条件删除的p16鼠标。第二个目的是表征SMAD4/MT-TGFalpha小鼠。我们的第三个目标是HER-2。HER-2在胰腺肿瘤发生早期表达上调。我们认为HER-2在转基因小鼠中的胰腺特异性表达将为p16和SMAD4敲除小鼠提供必要的第一击。我们的策略强调条件基因靶向的使用，这将允许胰腺特异性基因调控和肿瘤的发展，并避免小鼠不良表型的发展。检测和治疗这种致命疾病的紧迫性促使NCI发布了一份进展审查小组报告，其中NCI将胰腺癌动物模型的开发确定为其研究重点之一。这个提议100%与胰腺癌有关。

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 prognosis of pancreatic cancer patients can be attributed to the lack of early detections and effective treatments. Efforts to fight pancreatic cancer 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; the tumor-suppressor genes most frequently inactivated include pl6/INK4a and SMAD4/DPC4, while oncogene HER-2/neu/ERBB2 is often overexpressed in human pancreatic adenocarcinoma. This valuable information can be utilized to create mouse models that directly mirror human pancreatic adenocarcinoma. The main objective of the project is to create mouse models of ductal pancreatic adenocarcinoma. Here we propose three complementary strategies to accomplish this goal. The first aim is to create a conditionally deleted p16 mouse. The second aim is to characterize SMAD4/MT-TGFalpha mice. Our third aim targets HER-2. HER-2 is upregulated at early stage of pancreatic tumorigenesis. We reason that pancreas-specific expression of HER-2 in a transgenic mouse line would provide the necessary first-hit to complement our p16 and SMAD4 knock-out mice. Our strategies emphasize the uses of conditional gene targeting, which would allow pancreas-specific gene regulation and tumor development, and avoid the development of undesirable phenotypes in mice. The urgency to detect and treat this deadly disease has prompted the NCI to issue a Progress Review Group report, in which the NCI identifies the development of an animal model of pancreatic cancer as one of its research priorities. This proposal is 100% pancreatic cancer relevant.