Mouse Model for Human Pancreatic Ductal Adenocarcinoma

描述(申请人提供)：胰腺癌是这个国家第五大癌症死亡原因，几乎都是致命的。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。迫切需要一个可靠的小鼠模型。近十年来，人们对胰腺癌的分子遗传学研究取得了很大进展。现已明确，胰腺癌是一种遗传性疾病，最常失活的抑癌基因包括p6/INK4a和Smad4/DPC4，而癌基因HER-2/neu/ERBB2在人胰腺癌中经常过表达。这些有价值的信息可以用来建立直接反映人胰腺癌的小鼠模型。该项目的主要目标是建立导管型胰腺癌的小鼠模型。在这里，我们提出三个相辅相成的战略来实现这一目标。第一个目标是创造一个有条件删除的p16鼠标。第二个目的是研究Smad4/MT-TGFpha小鼠的特性。我们的第三个目标是HER-2。HER-2在胰腺肿瘤发生的早期表达上调。我们推测，在转基因小鼠系中胰腺特异性表达HER-2将提供必要的第一次打击，以补充我们的p16和Smad4基因敲除小鼠。我们的策略强调使用条件性基因打靶，这将允许胰腺特异性基因调控和肿瘤发展，并避免在小鼠中发展不希望看到的表型。发现和治疗这种致命疾病的紧迫性促使NCI发布了一份进度审查小组报告，其中NCI将发展胰腺癌动物模型确定为其研究重点之一。这项提议与胰腺癌100%相关。

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.