Pancreatic Tumor Progression in the Absence of ADAM-mediated alpha-secretase Acti

描述(申请人提供)：在美国，只有4%的胰腺导管腺癌(PDAC)患者在确诊后存活5年，大多数人在1年内死于这种疾病。这些患者结局惨淡的原因之一是目前的化疗药物无效。随着我们逐渐了解启动胰腺肿瘤发生及其继续发展为癌症的重要生物学机制，很明显，胰腺肿瘤重新激活了信号通路，这些信号通路在正常成人组织中基本上是沉默的，但积极参与胰腺器官的发育和细胞分化。在PDAC中明显被重新激活的一个这样的通路是Notch。在发育过程中，Notch活性对于维持胰腺中未分化的祖细胞种群至关重要，可能在成年器官中也是如此。在某种程度上，正是这些稀有的成体祖细胞的持续存在，使胰腺在胰腺炎等疾病受损时能够再生。然而，通过Notch的慢性重新激活，肿瘤细胞利用这种能力来阻止分化，允许它们继续增殖，同时忽略了活跃的癌基因和信号的有害影响，这些信号将促进正常祖细胞的分化。为了针对胰腺中的Notch途径，我们为编码两种蛋白质的基因创建了条件性敲除动物，这两种蛋白质已被证明对Notch激活至关重要：ADAM-10(去整合素和金属蛋白酶-10)和ADAM-17。利用胰腺特异的这些基因敲除，我们提议进行一项初步研究，以检验组织发育和细胞分化，以更好地了解哪个亚当在这些过程中控制Notch。2)雨蛙素诱导的胰腺炎后的组织再生，以测试成体祖细胞群的维持以及这些细胞在修复受损胰腺方面的有效性。3)PDAC的形成，通过将ADAM基因敲除动物与p48Cre-LSLKrasG12D小鼠PDAC模型交配而形成PDAC，这是最准确的人PDAC动物模型。由于它们在Notch激活中的作用，以及其他促进PDAC进展的信号转导通路的激活，这些研究将测试这两种ADAM酶中的一种或两种是否都是治疗PDAC患者的有前景的新治疗靶点。胰腺导管腺癌(PDAC)是人类最致命的癌症之一。这种疾病结果令人沮丧的原因之一是目前的化疗无效。在这项初步研究中，我们删除了两种蛋白质的基因，称为Adam-10和Adam-17，特别是从胰腺中。这些蛋白质已被证明控制促进PDAC的多种信号。这项先导性研究的结果将有助于我们测试ADAM-10和ADAM-17是否是治疗PDAC患者的合适靶点。

DESCRIPTION (provided by applicant): In the United States, only 4% of pancreatic ductal adenocarcinoma (PDAC) patients live 5- years past diagnosis, with most succumbing to the disease within 1 year. One of the reasons for the dismal outcome for these patients is the ineffectiveness of current chemotherapeutic agents. As we have come to understand the important biological mechanisms that initiate pancreatic tumorigenesis and its continued progression to cancer, it is clear that pancreatic tumors have reactivated signaling pathways that are largely silent in normal adult tissue but that are, instead, actively involved in pancreatic organ development and cellular differentiation. One such pathway that is apparently reactivated in PDAC is Notch. Notch activity is critical for maintaining an undifferentiated progenitor cell population in the pancreas during development and probably in the adult organ as well. In part, it is the continued existence of these rare adult progenitor cells that allows the pancreas to regenerate when damaged in diseases such as pancreatitis. However, by chronic reactivation of Notch, tumor cells take advantage of this ability to block differentiation, allowing them to continue to proliferate while ignoring the detrimental effects of active oncogenes and signals that would promote the differentiation of a normal progenitor cell. In an effort to target the Notch pathway in the pancreas, we have created conditional knockout animals for the genes encoding two proteins that have been shown to be critical for Notch activation: ADAM-10 (A Disintegrin And Metalloprotease-10) and ADAM-17. Using pancreas-specific knockouts of these genes, we propose a pilot study to examine 1) Tissue development and cellular differentiation, to better understand which ADAM controls Notch in these processes. 2) Tissue regeneration after cerulein-induced pancreatitis, to test the maintenance of an adult progenitor cell population as well as the effectiveness of these cells in healing the injured pancreas. 3) PDAC formation, by mating the ADAM knockout animals to the p48Cre-LSLKrasG12D mouse PDAC model, the most accurate animal model of human PDAC. Because of their role in Notch activation, as well as the activation of other signal transduction pathways that promote PDAC progression, these studies will test whether one or both of these ADAM proteases are promising novel therapeutic targets for treating PDAC patients. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of human cancer. One of the reasons for the dismal outcome of this disease is the ineffectiveness of current chemotherapy. For this pilot study, we have deleted the genes for two proteins, known as ADAM-10 and ADAM-17, specifically from the pancreas. These proteins have been shown to control multiple signals that promote PDAC. The results of this pilot study will help us test if ADAM-10 and ADAM-17 are appropriate targets for treating of PDAC patients.