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

描述（由申请人提供）：在美国，只有4%的胰腺导管腺癌（PDAC）患者在诊断后存活5年，大多数在1年内死于该病。对这些患者的结果令人沮丧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持续发展为癌症的重要生物学机制，很明显，胰腺肿瘤已经重新激活了在正常成人组织中基本上沉默的信号通路，但这些信号通路积极参与胰腺器官发育和细胞分化。在PDAC中明显被重新激活的一个这样的途径是Notch。Notch活性对于在发育过程中维持胰腺中的未分化祖细胞群体是至关重要的，并且可能在成年器官中也是如此。在某种程度上，正是这些罕见的成人祖细胞的持续存在，使胰腺在胰腺炎等疾病中受损时能够再生。然而，通过Notch的慢性再激活，肿瘤细胞利用这种能力来阻断分化，使它们继续增殖，同时忽略了活性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。为了靶向胰腺中的Notch途径，我们已经创建了编码两种蛋白质的基因的条件性敲除动物，这两种蛋白质已被证明对Notch激活至关重要：ADAM-10（一种去整合素和金属蛋白酶-10）和ADAM-17。使用胰腺特异性敲除这些基因，我们提出了一项初步研究，以检查1）组织发育和细胞分化，以更好地了解ADAM在这些过程中控制Notch。2)在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愈合受损胰腺中的有效性。3)PDAC形成，通过将ADAM敲除动物与p48 Cre-LSLKrasG 12 D小鼠PDAC模型（人PDAC的最准确的动物模型）交配。由于它们在Notch激活中的作用，以及促进PDAC进展的其他信号转导途径的激活，这些研究将测试这些ADAM蛋白酶中的一种或两种是否是治疗PDAC患者的有希望的新治疗靶点。胰腺导管腺癌（PDAC）是人类最致命的癌症之一。这种疾病令人沮丧的结果的原因之一是目前化疗的无效。在这项初步研究中，我们删除了两种蛋白质的基因，即ADAM-10和ADAM-17，特别是从胰腺中删除的。这些蛋白质已被证明可以控制促进PDAC的多种信号。这项初步研究的结果将帮助我们测试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.