ADAM17 in pancreatic cancer and pancreatitis

描述（由申请人提供）：胰腺导管腺癌是一种相对罕见的癌症，几乎普遍致命。慢性胰腺炎（CP）是胰腺导管腺癌（PDA）的危险因素，可能是由于炎症微环境的致瘤作用。除了炎症外，这两种疾病还有许多共同特征，包括导管化生和纤维化，这两种疾病都可能显著促进PDA的形成。我们发现，胰腺细胞表面金属蛋白酶ADAM17的遗传消融使小鼠对CP和PDA具有高度抗性，从而代表了这些疾病之间的精确分子联系。当前提案的目的是剖析机制并定义促进胰腺疾病进展的ADAM17底物。在Aim 1中，我们将使用ADAM17底物依赖途径的基因消融和药理抑制来确定哪些底物在体外影响腺泡到导管的转分化和炎症细胞趋化性。在Aim 2中，我们将使用基因消融和药物抑制表皮生长因子受体（EGFR）及其家族成员ERRBB3，在体内小鼠模型中测试ADAM17释放的EGFR配体是否对其对CP和PDA的影响负责。在Aim 3中，我们将使用药物抑制ADAM17释放的细胞因子肿瘤坏死因子α (TNFa)和白细胞介素6受体（IL6R）来测试它们对体内胰腺炎症和PDA病因学的影响。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma is a relatively uncommon cancer with an almost universally fatal outcome. Chronic pancreatitis (CP) is a risk factor for pancreatic ductal adenocarcinoma (PDA), presumably due to the pro-tumorigenic effects of the inflammatory microenvironment. Besides inflammation, the two diseases have many common features, including ductal metaplasia and fibrosis, both of which may significantly enhance PDA formation. We have found that genetic ablation of the cell surface metalloproteinase ADAM17 specifically from the pancreas makes mice highly resistant to both CP and PDA, thus representing a precise molecular link between these diseases. The purpose of the current proposal is to dissect the mechanisms and define the ADAM17 substrates that contribute to pancreatic disease progression. In Aim 1 we will use genetic ablation and pharmacological inhibition of ADAM17 substrate-dependent pathways to determine which substrates influence both acinar-to-ductal transdifferentiation and inflammatory cell chemotaxis, in vitro. In Aim 2, we will use genetic ablation and pharmacological inhibition of the epidermal growth factor receptor (EGFR) and its family member ERRBB3 to test if EGFR ligands released by ADAM17 are responsible for its effects on CP and PDA using in vivo mouse models. In Aim 3, we will use pharmacological inhibition of ADAM17 released cytokines tumor necrosis factor alpha (TNFa) and interleukin 6 receptor (IL6R) to test for their influence on the etiology of pancreatic inflammation and PDA in vivo.