ADAM17 in pancreatic cancer and pancreatitis

描述（由申请方提供）：胰腺导管腺癌是一种相对罕见的癌症，几乎普遍具有致死性结局。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促肿瘤发生作用。 除了炎症，这两种疾病有许多共同的特点，包括导管化生和纤维化，这两种疾病都可能显着增加PDA的形成。 我们已经发现，从胰腺特异性地基因消融细胞表面金属蛋白酶ADAM 17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。 目前提案的目的是剖析机制，并确定有助于胰腺疾病进展的ADAM 17底物。 在目的1中，我们将使用基因消融和药物抑制的ADAM17底物依赖性途径，以确定哪些底物影响腺泡导管转分化和炎症细胞的趋化性，在体外。 在目标2中，我们将使用表皮生长因子受体（EGFR）及其家族成员ERRBB3的遗传消融和药理学抑制来测试ADAM 17释放的EGFR配体是否是其对CP和PDA的影响的原因。 目的3：利用药物抑制ADAM17释放的细胞因子肿瘤坏死因子α（TNF α）和白细胞介素6受体（IL 6 R），检测其对胰腺炎症和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.