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ADAM17 in pancreatic cancer and pancreatitis

ADAM17 在胰腺癌和胰腺炎中的作用

基本信息

批准号：
8236859
负责人：
Howard C Crawford
金额：
$ 39.01万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8236859
关键词：
Ablation Acinar Cell Address Area Bypass Cancer Etiology Cell surface Cells Cessation of life Chemotaxis Chronic Dependency Development Diagnosis Disease Disease Progression Duct (organ) structure Ductal EGFR gene ERBB3 gene Epidermal Growth Factor Receptor Epithelial Etiology Exocrine pancreas Family Family member Fatal Outcome Fibrosis Gene Deletion Genetic Genetic Recombination Growth Factor Human In Vitro Inflammation Inflammatory Inflammatory Response Interleukin 6 Receptor Knockout Mice Leukocyte Chemotaxis Ligands Link Malignant Neoplasms Malignant neoplasm of pancreas Mediating Membrane Metalloproteases Metaplasia Metaplastic Modeling Molecular Mus Mutation Neoplasms Oncogenic Pancreas Pancreatic Diseases Pancreatic Ductal Adenocarcinoma Pancreatitis Partner in relationship Pathway interactions Patients Peptide Hydrolases Phenotype Property Receptor Activation Resistance Risk Factors Role Signal Transduction Source System T-Lymphocyte Testing Time Tumor Necrosis Factor-alpha cancer risk chronic pancreatitis cytokine in vivo in vivo Model inhibitor/antagonist macrophage member mouse model neutrophil pancreatic neoplasm pancreatic tumorigenesis progenitor public health relevance receptor therapy design transdifferentiation tumor tumorigenesis tumorigenic

项目摘要

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. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is virtually always fatal within a very short time after diagnosis. Inflammation of the pancreas has been shown to enhance pancreatic tumor formation. Using genetic mouse models of these diseases, we have found that deletion of the gene encoding the cell surface proteinase ADAM17 protects mice from both pancreatitis and pancreatic cancer formation. The purpose of this proposal is to define the mechanisms by which ADAM17 contributes to these diseases and to assess the potential for designing therapies targeting ADAM17 and the pathways it regulates for treating 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。公共卫生相关性：胰腺癌几乎总是在诊断后很短的时间内致命。胰腺的炎症已被证明会促进胰腺肿瘤的形成。使用这些疾病的遗传小鼠模型，我们发现编码细胞表面蛋白酶ADAM 17的基因的缺失可以保护小鼠免受胰腺炎和胰腺癌的形成。该提案的目的是确定ADAM 17促进这些疾病的机制，并评估设计靶向ADAM 17的治疗方法及其调节治疗胰腺癌和胰腺炎的途径的潜力。