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：
8450710
负责人：
Howard C Crawford
金额：
$ 36.67万
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/8450710
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.

描述（由申请人提供）：胰腺导管腺癌是一种相对罕见的癌症，几乎具有普遍致命的结果。慢性胰腺炎（CP）是胰腺导管腺癌（PDA）的危险因素，这可能是由于炎症微环境的促肿瘤作用。除炎症外，两种疾病还具有许多常见特征，包括导管化生和纤维化，两者都可能显着增强PDA的形成。我们发现，细胞表面金属蛋白酶ADAM17的遗传消融特别是从胰腺中使小鼠对CP和PDA的高度抗性，从而代表了这些疾病之间的精确分子联系。当前建议的目的是剖析机制并定义有助于胰腺疾病进展的ADAM17底物。在AIM 1中，我们将使用ADAM17底物依赖性途径的遗传消融和药理学抑制来确定哪些底物在体外影响腺泡到连接转分化和炎性细胞趋化性。在AIM 2中，我们将使用对表皮生长因子受体（EGFR）及其家庭成员ERRBB3的遗传消融和药理抑制作用来测试ADAM17释放的EGFR配体是否负责使用体内小鼠模型对其对CP和PDA的影响。在AIM 3中，我们将使用ADAM17释放的细胞因子肿瘤坏死因子Alpha（TNFA）和白介素6受体（IL6R）的药理抑制作用来测试其对VIVO中胰腺炎症和PDA的病因的影响。