权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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(申请人提供)：胰腺导管腺癌是一种相对少见的癌症，几乎所有人都有致命的结局。慢性胰腺炎(CP)是胰腺导管腺癌(PDA)的危险因素，可能是由于炎性微环境的促肿瘤作用。除了炎症，这两种疾病还有许多共同的特征，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，特异性来自胰腺的细胞表面金属蛋白酶ADAM17的遗传消融使小鼠对CP和PDA都具有高度的抵抗力，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ADAM17促进胰腺疾病进展的机制并确定ADAM17底物。在目标1中，我们将使用遗传消融和药物抑制ADAM17底物依赖的通路来确定哪些底物在体外影响腺泡到导管的转分化和炎性细胞的趋化。在目标2中，我们将通过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来验证ADAM17释放的EGFR配体是否与其对CP和PDA的影响有关。在目的3中，我们将通过药物抑制ADAM17释放的细胞因子肿瘤坏死因子α(TNFa)和白介素6受体(IL6R)来检测它们在体内对胰腺炎症和PDA病因的影响。