Smoking carcinogen-induced initiation of pancreatic cancer

吸烟致癌物诱发胰腺癌

基本信息

批准号：
10043057
负责人：
Peter Storz
金额：
$ 40.24万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-10 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10043057
关键词：
Acinar Cell Adult Antibodies Aromatic Polycyclic Hydrocarbons Attenuated Benzo(a)pyrene Carcinogens Cells Cigarette Smoker Cleaved cell Complex Mixtures Cytochrome P450 Data Detection Development Diagnosis Early Diagnosis Early Intervention Epoxide hydrolase Epoxy Compounds Estrogen receptor positive Event Free Radicals Gene Expression Profile Gene Mutation Glycols Goals Immune response Inflammation Inflammatory KRAS2 gene Knock-out Lead Length Malignant Neoplasms Malignant neoplasm of pancreas Mediating Methods Molecular Mus Mutagens Mutation Oncogenic Pancreas Pancreatic Ductal Adenocarcinoma Pancreatitis Patients Phosphotransferases Protein Kinase Proteolysis Pyrenes Risk Factors Sampling Severities Signal Transduction Smoker Smoking Testing Time Tissue Sample Tobacco smoke Tobacco use United States Work in vivo non-smoker novel outcome forecast pancreas development protein activation tumor initiation tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis. Understanding the mechanisms that drive the development and progression of PDA is the greatest hope to identify novel methods for early detection or intervention. Smoking is a known risk factor for pancreatic cancer and cigarette smokers are two or three times more likely to develop pancreatic cancer than nonsmokers. However, the molecular mechanisms underlying smoking-induced development of pancreatic cancer are largely unknown. This proposal will investigate the contribution of smoking-induced carcinogens to the development of pancreatic cancer. It is our hypothesis that smoking-related carcinogens can lead to the formation of a constitutively-active PKD1 fragment in pancreatic acinar cells. We further hypothesize that this active PKD1 fragment in presence of an oncogenic KRAS mutation accelerates development of pancreatic cancer. To test our hypothesis we will: Determine if smoking-induced carcinogens such as BPDE mediate unregulated activation of PKD1 (Specific Aim 1); determine if an unregulated active PKD fragment can be detected in patient samples of smokers versus nonsmokers. (Specific Aim 2); and determine if the smoking- related carcinogen BPDE generates an unregulated active PKD fragment in mice and if this contributes to development of PDA (Specific Aim 3). A successful completion of our project will not only lead to further understanding of how known risk factors such as smoking can contribute to the initiation of pancreatic cancer, but also provide the rationale for developing methods for early detection and intervention.

项目摘要/摘要胰腺导管腺癌（PDA）带有令人沮丧的预后。了解该机制推动PDA的发展和发展是识别早期新方法的最大希望检测或干预。吸烟是胰腺癌的已知危险因素，吸烟者是两个患胰腺癌的可能性是非吸烟者的三倍。但是，分子吸烟引起的胰腺癌发展的机制在很大程度上是未知的。这提案将调查吸烟引起的致癌物对胰腺发展的贡献癌症。我们的假设是吸烟相关的致癌物会导致形成胰腺腺泡细胞中的组成型PKD1片段。我们进一步假设这个活跃在存在致癌KRAS突变的存在下PKD1碎片加速了胰腺的发育癌症。为了检验我们的假设，我们将：确定吸烟引起的致癌物（例如BPDE）是否介导 PKD1的不受调节激活（特定目标1）；确定不受监管的活动PKD片段是否可以是在吸烟者与非吸烟者的患者样本中检测到。（特定目标2）;并确定是否吸烟 - 相关的致癌BPDE在小鼠中产生不受管制的活性PKD片段，如果这有助于 PDA的开发（特定目标3）。我们项目的成功完成不仅会导致进一步了解已知的危险因素（例如吸烟）如何有助于胰腺癌的开始，但也提供了开发早期检测和干预方法的理由。