Smoking carcinogen-induced initiation of pancreatic cancer

项目摘要/摘要 胰腺导管腺癌(PDA)预后很差。了解以下机制 推动PDA的发展和进步是早期发现新方法的最大希望 侦测或干预。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不吸烟者的三倍。然而，分子 吸烟导致胰腺癌发生的机制在很大程度上还不清楚。这 将调查吸烟诱导的致癌物对胰腺发育的贡献 癌症。我们的假设是，与吸烟相关的致癌物会导致 胰腺腺泡细胞中具有结构性活性的PKD1片段。我们进一步假设，这一活动 存在KRAS癌基因突变的PKD1片段促进胰腺发育 癌症。为了验证我们的假设，我们将：确定吸烟诱导的致癌物质(如BPDE)是否起中介作用 非调控激活PKD 1(特异性靶点1)；确定非调控激活的PKD片段是否可以 在吸烟者和不吸烟者的患者样本中检测到。(具体目标2)；以及确定吸烟是否- 相关致癌物BPDE在小鼠体内产生一段未受调控的活性PKD片段，如果这有助于 PDA的发展(具体目标3)。我们项目的成功完成不仅将导致进一步的 了解吸烟等已知风险因素如何导致胰腺癌的发生， 而且还为开发早期检测和干预方法提供了理论基础。

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.