Biomarkers of exposure and response to environmental tobacco smoke in the pancrea

描述(由申请人提供) 这项建议描述了一种系统生物学方法来发现和验证生物标记物，重点是暴露于环境烟草烟雾(ETS)及其与胰腺导管腺癌(PDAC)的因果联系。香烟烟雾是一种极其复杂的混合物，包括大量烟草特有的亚硝胺(TSNAs)。本建议源于研究人员在使用稳定同位素方法对烟草衍生化合物和蛋白质生物标记物进行量化方面取得的重大进展。CS是PDAC的主要已知环境风险因素，最近的研究表明，主流烟草烟雾和ETS都与CS有关。PDAC是美国癌症相关死亡的第四大常见原因，而且普遍是致命的。这项研究计划基于四个重要的观察：1)TSNA的代谢在个体之间有很大的差异，高水平与肺癌有关。2)TSNAs也被证明能引起实验动物的PDAC。3)含有TSNAs的ETS可引起大鼠胰腺炎症。4)胰腺炎症和PDAC导致胰腺细胞分泌蛋白质的特异性改变，我们已经广泛地描述了这一变化。基于这些观察，研究人员提出了以下假设：内毒素使胰腺暴露在以NNK及其代谢物NNAL为代表的有毒化学物质中。新陈代谢的个体差异导致这些有毒化学物质的血清和组织水平差异很大，从而导致PDAC易感性的差异。胰腺暴露于这些有毒化学物质会导致炎症和生物标志物的分泌，这些生物标志物可以量化并用于评估个人患PDAC的风险。为了验证这些假设，将追求以下目标/特定目标：1)使用体外系统来表征和量化胰腺ETS暴露和生物反应的蛋白质组和代谢组生物标志物。2)利用稳定同位素标记方法建立生物标志物面板，以严格评估胰腺ETS暴露和生物学反应。3)使用具有量化水平的ETS暴露和非暴露对照的PDAC受试者的血清和尿样来完善目标2中确定的ETS暴露和生物反应的生物标志物小组。4)对目标3中开发的生物标志物小组进行重复研究，以评估个体患PDAC风险的敏感性和特异性。该提案将详细说明首席调查员开发的创新方法和已经取得的重大发现。已经开发了一种独特的跨学科方法来执行所述的研究。通过实现这些具体目标，这项提议将对该领域产生非常重大的影响。此外，研究人员的结果将对ETS在PDAC中的病因学作用提供重要的帮助。开发的生物标记物将用于识别早期PDAC风险增加的人。这种转化性的方法将通过提供手术切除的可能性来影响临床实践，这是目前提高这种毁灭性疾病存活率的唯一现实选择。

DESCRIPTION (provided by applicant) This proposal describes a systems biology approach to biomarker discovery and validation focused on exposure to environmental tobacco smoke (ETS) and its causal link to pancreatic ductal adenocarcinoma (PDAC). Cigarette smoke (CS) is an extremely complex mixture, including numerous tobacco-specific nitrosamines (TSNAs). The present proposal stems from significant advances the investigators have made in the quantification of tobacco-derived compounds and protein biomarkers using stable isotope methodology. CS is the major known environmental risk factor for PDAC, with recent studies implicating both mainstream tobacco smoke and ETS. PDAC is the 4th most common cause of cancer-related mortality in the US and is universally lethal. This research plan is based on four important observations: 1) TSNA metabolism varies greatly among individuals, and higher levels have been associated with lung cancer. 2) TSNAs have also been shown to cause PDAC in laboratory animals. 3) ETS, which contains TSNAs, causes pancreatic inflammation in exposed rats. 4) Pancreatic inflammation and PDAC result in specific changes in proteins secreted by pancreatic cells which we have extensively characterized. Based on these observations, the investigators have developed the following hypotheses: ETS exposes the pancreas to toxic chemicals exemplified by NNK and its metabolite NNAL. Inter-individual differences in metabolism cause serum and tissue levels of these toxic chemicals to vary widely, contributing to differences in PDAC susceptibility. Exposure of the pancreas to these toxic chemicals results in inflammation and secretion of biomarkers that can be quantified and used to asses an individual's risk for PDAC. To test these hypotheses, the following objectives/specific aims will be pursued: 1) To use an in vitro system to characterize and quantify proteomic and metabolomic biomarkers of pancreatic ETS exposure and biological response. 2) To develop panels of biomarkers using stable isotope labeling methodology in order to rigorously assess pancreatic ETS exposure and biological response. 3) To use serum and urine samples from PDAC subjects with quantified levels of ETS exposure and non-exposed controls to refine a biomarker panel of ETS exposure and biological response identified in aim 2. 4) To perform a replication study of the biomarker panel developed in aim 3 to assess the sensitivity and specificity of an individual's risk for PDAC. This proposal will elaborate on the innovative methods developed and significant findings already made by the principal investigator. A unique, interdisciplinary approach has been developed to execute the research described. By achieving these specific aims, this proposal will have a highly significant impact on the field. Furthermore, the investigators' results will shed important light on the etiological role of ETS in PDAC. Biomarkers developed will be used for identifying persons at increased risk for and with early stage PDAC. This translational approach will impact on clinical practice by offering the possibility of surgical resection, which is currently the only realistic option for improving survival from this devastating disease.