Identification of the molecules/pathways that confer acquired radioresistance in

描述(申请人提供)：胰腺癌是一种侵袭性极强的癌症。它是美国癌症死亡的第四大原因，而且发病率正在上升。胰腺癌病死率高的主要原因之一是大多数胰腺癌患者对放化疗的反应不佳。我们的长期目标是了解胰腺癌特殊的放射和化疗耐药的分子机制。我们最近成功地建立了胰腺癌等基因细胞系，它们对辐射的敏感性与亲代细胞不同。放射抗性细胞系是通过将胰腺癌细胞暴露于分割的电离辐射中而产生的，这种程序模拟了典型的放射治疗过程。我们假设胰腺癌细胞的获得性放射抗性是由参与细胞增殖和/或生存的一种或多种蛋白质的异常表达所致。我们的初步结果显示，抗辐射的胰腺癌细胞中的几条通路已经发生了明显的变化。我们建议使用先进的亚细胞分离、新的定量蛋白质组图谱和生物信息学分析来系统地鉴定最有可能导致胰腺癌细胞获得性放射抵抗的蛋白质(特定目标1)，并使用分子和细胞生物学方法来确定一组明确的已识别蛋白质在胰腺癌放射和化疗耐药中的作用(特定目标2)。这项工作的结果将有助于理解胰腺癌特殊的放射和化疗耐药的分子机制，并将有助于设计新的策略来提高胰腺癌的治愈率。

DESCRIPTION (provided by applicant): Pancreatic cancer is an exceptionally aggressive cancer. It is the fourth leading cause of cancer death in the United States and is increasing in incidence. One of the major factors contributing to the high fatality of pancreatic cancer is the poor responses of most pancreatic cancer patients to radio- and chemo-therapy. Our long-term goal is to understand the molecular mechanisms underlying the exceptional radio- and chemo-resistance in pancreatic cancer. We have recently succeeded in creating pancreatic cancer isogenic cell lines that differ in radiosensitivity from the parental cells. The radioresistant cel lines were generated by exposing pancreatic cancer cells to fractionated ionizing radiation programmed in a way that mimics a typical course of radiotherapy. We hypothesize that the acquired radioresistance in the pancreatic cancer cells are conferred by the aberrant expression of one or more proteins that are involved in cell proliferation and/or survival. Our preliminary results show that several pathways in the radioresistant pancreatic cancer cells have been markedly altered. We propose to use advanced subcellular fractionations, novel quantitative proteomic profiling, and bioinformatics analysis to systematically identify the proteins that are mostly likely to be responsible for the acquired radioresistance in the pancreatic cancer cells (Specific Aim 1), and use molecular and cell biology methods to functionally characterize a well-defined set of the identified proteins with regards to their roles in radio- and chemoradio-resistance in pancreatic cancer (Specific Aim 2). The results from the proposed work will contribute to understanding the molecular mechanisms underlying the exceptional radio- and chemoradio-resistance in pancreatic cancer, and will contribute to designing new strategies to improve the cure rate of pancreatic cancer.