Identification of the molecules/pathways that confer acquired radioresistance in

描述（由申请人提供）：胰腺癌是一种异常侵袭性的癌症。它是美国癌症死亡的第四大原因，并且发病率正在增加。导致胰腺癌高死亡率的主要因素之一是大多数胰腺癌患者对放疗和化疗的反应较差。 我们的长期目标是了解胰腺癌中特殊的放射和化学抗性的分子机制。我们最近成功地创建了与亲代细胞放射敏感性不同的胰腺癌同基因细胞系。通过将胰腺癌细胞暴露于以模拟典型放疗过程的方式编程的分次电离辐射来产生抗辐射细胞系。我们假设胰腺癌细胞中获得性辐射抗性是由参与细胞增殖和/或存活的一种或多种蛋白质的异常表达所赋予的。我们的初步结果表明，在放射抗性胰腺癌细胞的几个途径已显着改变。我们建议使用先进的亚细胞分离、新的定量蛋白质组学分析和生物信息学分析来系统地鉴定胰腺癌细胞中最可能导致获得性辐射抗性的蛋白质（具体目标1），并使用分子和细胞生物学方法来在功能上表征一组明确定义的已鉴定蛋白质，胰腺癌的耐药性（具体目标2）。这项工作的结果将有助于理解胰腺癌中特殊的放射性和放射性化疗抗性的分子机制，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.