Identification of the molecules/pathways that confer acquired radioresistance in

描述（申请人提供）：胰腺癌是一种极具侵袭性的癌症。它是美国癌症死亡的第四大原因，并且发病率正在上升。导致胰腺癌高病死率的主要因素之一是大多数胰腺癌患者对放疗和化疗的不良反应。我们的长期目标是了解胰腺癌异常放射和化疗耐药的分子机制。我们最近成功地创造了胰腺癌等基因细胞系，其放射敏感性与亲代细胞不同。耐辐射细胞系是通过将胰腺癌细胞暴露在以模仿典型放射治疗过程的方式编程的分离电离辐射中产生的。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，放射耐药胰腺癌细胞的几个途径已经明显改变。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识别最有可能对胰腺癌细胞获得性放射抗性负责的蛋白质（Specific Aim 1）。并使用分子和细胞生物学方法对一组定义明确的已鉴定蛋白质进行功能表征，以了解它们在胰腺癌放射和放化疗耐药中的作用（Specific Aim 2）。本研究的结果将有助于理解胰腺癌异常放射和放化疗耐药的分子机制，并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.