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Computational exploration of the DNA damage response pathways in cancer.

机译：癌症中DNA损伤反应途径的计算探索。

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摘要

DNA damage responses play a significant role in maintaining the general genome stability and preventing the development of cancer in cells. The realization that DNA damage triggers responses from a network of interacting pathways in the cell marks a milestone in the study of the DNA repair systems. The main goal of my research work is to develop computational approach to explore the activated signaling pathways associated with DNA damage response in cancer. We established the RepairPLAT, an integrative experimental platform for comprehensive studies of the regulatory control mechanisms of DNA damage response in cancer.; RepairPLAT platform has three components: (1) RepairNET, a protein-protein interaction network associated with the DNA damage response. RepairNET currently contains more than 1,200 proteins with over 2,300 functional interactions. It was assembled by using a protocol that involved computational data mining of MEDLINE as well as extracting data from various databases like SwissProt, DIP, and Pfam. (2) RepairCHIP, a 60-mer oligonucleotide microarray chip contains genes corresponding to the proteins in RepairNET. In contrast to generic arrays, RepairCHIP contains genes of known functional relationship, which significantly reduces the complications for microarray data interpretation. (3) RepairPATH, a pathway-exploration algorithm that integrates RepairNET with the gene expression profiles derived from microarray data. Based on the observation that co-functional proteins often exhibit correlated gene expression profiles, RepairPATH identifies the activated signaling pathways in cancer by systematically searching the RepairNET for proteins with significantly correlated gene expression profiles. Analyzing the gene expression profiles of breast cancer by using RepairPATH, we found distinct similarities and differences in the activated signaling pathways between the samples from the patients who developed metastases and the samples from the patients who were disease free within 5 years.; With the RepairPLAT platform, we first explored the activated DNA damage response pathways in cancer on a global scale, and then biological function of these potentially activated pathways were verified at molecular level by using biochemical assays.
机译：DNA损伤反应在维持总体基因组稳定性和预防细胞癌发展中起着重要作用。 DNA损伤触发了细胞相互作用路径网络的响应，这一认识标志着DNA修复系统研究的一个里程碑。我研究工作的主要目标是开发一种计算方法，以探索与癌症中DNA损伤反应相关的激活信号通路。我们建立了RepairPLAT，这是一个综合实验平台，用于全面研究癌症中DNA损伤反应的调控机制。 RepairPLAT平台具有三个组成部分：（1）RepairNET，与DNA损伤反应相关的蛋白质-蛋白质相互作用网络。 RepairNET当前包含1,200多种蛋白质，具有2,300多种功能相互作用。它是使用协议进行组装的，该协议涉及MEDLINE的计算数据挖掘以及从SwissProt，DIP和Pfam等各种数据库中提取数据。 （2）RepairCHIP，一种60-mer寡核苷酸微阵列芯片，包含与RepairNET中的蛋白质相对应的基因。与通用阵列相反，RepairCHIP包含具有已知功能关系的基因，从而大大降低了微阵列数据解释的复杂性。 （3）RepairPATH，一种途径探索算法，将RepairNET与源自微阵列数据的基因表达谱整合在一起。基于共同功能蛋白通常表现出相关的基因表达谱的观察，RepairPATH通过系统地在RepairNET中搜索具有显着相关的基因表达谱的蛋白来鉴定癌症中激活的信号传导途径。通过使用RepairPATH分析乳腺癌的基因表达谱，我们发现在5年内发生转移的患者的样品与无疾病的患者的样品之间的激活信号通路存在明显的异同。使用RepairPLAT平台，我们首先在全球范围内探索了癌症中激活的DNA损伤应答途径，然后使用生化分析在分子水平上验证了这些潜在激活的途径的生物学功能。

著录项

  • 作者

    Li, Wei.;

  • 作者单位

    Temple University.;

  • 授予单位 Temple University.;
  • 学科 Biology Biostatistics.; Chemistry Biochemistry.; Biology Bioinformatics.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 117 p.
  • 总页数 117
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物数学方法;生物化学;
  • 关键词

  • 入库时间 2022-08-17 11:39:01

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