CONTRACT #N43-CO-95012-616 MONTHS FUNDING -PHASE 1 TOPIC 265 DEVELOPMENT OF SHRN

尽管在阐明癌症的分子基础方面取得了快速进展，但表面上更困难的后基因组挑战将是疾病特异性信号通路的功能注释。RNA干扰使得首次使用大规模功能基因组策略进行靶标鉴定成为可能。该项目的最终目标是开发和建立一个定制的RNAi筛选服务，该服务基于功能验证（FV）的人类和小鼠全基因组慢病毒shRNA库，以及用于在药物发现过程中分析和使用这些信息的生物信息学工具。第一阶段，开发和筛选集中的FV shRNA集合，以确定参与MCL-1和p27kip1信号通路的因子。除了这些原理验证性研究之外，还建议将遗传筛选数据与转录组分析和从科学文献中挖掘的分子网络信息进行验证和整合。上述遗传筛选和生物信息学策略将为研究界提供高度模块化的、具有成本效益的方法，以理解和整合这些信号转导网络中的变化，从而可以描绘癌症表型。

Despite the rapid advances in elucidating the molecular basis of cancer, an ostensibly more difficult post-genomic challenge will be the functional annotation of Disease-specific signaling pathways. RNA interference makes possible for the first time, the use of large-scaile functional genomic strategies for target identification. The ultimate goal of the proposed project is to develop and establish a custom RNAi screening service based on functionally validated (FV) genome-wide human and mouse lentiviral shRNA libraries in arrayed and multiplex formates, and bioinformatics tools for analysis and use of this information in the drug discovery process. Phase I, Develop and screen a focused, FV shRNA collection to identify factors that are involved in the MCL-1 and p27kip1 signaling pathways. In addition to these proof-of-principle studies, proposed to validate and integrate genetic screening data with transcriptome profiling and molecular network information mined from scientific literature. The aforementioned genetic screening and bioinformatic strategies will provide the research community with hoghly modular, cost-effective approaches to understand and integrate the changes in these signal trasduction networks so that cnacer phenotypes can be delineated.