TAS::75 0849::TAS R&D-OTHER SCIENCES-ENG DEV

尽管在阐明人类疾病的分子基础方面取得了快速进展，但一个表面上更困难的后基因组挑战是疾病特异性信号通路的功能注释以及将这些信息应用于新药开发。RNA干扰（RNAi）使得利用高通量功能基因组策略鉴定SL靶标成为可能。不幸的是，虽然RNAi为改善药物发现过程开辟了新的途径，但这些途径仍然只是潜在的机会，直到我们开发出强大的RNAi筛选技术，包括用于数据验证和整合到基于操作细胞的模型中的实验和生物信息学工具。为了解决这些问题，正如299sbir合同提案中概述的那样，它将需要开发一种基于经过验证的慢病毒shRNA文库的新型正交功能基因组学平台，以促进SL分子靶标的发现。因此，290个课题的研究项目的最终目标是开发一套针对所有典型DDR基因组合的人类和小鼠汇集的SL shRNA文库并将其商业化，并验证其在癌细胞模型中用于RNAi筛选的应用。作为一种辅助工具，它还需要开发方案、试剂和软件工具，用于体外和体内筛选特异性控制癌细胞增殖和存活的SL命中验证和治疗靶点优先级。上述基因筛选和生物信息学工具将为研究界提供高度模块化、成本效益高的方法，以理解和整合DDR信号网络的动态变化，从而发现新的抗癌SL靶点。

Despite rapid advances in elucidating the molecular basis of human diseases, an ostensibly more difficult post-genomic challenge is the functional annotation of disease-specific signaling pathways and the application of this information for the development of novel drugs. RNA interference (RNAi) now makes it possible to use high-throughput functional genomic strategies for SL target identification. Unfortunately, while RNAi has opened new avenues for improving the drug discovery process, these avenues remain only potential opportunities until we develop robust RNAi screening technologies, including experimental and bioinformatics tools for data validation and integration into operational cell-based models. To address these issues and, as outlined in the 290 SBIR contract proposal, it will require to develop a novel orthogonal functional genomics platform based on validated lentiviral shRNA libraries to facilitate discovery of SL molecular targets en masse. Accordingly, the ultimate goal of the 290 topic research project is to develop and commercialize a set of human and mouse pooled SL shRNA libraries targeting all cannonical DDR gene combinations and validate their application for RNAi screens in cancer cell models. As a supporting tools, it will also require to develop protocols, reagents and software tools for in vitro and in vivo screening SL hit validation and therapeutic target prioritization that specifically control the proliferation and survival of cancer cells. The aforementioned genetic screening and bioinformatic tools will provide the research community with highly modular, cost-effective approaches to understand and integrate the dynamic changes in DDR signaling networks for the discovery of novel anti-cancer SL targets.