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这些信息在新药开发中的应用。RNA干扰(RNAi)现在使得使用高通量的功能基因组策略来识别SL靶成为可能。不幸的是，虽然RNAi为改进药物发现过程开辟了新的途径，但在我们开发出强大的RNAi筛选技术之前，这些途径仍然只是潜在的机会，包括用于数据验证和整合到基于细胞的操作模型中的实验和生物信息学工具。为了解决这些问题，正如290 SBIR合同提案中概述的那样，它将需要开发一个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，以促进发现SL分子靶标。因此，290主题研究项目的最终目标是开发和商业化一套针对所有常规DDR基因组合的人和鼠池SL shRNA文库，并验证它们在癌细胞模型RNAi筛选中的应用。作为辅助工具，它还需要开发用于体外和体内筛选SL HIT验证和治疗目标优先顺序的方案、试剂和软件工具，以具体控制癌细胞的增殖和存活。上述遗传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，以了解和整合DDR信号网络的动态变化，以发现新的抗癌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.