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

塔斯马尼亚::75 0849::塔斯马尼亚 R

• 批准号: 8164007
• 负责人: ALEXANDR CHENCHIK
• 金额: $ 19.97万
• 依托单位: CELLECTA, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-24 至 2011-06-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8164007
• 关键词: Address; Bioinformatics; Candidate Disease Gene; Cell Line; Cell model; Cells; Communities; Contracts; Data; Development; Disease; Gene Combinations; Genes; Genetic Screening; Genomics; Goals; Human; In Vitro; Libraries; Malignant Neoplasms; Modeling; Molecular; Molecular Target; Mus; Performance; Pharmaceutical Preparations; Process; Protocols documentation; RNA Interference; Reagent; Research; Research Project Grants; Science; Screening procedure; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Software Tools; Spliced Leader RNA; Technology; Validation; base; cancer cell; cost effective; drug discovery; expression vector; functional genomics; human disease; improved; in vivo; novel; small hairpin RNA; therapeutic target; tool

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.

尽管在阐明人类疾病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）技术的发展使得高通量的功能基因组策略用于SL靶标的鉴定成为可能。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合同提案中所概述的那样，将需要开发一种基于经验证的慢病毒shRNA文库的新型正交功能基因组学平台，以促进SL分子靶点的发现。因此，290课题研究项目的最终目标是开发和商业化一套针对所有典型DDR基因组合的人和小鼠混合SL shRNA文库，并验证其在癌细胞模型中的RNAi筛选中的应用。作为支持工具，还需要开发用于体外和体内筛选SL命中验证和治疗靶点优先化的方案、试剂和软件工具，其特异性地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、具有成本效益的方法，以了解和整合DDR信号网络的动态变化，从而发现新型抗癌SL靶点。