A multiplex genome-wide shRNA screening platform for cancer-lethal gene discovery

用于发现癌症致死基因的多重全基因组 shRNA 筛选平台

基本信息

批准号：
8115016
负责人：
STEPHEN J ELLEDGE
金额：
$ 34.06万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8115016
关键词：
Antineoplastic Agents Cancer Patient Cancer cell line Cell Line Cell Survival Cells Collaborations Complex Data Set Dependency Development Drug Delivery Systems Effectiveness Eligibility Determination Epithelial Cells Funding Funding Opportunities Genes Genetic Screening Genome Genomics Goals Human Human Genome Incidence Individual Intervention Laboratories Lethal Genes Libraries Malignant Neoplasms Malignant neoplasm of lung Methodology Methods Noise Normal Cell Outcome Measure Positioning Attribute Proteomics Quality Control RNA Interference RNA Sequences RNA library Screening Result Screening procedure Signal Pathway Signal Transduction Technology Testing Time base cancer cell cancer therapy cancer type cost effective design drug discovery effective therapy gene discovery genome wide association study genome-wide high throughput screening improved interest lung cancer screening next generation novel outcome forecast research study small hairpin RNA technology development technology validation

项目摘要

DESCRIPTION (provided by applicant): A major bottleneck in devising effective targeted therapies for cancer treatment lies at the identification of relevant drug targets. Genetic screens that measure the outcome of inhibiting individual genes in cancer cells and in normal cells on a genome-scale are powerful experiments that could identify such drug targets. Until recently these screens could not be performed in human cells. To perform such screens, my laboratory has developed new methods, based on the principle of RNA interference (RNAi), to individually inactivate every gene in the human genome, approximately 32,000 genes, one at a time. Furthermore, we have developed technologies to carry out these screens in high throughput fashion. Through this funding opportunity, I aim to further develop our RNAi technology platform to enhance its throughput and fidelity. I will use lung cancer cell lines as a discovery paradigm for this technology development effort. The ultimate goal is to enable the genome-wide interrogation of large numbers of cancer cell lines to comprehensively identify the dependencies and vulnerabilities specific to cancer cells but not normal cells. This approach should uncover many previously unrecognized targets for drug discovery and has the potential to provide additional, more effective treatment options for cancer patients.

描述（申请人提供）：设计有效的癌症靶向疗法的主要瓶颈在于相关药物靶点的识别。在基因组规模上测量抑制癌细胞和正常细胞中单个基因的结果的遗传筛选是可以识别此类药物靶标的强大实验。直到最近，这些筛选还无法在人体细胞中进行。为了进行此类筛选，我的实验室开发了基于 RNA 干扰 (RNAi) 原理的新方法，一次单独灭活人类基因组中的每个基因，大约 32,000 个基因。此外，我们还开发了以高通量方式进行这些筛选的技术。通过这次融资机会，我的目标是进一步开发我们的 RNAi 技术平台，以提高其吞吐量和保真度。我将使用肺癌细胞系作为这项技术开发工作的发现范例。最终目标是能够对大量癌细胞系进行全基因组询问，以全面识别癌细胞而非正常细胞特有的依赖性和脆弱性。这种方法应该会发现许多以前未被识别的药物发现靶点，并有可能为癌症患者提供额外、更有效的治疗选择。