Project description:To establish a systematic approach for the determination of human biological & disease relevance through the generation of epigenome data in cell types of interest. Integration of cell type epigenome data with existing & newly generated reference data from human tissue and cell types to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. To provide a framework for the identification of optimal cell types for target identification/validation studies and drug discovery programs across multiple therapeutic areas. Development of bioinformatics pipelines and CTTV components for analysis and provision of data
2015-06-09 | E-ERAD-369 | biostudies-arrayexpress
Project description:CRISPR/Cas9-based Drug Target Screening Library
Project description:The experimental high-throughput screening (HTS) methods, exemplified by CRISPR-based screening, have revolutionized target identification in drug discovery. However, such screens frequently yield extensive and unrelated target lists necessitating costly and time-intensive experimental validation. Here, we propose a dual-filter strategy that integrates literature-mined targets with CRISPR/Cas9 screening outputs, systematically prioritizing the most credible candidates and thereby reducing the experimental validation burden and increasing success rate. To validate this strategy, we applied it with hand-foot syndrome (HFS), a clinically challenging side effect induced by fluoropyrimidine treatment. We identified ATF4 as a key regulator of 5-fluorouracil (5-FU) toxicity in the skin and revealed forskolin as a potential therapeutic agent of HFS through the strategy. Mechanistically, forskolin triggers MEK/ERK-dependent ATF4 induction, subsequently driving 5-FU detoxification via the ATF4-mediated eIF2α/IκB signaling pathway. Our findings demonstrate that this dual-filter strategy could notably accelerate drug discovery by reducing experimental validation burden after target screening.
