PMC:6610382 / 315-1406 JSONTXT

{"project":"testtesttest","denotations":[{"id":"T2","span":{"begin":87,"end":96},"obj":"Body_part"},{"id":"T3","span":{"begin":367,"end":374},"obj":"Body_part"},{"id":"T4","span":{"begin":448,"end":454},"obj":"Body_part"},{"id":"T5","span":{"begin":510,"end":523},"obj":"Body_part"},{"id":"T6","span":{"begin":910,"end":917},"obj":"Body_part"}],"attributes":[{"id":"A2","pred":"uberon_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/UBERON_0000955"},{"id":"A3","pred":"uberon_id","subj":"T3","obj":"http://purl.obolibrary.org/obo/UBERON_0000467"},{"id":"A4","pred":"uberon_id","subj":"T4","obj":"http://purl.obolibrary.org/obo/UBERON_0000479"},{"id":"A5","pred":"uberon_id","subj":"T5","obj":"http://purl.obolibrary.org/obo/GO_0005886"},{"id":"A6","pred":"uberon_id","subj":"T6","obj":"http://purl.obolibrary.org/obo/UBERON_0000467"}],"text":"The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning (“Causal Reasoning Analytical Framework for Target discovery”-CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in 3 preclinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. The CRAFT is applicable to disease settings other than epilepsy."}