In vitro tool to screen drugs

Cell culturebased tools will be developed and tested towards in vitro highthroughput screening of PP safety profile of candidate pharmaceuticals at the lead optimization stage aiming to detect early signalling PP toxicity signaturesTranscriptomics analysis first tier and proteomics analysis second tier will be run on appropriate hiPSCderived neuronal and glial cell models as well as other cell lines highly responsive to immunomodulatory molecules eg neuroblastoma SHSY5Y to identify modifications occurring at gene andor protein expression levels with focus on immunomodulation Proteins andor genes that show a clear activation or suppression of their expression in these omics analysis will be selected as specific endpoints to screen PP adverse effects and to further elucidate the mechanisms of PP toxicity D25Epigenetic modifications eg RNA editing DNA methylation or histone deacetylation which have already been associated with the fine tuning of neuronal cells mechanisms at the molecular level and reported as important modulators of the neuroimmune response will also be addressed In particular distinct epigenetic alterations of the RNA editing activity on the serotonin receptor 2C 5HT2cR premRNA known to greatly impair 5HT2cR pharmacological properties will be evaluated since anomalies of serotonin biology in brain appear to be a characteristic trait underlying depression andor suicidal behaviour