Obiettivo Drug treatment is often inefficient. Only 30–60% of patients respond properly to treatment with e.g. antidepressants, beta-blockers, statins and antipsychotics. Furthermore, adverse drug reactions (ADRs) frequently occur and cause about 7% of all hospital admissions, a frequency that is increased to 30% in elderly subjects above 70 years of age. This is due to a great extent to pharmacokinetics differences.Epigenetic modifications have been demonstrated to potentially participate in the regulation of ~60 human ADME genes. A correlation between the gene’s epigenetic state and possible influence on drug therapy outcome has been experimentally established only in relation to a few ADME genes.Several drugs with epigenetic actions are currently used or on clinical trials. The best examples are DNA Methyltransferases (DNMTs) and Histone Deacetylase (HDACs) inhibitors.In this project, we propose to elucidate the substantial unexplained fraction of interindividual variability in drug response and metabolism using a 3D multi-cell in vitro model of human liver in comparison to transcriptome and phenotype data obtained from a bank of 130 human livers with the following AIMS:AIM1: to unmask the epigenetically regulated ADME genesAIM2: to evaluate the epigenetically regulated ADME genes as interindividual variability biomarkersA list of epimarks of interindividual variation of drug ADME processes will be generated.AIM3: to test the epigenetic influence of candidate drugs. Our objective is to identify the specific ADME genes epigenetically altered by each drug treatment and elucidate the possibilities of interindividual variation in the ADME processes for each of the tested drugs.This approach is extensively multidisciplinary and multisectorial. The experimental design includes tissue bioengineering techniques to develop liver organotypic cultures, drug metabolism functional profiling, and molecular biology approaches, from the perspective of cutting-edge technology. Campo scientifico natural sciencesbiological sciencesgeneticsDNAmedical and health sciencesbasic medicinepharmacology and pharmacypharmacokineticsmedical and health sciencesbasic medicinepharmacology and pharmacyadverse drug reactionsnatural sciencesbiological sciencesgeneticsepigeneticsnatural sciencesbiological sciencesmolecular biology Programma(i) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) FP7-PEOPLE-2012-CIG - Marie-Curie Action: "Career Integration Grants" Invito a presentare proposte FP7-PEOPLE-2012-CIG Vedi altri progetti per questo bando Meccanismo di finanziamento MC-CIG - Support for training and career development of researcher (CIG) Coordinatore KAROLINSKA INSTITUTET Contributo UE € 100 000,00 Indirizzo Nobels vag 5 17177 Stockholm Svezia Mostra sulla mappa Regione Östra Sverige Stockholm Stockholms län Tipo di attività Higher or Secondary Education Establishments Contatto amministrativo Eva Gipperth (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato