Project description DEENESFRITPL An in vitro cell model for cardiac arrhythmias Human induced pluripotent stem cells (iPSCs) have recently emerged as good in vitro models for studying tissue pathophysiology. Scientists of the EU-funded SiGNATURE project will employ iPSCs to develop cardiomyocytes and study cardiac arrhythmias, a group of conditions that are increasing in prevalence among European citizens. Using a unique 3D culture system, researchers will mature iPSC-derived cardiomyocytes and investigate them at the genetic and functional level. The work will focus on two gene-associated heart diseases. The iPSC-derived cardiomyocytes will advance modelling of cell-autonomous cardiac diseases and pave the way for personalised in vitro drug screening strategies. Show the project objective Hide the project objective Objective The incidence of cardiac arrhythmias in Europe is increasing because of aging and unexpected side effects of drugs, such as chemotherapeutics. To understand mechanisms underlying these conditions requires reliable preferably human models. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are presently good candidates since they share the genome of the individual from whom they are derived and can thus recapitulate genetic, ethnic and gender contributions to the cardiac disease phenotypes. However, their immature state and high inter- and intra-line variability is limiting their value as preclinical models. In the proposed project, I will address these issues through an interdisciplinary approach combining a unique 3D culture maturation system developed in my host lab with my expertise in electrophysiology. I will characterize gene expression and electrical properties of single cardiomyocytes simultaneously with view to directly correlating genes with function and identify molecular markers associated with the functionally mature cardiac phenotype. Two genetic cardiac diseases (one caused by an imprinted gene, the other by a postnatally expressed splice variant) for which the host already has hiPSC lines, will be used as proof of concept that hiPSC-CM maturation in this system is sufficient (i) to reveal disease phenotypes not evident in conventional culture and (ii) to identify molecular markers suitable for selecting mature hiPSC-CMs for drug testing. Overall, this project will provide the first functionally-relevant gene signature of (mature) hiPSC-CMs, and thus be an important advance in modelling all cardiomyocyte autonomous cardiac diseases more precisely for (personalized) drug screening. The outcome will be available to academic and private researchers to enhance rates of drug discovery and safety, and promote hiPSC-CMs as validated adult cardiac models to replace, at least in part, the use of animal models. Fields of science medical and health sciencesbasic medicinepharmacology and pharmacydrug discoverymedical and health sciencesclinical medicinecardiologycardiovascular diseasescardiac arrhythmianatural sciencesbiological sciencesgeneticsgenomes Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2018 - Individual Fellowships Call for proposal H2020-MSCA-IF-2018 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator ACADEMISCH ZIEKENHUIS LEIDEN Net EU contribution € 187 572,48 Address Albinusdreef 2 2333 ZA Leiden Netherlands See on map Region West-Nederland Zuid-Holland Agglomeratie Leiden en Bollenstreek Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
