Objective The fundamental limitation in our ability to dissect human diseases is the scarce availability of human tissues at relevant disease stages, which is particularly salient for neural disorders. Somatic cell reprogramming is overcoming this limitation through the derivation of patient-specific induced pluripotent stem cells (iPSC) that can be differentiated into disease-relevant cell-types. Despite these tantalizing possibilities, there are critical issues to be addressed in order to secure iPSC-modeling as a robust platform for the interrogation of disease aetiology and the development of new therapies. These concern the taming of human genetic variation, the identification of differentiation stages in which to uncover and validate phenotypes, and finally their translational into drug discovery assays. This project confronts these challenges focusing on the paradigmatic case of two rare but uniquely informative disorders caused by symmetric gene dosage imbalances at 7q11.23: Williams Beuren Syndrome and the subset of autism spectrum disorders associated to 7q11.23 microduplication. The hallmark of WBS is a unique behavioral-cognitive profile characterized by hypersociability and intellectual disability in the face of comparatively well-preserved language abilities. Hence, the striking symmetry in genotype and phenotype between WBS and 7dupASD points to the 7q11.23 cluster as a surprisingly small subset of dosage-sensitive genes affecting social behaviour and cognition. We build on a large panel of iPSC lines that we already reprogrammed from a unique cohort of WBS and 7dupASD patients and whose characterization points to specific derangements at the level of transcriptional/epigenetic control, protein synthesis and synaptic dysfunction. Through the integration of transcriptomic and epigenomic profiling with targeted mass spectrometry and gene network prediction we propose an innovative drug discovery pipeline for the identification of new therapeutic leads. Fields of science medical and health sciencesbasic medicinepharmacology and pharmacydrug discoverynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesmedical biotechnologycells technologiesstem cellsnatural scienceschemical sciencesanalytical chemistrymass spectrometry Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-CG-2013-LS7 - ERC Consolidator Grant - Diagnostic Tools, Therapies and Public Health Call for proposal ERC-2013-CoG See other projects for this call Funding Scheme ERC-CG - ERC Consolidator Grants Host institution UNIVERSITA DEGLI STUDI DI MILANO EU contribution € 1 407 800,00 Address Via Festa Del Perdono 7 20122 Milano Italy See on map Region Nord-Ovest Lombardia Milano Activity type Higher or Secondary Education Establishments Administrative Contact Gerardo D'errico (Dr.) Principal investigator Giuseppe Testa (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (3) Sort alphabetically Sort by EU Contribution Expand all Collapse all UNIVERSITA DEGLI STUDI DI MILANO Italy EU contribution € 1 407 800,00 Address Via Festa Del Perdono 7 20122 Milano See on map Region Nord-Ovest Lombardia Milano Activity type Higher or Secondary Education Establishments Administrative Contact Gerardo D'errico (Dr.) Principal investigator Giuseppe Testa (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH Switzerland EU contribution € 200 004,00 Address Raemistrasse 101 8092 Zuerich See on map Region Schweiz/Suisse/Svizzera Zürich Zürich Activity type Higher or Secondary Education Establishments Administrative Contact Rudolf Aebersold (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data ISTITUTO EUROPEO DI ONCOLOGIA SRL Participation ended Italy EU contribution € 390 000,00 Address VIA FILODRAMMATICI 10 20121 Milano See on map Region Nord-Ovest Lombardia Milano Activity type Private for-profit entities (excluding Higher or Secondary Education Establishments) Administrative Contact Ilaria Foti (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
