Obiettivo Common fragile sites (CFSs) are large chromosomal regions identified by conventional cytogenetics as sequences prone to breakage in cells subjected to replication stress. The interest in CFSs stems from their key role in DNA damage, resulting in chromosomal rearrangements. The instability of CFSs was correlated with genome instability in precancerous lesions and during tumour progression. Two opposing views dominate the discussion regarding the role of CFSs. One school of thought suggested that genomic instability during cancer progression causes collateral damage to genes residing within CFSs, such as WWOX and FHIT. These genes are proposed to be unselected ‘‘passenger’’ mutations. The counter argument is that deletions and other genomic alterations in CFSs occur early in cancer development. Cancer cells with deletions in genes that span CFSs are then selectively expanded due to loss of tumour suppressor functions such as protection of genome stability, coordination of cell cycle or apoptosis. Recent observations from my lab clearly suggest that gene products from CFSs play driver roles in cancer transformation. Moreover, we have evidence for the involvement of DNA damage and Wwox in pancreatic β-cells in the context of diabetes. Here, I propose to investigate the role of tumour suppressor gene products (TSGPs) of CFSs in human diseases. Three approaches will be taken to tackle this question. First, molecular functions of TSGPs of CFSs will be determined using state-of-the-art genetic tools in vitro. Second, novel transgenic mouse tools will be used to study CFSs and their associated TSGs in preneoplastic lesions and tumours in vivo, with confirmatory studies in human material. Third, we will examine the potential involvement of CFSs and their TSGPs in type-2 diabetes (T2D). The expected outcome is a detailed molecular understanding of CFSs and their associated TSGPs in genomic instability as well as their roles in cancer and metabolic diseases. Campo scientifico medical and health sciencesbasic medicineneurologyepilepsynatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicineendocrinologydiabetesnatural sciencesbiological sciencesgeneticsgenomesmedical and health sciencesbasic medicinephysiologyhomeostasis Programma(i) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Argomento(i) ERC-CoG-2015 - ERC Consolidator Grant Invito a presentare proposte ERC-2015-CoG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-COG - Consolidator Grant Istituzione ospitante THE HEBREW UNIVERSITY OF JERUSALEM Contribution nette de l'UE € 2 000 000,00 Indirizzo EDMOND J SAFRA CAMPUS GIVAT RAM 91904 Jerusalem Israele Mostra sulla mappa Tipo di attività Higher or Secondary Education Establishments Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 2 000 000,00 Beneficiari (1) Classifica in ordine alfabetico Classifica per Contributo netto dell'UE Espandi tutto Riduci tutto THE HEBREW UNIVERSITY OF JERUSALEM Israele Contribution nette de l'UE € 2 000 000,00 Indirizzo EDMOND J SAFRA CAMPUS GIVAT RAM 91904 Jerusalem Mostra sulla mappa Tipo di attività Higher or Secondary Education Establishments Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 2 000 000,00