Obiettivo My aim is to understand the exact genetic contribution in every patient with Amyotrophic Lateral Sclerosis (ALS), a lethal disease with a life time risk of 0.3% and an urgent unmet therapeutic need. I have recently shown a disproportionate large contribution from low-frequency genetic variants in ALS. ALS is not simply a collection of unique rare diseases with a monogenetic cause nor is it a diagnostic continuum with a complex contribution of thousands of small effect factors. ALS is in-between, which I call “simplex”, where in each patient a few, considerably strong genetic factors with or without environmental factors are at play. ALS mutations are characterized by reduced penetrance, variable clinical expressivity, have specific pleiotropic clinical features and interact with environmental factors. These phenomena are unexplained, but provide me with important and new opportunities in order to unravel the clinical, genetic and biological heterogeneity in ALS. I have created new research fields to go an important step beyond the state of the art: Splitting by lumping uses novel machine learning algorithms to reclassify patients using clinical pleiotropic features, environmental factors and blood epigenetic profiles to identify novel ALS mutations. Imaging genomics overlays patterns in ALS-associated brain morphology on MRI with brain gene-expression patterns to find ALS mutations. ALS risk in 3D integrates data on three-dimensional folding of DNA with genetic data to identify causal mutations and mutation-to-mutation interaction. ALS genomic modifiers in 3D identifies modifiers of C9orf72 mutations through the development of cellular reporter assays and CRISPR-Cas9 based screens. Genomic findings are translated using cellular models which can be used for targeted and unbiased drug screens. If successful, my approaches can be applied beyond the scope of this ERC and will have a clear impact on clinical trial design and genetic counselling in ALS in particular. Campo scientifico scienze naturaliscienze biologichegeneticaDNAscienze naturaliscienze biologichegeneticamutazionescienze naturaliinformatica e scienze dell'informazioneintelligenza artificialeapprendimento automaticoscienze mediche e della salutemedicina di baseneurologiasclerosi laterale amiotrofica Programma(i) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Argomento(i) ERC-2017-COG - ERC Consolidator Grant Invito a presentare proposte ERC-2017-COG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-COG - Consolidator Grant Coordinatore UNIVERSITAIR MEDISCH CENTRUM UTRECHT Contribution nette de l'UE € 1 980 434,00 Indirizzo Heidelberglaan 100 3584 CX Utrecht Paesi Bassi Mostra sulla mappa Regione West-Nederland Utrecht Utrecht 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 Altri finanziamenti € 0,00 Beneficiari (1) Classifica in ordine alfabetico Classifica per Contributo netto dell'UE Espandi tutto Riduci tutto UNIVERSITAIR MEDISCH CENTRUM UTRECHT Paesi Bassi Contribution nette de l'UE € 1 980 434,00 Indirizzo Heidelberglaan 100 3584 CX Utrecht Mostra sulla mappa Regione West-Nederland Utrecht Utrecht 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 Altri finanziamenti € 0,00
