Descrizione del progetto
La displasia corticale e il suo legame con l’epilessia
La displasia corticale focale è una malformazione genetica rara della corteccia cerebrale che può portare allo sviluppo dell’epilessia focale. Sebbene sia verosimile che la fonte dell’attività epilettogena sia rappresentata dalle cellule anomale presenti nelle lesioni dovute alla displasia corticale focale, l’origine di tali cellule non è tuttora chiara. Il progetto CODICES, finanziato dall’UE, intende effettuare una caratterizzazione molecolare e genetica di queste cellule anomale che manifestano un’iperattivazione del percorso mTOR. I ricercatori impiegheranno organoidi umani per decifrare i meccanismi di sviluppo coinvolti nell’epilettogenesi. A lungo termine, CODICES porterà a trattamenti più efficaci e meno invasivi per l’epilessia focale.
Obiettivo
Focal cortical dysplasia (FCD) is a rare, genetic, non-syndromic developmental malformation of the cerebral cortex that accounts for 5-10% of patients with focal epilepsy. FCD represents the main cause of pharmacologically intractable epilepsy, the only treatment available consisting of invasive surgical resection of the epileptogenic zone, which results effective in only 62% of patients. Thus, a better understanding of this disorder is necessary to develop more effective and less invasive treatments. FCD type 2 (FCD2) is an mTORopathy caused by genetic mutations that cause hyperactivation of the mTOR pathway, leading to abnormal cell size (cytomegalic dysmorphic neurons and balloon cells) and disruption of the structure of the cortex. Recently, the supervisor S. Baulac and others have partially explained the focal nature of the disorder by identifying post-zygotic somatic (mosaic) mutations in a percentage of cells that correlates with the size of the lesion. Despite this, the underling genetics remains unknown for ~40% of FCD2 patients. My first objective is to perform deep whole-exome sequencing of a cohort of 60 unsolved FCD2 cases to explore alternative pathways and find possibly pathogenic variants, focusing on those with an established link with mTOR pathway and/or neurodevelopment. Abnormal cells found in FCD2 lesions have been hypothesized as the source of the epileptogenic activity. However, the developmental origins of these cells are still unclear, and there is a need to find clear biomarkers that can clarify the link between mTOR hyperactivation and neuronal hyperexcitability. This project aims to clarify these aspects by applying my expertise in single cell genomics and S. Baulac’s expertise in functional studies and disease modelling in human brain organoids. The MSCA IF will allow me to reintegrate in Europe after a 4-years+ postdoc in the US and complete my training with the objective of applying to set up my own lab at the end of the two years.
Campo scientifico
Parole chiave
Programma(i)
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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
75013 Paris
Francia