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miRNA regulation of developmental sodium channel isoform transition and its implications for Dravet syndrome

Project description

A novel therapy for epilepsy

Dravet syndrome (DS) is a rare genetic type of epilepsy with seizures that begin early on in life and cause developmental delays. Patients do not respond to conventional medications, and a significant proportion do not reach adulthood. DS is caused by mutations in the SCN1A gene that encodes a transmembrane protein responsible for ion transport in neuronal cells. Funded by the Marie Skłodowska-Curie Actions programme, the miRSodium project aims to understand how the mutated SCN1A isoform emerges during development. The goal is to develop a gene therapy approach for DS based on microRNA mediated regulation.

Objective

Dravet syndrome (DS) is a rare epileptic encephalopathy affecting ~1:20000 children, who suffer from infantile seizures and lifelong deficits in cognitive, motor, behavioural, and social skills. DS can cause premature mortality with up to 21% of patients not reaching adulthood. Despite the known genetic origin – 80% of patients carry a mutation in the SCN1A gene encoding the alpha1 subunit of the sodium voltage gated channel – there is no cure for this disease. The symptoms of DS start at ~ six months of age, shortly after the transition from the developmental Nav1.3 (SCN3A gene) to the postnatal Nav1.1 (SCN1A) channel isoform carrying the mutation. The mechanism of this transition remains unexplained, which hinders the Nav1.3 isoform-based DS therapy. I will build upon the recently discovered miRNAs’ (short, non-coding RNA) regulatory effect on SCN1A and 3A genes to elucidate regulation of the isoform transition. My ULTIMATE AIM is to harness the protective effect of the Nav1.3 isoform via miRNA regulation as a DS treatment. I will untangle the miRNA profile of DS from birth to the symptom onset in a well-established mouse model. Through miRNA expression manipulation, I will resolve miRNA function in SCN1A and 3A regulation, its impact on the brain, and ultimately on DS symptoms. My skills in developmental epilepsy models will combine with Prof Henshall’s expertise in miRNA function and use in treatment (shown by miRNA-based treatments for epilepsy in pre-clinical development) to deliver novel treatment options for devastating DS and advance the field of miRNA regulation in the brain. This training & collaboration with top neurobiologists at three excellent institutions – RCSI (host), UA & UMCU (secondment partners) – will advance my skills & employability and propel my career in developmental neurobiology. It will also contribute to the quality of Europe's research and innovation, increasing its competitiveness and attractiveness as a leading research destination.

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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(opens in new window) HORIZON-MSCA-2021-PF-01

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Coordinator

ROYAL COLLEGE OF SURGEONS IN IRELAND
Net EU contribution

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€ 215 534,40
Address
ST STEPHEN'S GREEN 123
2 DUBLIN
Ireland

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Activity type
Higher or Secondary Education Establishments
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