GEMZ · Genetic Epilepsy Models in Zebrafish
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-01-01 → 2020-12-31
- EU contribution
- €196,400
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Genetic Epilepsy Models in Zebrafish
Epilepsy is a common, severe neurological disorder, marked by abnormal synchronous activity in the brain (seizures), typically characterized by either a sudden brief period of altered or lost consciousness, involuntary movements or convulsions. Epilepsy affects about 65 million people worldwide, with approximately 30% of patients currently resistant to available medication. Within the last two decades, a tremendous increase in our knowledge and understanding of the molecular mechanisms underlying epilepsies has been achieved. The discovery of highly penetrant single gene mutations in rare monogenic forms of epilepsies and the common genetic risk factors in prevalent forms of epilepsies have served as key findings in accelerating the progress in this research field. Nevertheless, the majority of genetic factors is still unknown and important questions as to how these identified genetic defects exactly lead to epileptic seizures and how such epileptogenic mechanisms interact with brain development remain largely unanswered. Thus, there is an urgent need for the rapid functional evaluation of candidate genes. Taking this into account, the overall objective of the project was to generate novel genetic epilepsy models in zebrafish and elucidate the molecular mechanisms underlying epileptogenesis during early brain development, by identifying the signalling pathways activated as a result of selected genetic mutations. In conclusion, the obtained data contributes significantly to the state of the art with regard to early childhood epilepsies and provides new in vivo scientific knowledge about pathogenetic mechanisms related to the mutations of interest.
Data: CORDIS, © European Union
Project objective
Recent advances in clinical genetic studies of epilepsies have identified a steadily growing number of mutations in new candidate genes, creating a need for an effective approach to rapidly provide functional data as to their in vivo function. Furthermore, there is an urgent need to create new, cost- and time-effective animal models which successfully mimic genetic epilepsies in humans, as well as efficient drug discovery approaches to identify compounds useful in the management of these diseases. Here, using established genetic methods, loss- and gain-of-function zebrafish epilepsy models for gene variants recently identified to cause severe, drug-resistant epileptic encephalopathies (EE) will be created. Using a multidisciplinary ""deep-phenotyping"" strategy of pharmacological profiling (i.e. assessment of antiepileptic drugs (AEDs) with known mechanisms of action), high-throughput analysis of locomotor activity and seizure-like behavior, electroencephalographic recordings, histopathological analysis of zebrafish mutant brains, single-cell RNA expression profiling and high-resolution (SPIM) Ca2+ imaging analysis of brain activity, these models will be fully characterized and validated. Finally, a large-scale screen using a library of synthetic small molecules, drug-like natural products and FDA-approved drugs to identify compounds with antiepileptic activity will be performed in one of these models. The main objective of this project is to create and validate new zebrafish models of epilepsy, which will provide both new insights into the mechanisms of epileptogenesis in vivo and indicate potentially novel entry routes for therapeutic intervention.""
Original text from CORDIS.
Participants
- UNIVERSITETET I OSLO · OsloCoordinatorNorway
Links
- View on CORDIS
- DOI: 10.3030/798703
- https://arquivo.pt/wayback/20210910114653/https://www.med.uio.no/english/about/news-and-events/news/2018/fire-marie-sklodowska-curie-individual-fellowships.html
Data: CORDIS, © European Union