Job ID: 96602
PhD position. Sudden Unexplained Death in Epilepsy (SUDEP) in mouse models: mechanisms and therapeutic approaches.
Position: Ph.D. Student
Deadline: 26 October 2022
Employment Start Date: 2 January 2023
Contract Length: 3 years
City: Valbonne - Sophia Antipolis
Institution: CNRS and University Cote d'Azur
Department: Institute of Molecular and Cellular Pharmacology (IPMC)
IMPORTANT! Applications have to be filled on the official job market site of the CNRS: https://emploi.cnrs.fr/Offres/Doctorant/UMR7275-MASMAN-007/Default.aspx?lang=EN
Sudden Unexplained Death in Epilepsy (SUDEP) is the sudden death of a person with epilepsy when no abnormal conditions are found at the autopsy. The rate of SUDEP is high in developmental and epileptic encephalopathies (DEEs), very severe epilepsies associated with cognitive and behavioral impairment, and particularly high in Dravet syndrome (DS), a severe, drug-resistant DEE caused by mutations in the NaV1.1/SCN1A sodium channel.
Experimental and clinical data suggest that SUDEP can result from fatal apnea after an epileptic seizure in a patient who has developed an epilepsy-related central respiratory vulnerability. Serotonin (5HT) dysfunction may play a role in the pathogenesis of epilepsy in DS and in seizure-related respiratory dysfunction. However, several questions remain unanswered. In our project, funded by the Agence Nationale de la Recherche (ANR), we will: (i) analyze the temporal relationship between epilepsy progression and cardiorespiratory function impairment in a mouse model of DS in which we can control the onset of the severe DEE phenotype and the SUDEP risk is progressively increased; (ii) determine, in mice, the relationship between alterations of the brainstem 5HT pathway and cardiorespiratory dysfunction (this relationship will be studied in parallel in patients by our clinical collaborators); (iii) validate that modulation of 5HT neuron activity by chemogenetic tools alters the risk of seizure-related fatal apnea; (iv) use drugs acting on serotoninergic pathways to reduce the risk of SUDEP.
The PhD student will use several techniques to carry out this project: chemogenetic control of neuronal activity (DREADD), chronic video-EEG recordings, multi-electrode intracerebral DC recordings, electrocardiogram recordings, brain signal analysis, chronic (with thermocouple probe) and acute (with plethysmography) recording of respiration, surgical implantations, use of transgenic, knock-in and cre-lox mice, genotyping by PCR.
Massimo Mantegazza’s team has a recognized expertise in the development and study of in vivo, ex vivo and in vitro genetic models of epilepsy: www.ipmc.cnrs.fr/?page=mantegazza&lang=uk
The Institute of Molecular and Cellular Pharmacology (IPMC, 220 people, 8000 m2 of buildings) is a joint research unit (UMR 7275) of the CNRS (the largest public research organization in France) and the Université Côte d’Azur (among the top 10 research-intensive universities in France; https://univ-cotedazur.fr/). Its 20 world-class research teams benefit from a high-level technological environment in rodent phenotyping, electrophysiology, molecular and cellular biology, imaging, cytometry, biomolecule analysis, functional genomics and integrative biology.
The student will join the doctoral school ED85 (http://www.unice.fr/ed-svs/fr/site/presentation-ed.php) of the Université Cote d’Azur. The UCA ED85 is part of the Ecole Universitaire de Recherche (EUR) Life (https://life.univ-cotedazur.fr/), which develops strong links between teaching, research and private companies
Mantegazza M. and Broccoli V. (2019) SCN1A/NaV1.1 channelopathies: mechanisms in expression systems, animal models and human iPSCs models. Epilepsia 60(S3):S25-S38. Invited review. https://doi.org/10.1111/epi.14700
Mantegazza M., Cestèle S and Catterall W.A. (2021) Sodium Channelopathies of Skeletal Muscle and Brain. Physiological Reviews https://doi.org/10.1152/physrev.00025.2020
Devinsky O, Hesdorffer DC, Thurman DJ, Lhatoo S, Richerson G. (2016) Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 15(10):1075-88. 10.1016/S1474-4422(16)30158-2