Description du projet
Les mitochondries dans les maladies immunitaires rares
Les interférons (IFN) représentent la première ligne de défense contre les virus et la régulation positive de la signalisation des IFN est le trait distinctif d’un groupe de pathologies génétiques rares appelé interféronopathies de type I (IFNpathies). Le métabolisme et les mitochondries des acides nucléiques semblent déclencher la signalisation des IFN et pourraient constituer de nouvelles cibles thérapeutiques pour les IFNpathies. Le projet MitoFeron, financé par l’UE, se concentrera sur la protéine mitochondriale impliquée dans la signalisation renforcée des IFN observée chez les patients atteints d’IFNpathies et examinera son rôle dans l’homéostasie des organites et l’induction des IFN. Les résultats aboutiront à un nouveau protocole de dépistage clinique pour les patients atteints d’IFNpathies ainsi qu’à de nouvelles cibles pour des interventions thérapeutiques.
Objectif
Type I interferonopathies (T1IFNs) are rare genetic diseases associated with an inappropriate upregulation of type I interferon (IFN) signalling. IFNs represent the first line of defence against viruses, and are induced by sensing of viral nucleic acids. Definition of the genetic basis of the T1IFNs has led to a coherent understanding of underlying pathology, involving previously unappreciated pathways of nucleic acid metabolism, and enabled the introduction of rational therapy targeted at blocking IFN signalling. Thus, it is important to identify new T1IFNs and determine their molecular and cellular basis.
Beyond their role in energy metabolism, mitochondria are also recognised to play a role in the immune response to infection. Interestingly, both mitochondrial (mt) DNA and mtRNA have the potential to trigger IFN. Indeed, loss of mt integrity promoting pathogenic IFN induction, through mt nucleic acids released into the cytosol, is a novel topic of high clinical and scientific interest. We have identified patients with mutations in a gene encoding a mt protein, in which we consider the observed enhanced IFN signalling directly relevant to the associated neuropathology. My project aims to better understand the link between mt homeostasis and IFN induction, thereby defining novel pathways relating to mt integrity, mt nucleic acids and innate immune surveillance. Specifically, I will study these relationships in the context of human disease, and I will search for further novel determinants of mt function linked to innate immune homeostasis using our unique clinical screening protocol.
I will bring my expertise in mt biology to the host laboratory. At the same time, this project will place me at the leading edge of clinically-directed research on nucleic acid sensing and autoinflammation. Thus, this training opportunity is designed to lead me towards independence through the acquisition of new skills and the discovery of novel research paths for my future career.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
75015 Paris
France