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Mitochondrial integrity and autoinflammation

Descrizione del progetto

I mitocondri nelle malattie immunitarie rare

Gli interferoni (IFN, interferon) rappresentano la difesa di prima linea contro i virus e la sovraregolazione della via di segnalazione dell’IFN è il marchio distintivo di un gruppo di malattie genetiche rare noto come interferonopatie di tipo I (T1IFN, type I interferonopathy). Il metabolismo degli acidi nucleici e i mitocondri sembrano innescare la segnalazione dell’IFN e potrebbero rappresentare nuovi bersagli terapeutici per le T1IFN. Il progetto MitoFeron, finanziato dall’UE, si concentrerà su una proteina mitocondriale coinvolta nel miglioramento della segnalazione di IFN osservata nei pazienti con T1IFN e studierà il suo ruolo nell’omeostasi degli organelli e nell’induzione dell’IFN. I risultati condurranno a un nuovo protocollo clinico di screening per i pazienti con T1IFN e a nuovi bersagli per l’intervento terapeutico.

Obiettivo

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.

Coordinatore

IMAGINE INSTITUT DES MALADIES GENETIQUES NECKER ENFANTS MALADES FONDATION
Contribution nette de l'UE
€ 184 707,84
Indirizzo
24 BD DU MONTPARNASSE
75015 Paris
Francia

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Regione
Ile-de-France Ile-de-France Paris
Tipo di attività
Research Organisations
Collegamenti
Costo totale
€ 184 707,84