Mitochondrial integrity and autoinflammation

Descripción del proyecto

Las mitocondrias en enfermedades inmunológicas raras

Los interferones (IFN) constituyen la primera línea de defensa contra los virus, y una regulación al alza de la señalización de IFN es la característica distintiva de un grupo genético raro de enfermedades conocidas como interferonopatías de tipo I (T1IFN). El metabolismo del ácido nucleico y las mitocondrias parecen desencadenar la señalización de IFN y podrían constituir nuevas dianas terapéuticas para las T1IFN. El proyecto MitoFeron, financiado con fondos europeos, se centrará en una proteína mitocondrial que participa en la señalización de IFN mejorada que se observa en los enfermos de T1IFN, e investigará su papel en la homeostasis organular y la inducción de IFN. Los resultados conducirán un nuevo protocolo de cribaje clínico para los enfermos de T1IFN y a nuevas dianas de intervención terapéutica.

Objetivo

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.