Description du projet
Le vieillissement et certaines de ses pathologies peuvent être liés à une crise d’identité cellulaire
Un noyau lié à la membrane est ce qui définit les cellules eucaryotes. Pour faire circuler les macromolécules entre le noyau et le cytoplasme, l’enveloppe nucléaire est dotée de très grands complexes de pores nucléaires (CPN) constitués, chez l’homme, de plus de 1 000 sous‑unités protéiques appelées nucléoporines. Ces CPN ont une durée de vie extrêmement longue et restent incorporés dans la membrane nucléaire pendant toute la durée de vie de la cellule. Des défauts dans les nucléoporines jouent un rôle dans le cancer et le vieillissement, et un lien a récemment été établi entre les nucléoporines, un régulateur de gène clé et le maintien de l’identité cellulaire dans les cellules progénitrices neurales (qui se différencient en neurones et en cellules gliales). Le projet EAGER, financé par l’UE, étudie la relation complexe entre la régulation des gènes spécifique au type de cellule, l’identité cellulaire et le vieillissement et la maladie.
Objectif
Ageing is one of the most critical risk factors for neurological and psychiatric diseases. However, the biological links between physiological ageing and pathological development are still largely unknown. A solid understanding of the biology of brain ageing will thus be a key to developing the means to treat these diseases. Since neurons in the brain are mostly generated during development with limited capacity of replacement after birth, they need to maintain their identity and function throughout our lives. This project aims at seeking a link between the fundamental mechanism underlying the long-term maintenance of neural identity and effects of ageing on that.
We recently discovered that a cell type-specific nuclear architecture organized by nucleoporins in cooperation with a key transcription factor (TF), work as a structural gatekeeper for the maintenance of neural progenitor cells (NPs). Strikingly, nucleoporins are the most long-lived proteins in a cell and are known to be damaged during brain ageing. Thus, the proposed experiments will test a specific hypothesis that the nucleoporin-TF directed nuclear architecture is a fundamental principle governing cell type-specific gene regulation, and that pathological ageing impairs that critical relationship.
To test this hypothesis, we will use interdisciplinary approaches. First, the changes of molecular constituents of nucleoporin-TF partnerships from NPs into the post-mitotic neurons are probed. Second, the roles of identified partnerships in the maintenance of neuronal identity and function will be investigated using biochemical, imaging, genome-wide and behavioural approaches. Efforts will be directed toward studying the effects of ageing and Alzheimer’s diseases on the identified mechanisms. The successful completion of this research will uncover a novel aspect of regulation in the maintenance of cellular identity and open up a new field of research in neuroscience.
Champ scientifique
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Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
91054 Erlangen
Allemagne