Descrizione del progetto
Possibilità di correlare l’invecchiamento e alcune patologie connesse a una crisi d’identità delle cellule
Un nucleo legato alla membrana è ciò che definisce le cellule eucariote. Per il traffico di macromolecole tra il nucleo e il citoplasma, l’involucro nucleare negli esseri umani presenta enormi complessi di pori nucleari composti da oltre 1 000 subunità proteiche chiamate nucleoporine. Questi complessi hanno una vita estremamente lunga e rimangono inseriti nella membrana nucleare per l’intera vita della cellula. I difetti delle nucleoporine svolgono un ruolo nel cancro e nell’invecchiamento e recentemente è stato scoperto un legame tra tale tipologia di proteine, un importante regolatore genico e il mantenimento dell’identità cellulare nelle cellule progenitrici neurali (che si differenziano in neuroni e cellule gliali). Il progetto EAGER, finanziato dall’UE, sta studiando la complicata relazione esistente tra la regolamentazione genica specifica del tipo cellulare, l’identità cellulare e l’invecchiamento, e la malattia.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
91054 Erlangen
Germania