Projektbeschreibung
Hängen die Alterung und einige damit verbundene Krankheiten mit einer zellulären Identitätskrise zusammen?
Eukaryotische Zellen werden durch einen membrangebundenen Nukleus bestimmt. Damit Makromoleküle zwischen dem Nukleus und Zytoplasma übertragen werden können, verfügt die Kernmembran über riesige Kernporenkomplexe, die beim Menschen aus mehr als 1 000 Proteinuntereinheiten bestehen (Nukleoporine). Diese Kernporenkomplexe sind extrem langlebig und verbleiben über das gesamte Leben der Zelle hinweg in der Kernmembran. Defekte in den Nukleoporinen spielen eine entscheidende Rolle bei Krebs und der Alterung. Unlängst wurde eine Verbindung zwischen Nukleoporinen, einem wichtigen Genregulator und der Aufrechterhaltung der Zellidentität in neuronalen Vorläuferzellen gefunden (die sich in Neuronen und Gliazellen ausdifferenzieren). Das EU-finanzierte Projekt EAGER untersucht die komplizierte Beziehung zwischen der für die Zelltypen spezifischen Genregulation, der Zellidentität, der Alterung und Erkrankungen.
Ziel
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.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-STG - Starting GrantGastgebende Einrichtung
91054 Erlangen
Deutschland