Descripción del proyecto
El envejecimiento y algunas de sus patologías podrían estar relacionados con una crisis de identidad celular
Un núcleo rodeado por una membrana es lo que define a las células eucariotas. Para transportar macromoléculas entre el núcleo y el citoplasma, la membrana nuclear posee enormes complejos de poros nucleares que constan de más de mil subunidades proteicas que, en los humanos, se denominan nucleoporinas. Estos complejos de poros nucleares son extremadamente longevos y permanecen incorporados en la membrana nuclear durante toda la vida de la célula. Los defectos en las nucleoporinas intervienen en el cáncer y el envejecimiento y, hace poco se encontró un vínculo entre las nucleoporinas, un regulador de genes clave y el mantenimiento de la integridad celular en las células progenitoras neurales (que se dividen en neuronas y células neurogliales). El proyecto EAGER, financiado con fondos europeos, está investigando la complicada relación entre la regulación génica de tipos de célula específicos, la identidad celular y el envejecimiento y la enfermedad.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
91054 Erlangen
Alemania