Regulation of nuclear envelope function and links with disease (360G-Wellcome-206242_Z_17_Z)

The nuclear envelope (NE) lies at the interface between the nucleus and the cytoskeleton. It forms a complex structure controlling cell compartmentalization and regulates many processes including nucleo-cytoplasmic transport of proteins and RNA, chromatin organization, DNA replication and DNA repair. Hence, defects in NE integrity and nuclear architecture cause drastic changes in cell homeostasis and are associated with a broad range of diseases including cancer, premature ageing syndromes, neurodegenerative diseases or muscular dystrophies, but also with physiological ageing. One of the main challenges is to understand how NE defects lead to so many types of diseases. Previous theories include changes in gene expression and mechanical weakness. My previous work has shown that subcellular processes including microtubule or chromatin organization can modulate NE function, and has identified the acetyltransferase NAT10 as a key regulatory node for control of nuclear architecture. My goal is to now investigate how NAT10 and other factors regulate the NE. I will thereby gain new understanding of how of nuclear architecture is orchestrated and how this is disrupted in age-related diseases including HGPS. This research will not only contribute to our fundamental understanding of nuclear architecture but will also potentially identify new therapeutic strategies for NE-associated syndromes.