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Project

Nucleaks. Screening for regulators of nuclear envelope integrity.

The nuclear lamina is a critical regulator of nuclear structure and function. Defects in its major constituent proteins, A-type lamins, cause diseases known as laminopathies. Laminopathy patient cells experience transient ruptures of the nuclear envelope, leading to uncoordinated exchange of proteins between the cytoplasm and the nucleus. This feature contributes significantly to disease development in laminopathies, but also plays a key role in cancer. However, as yet, little is known about the underlying mechanisms. We want to pinpoint the drivers of rupture induction and repair in a systematic manner. To this end, we will perform a gene-silencing screen that is based on live-cell imaging, using transient loss of nuclear compartmentalization as prime readout. To bypass the unpredictable nature of spontaneous ruptures, we will also optimize methods to mechanically induce ruptures. Putative hits that arise from the primary (spontaneous ruptures) and secondary screen (induced ruptures) will be validated and characterized by location proteomics and co-immunoprecipitation experiments. This functional genomics approach will further our understanding of laminopathy development, and may expose new therapeutic entry points with relevance for the broad spectrum of lamin-associated disorders.
Date:1 Oct 2018 →  30 Sep 2022
Keywords:NUCLEUS, LAMINOPATHIES, LAMINS, MICROSCOPY
Disciplines:Systems biology, Data visualisation and high-throughput image analysis, Cytoskeleton, Molecular and cellular biomechanics