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Untranslated regions of RNAs and protein networks in pathological phase separation: UNDERPIN

Phase separation and transition are concentration-dependent phenomena that play a crucial role in many cellular processes. Increased protein abundance can drive the formation of large assemblies within the cell. However, the abnormal upregulation of RNA-binding proteins can lead to detrimental effects such as RNA sequestration and toxicity. Thus, understanding the mechanisms of post-transcriptional regulation, controlling RNA-binding proteins expression, offers an opportunity to modulate protein concentration and influence the formation of these large assemblies. In my UNDERPIN project, the primary objective is to investigate regulatory regions responsible for protein condensation. Specifically, I aim to explore whether disease-associated variants could induce abnormal phase separation and associated toxicity. To achieve this, I will employ a combination of advanced computational approaches and experimental methods. The computational approaches will enable the identification of RNA-binding proteins that control the stability and translation of highly dosage-sensitive RNAs involved in human disease. These approaches will reveal sets of protein-RNA interactions, which will subsequently be validated in cellular models to assess the alteration of protein expression and the formation of condensates. In this part of the project, I plan, for instance, to utilize microscopy techniques to detect phase separation events, including the formation of stress granules, whose mis-regulation is often linked to neurodegenerative diseases. often associated. Finally, I will evaluate the effect of pathogenic variants on protein condensation and cell fitness. Successful completion of UNDERPIN will not only yield new insights into the biology of RNA-binding proteins but will also pave the way for understanding the early events associated with neurodegeneration.

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Laura Broglia
Laura Broglia
RNA Systems Biology
Total budget: 172.750,08€
Total contribution: 172.750,08€