Arkitektonisk kontroll av cellpolaritet genom signalerings proteiner och icke kodade RNA

Tidsperiod: 2015-01-01 till 2018-12-31

Projektledare: Aristidis Moustakas

Finansiär: Vetenskapsrådet

Bidragstyp: Projektbidrag

Budget: 3 200 000 SEK

Generation of architectural polarity impacts all cell types, ranging from epithelial cells to neurons and astrocytes, relates to tissue organization and links to disease development when misregulated. Thanks to VR-MH grants, my group studies plastic changes of cell polarity in the context of cancer, by focusing on the process of epithelial mesenchymal transition. In this new and independent project we shift our attention to the establishment of cell polarity. Our working hypothesis proposes coordinate control of cellular architecture in the nucleus and cytoplasm. Such coordination may be mediated by long non-coding RNAs (lncRNAs) acting at the chromatin and transcriptional level or at the post-transcriptional cytoplasmic level. We propose that expression and localization of lncRNAs is controlled by liver kinase B1 (LKB1), a regulator of epithelial and neuronal polarity, and Smad4, a signaling mediator of transforming growth factor beta. The project is methodologically structured as follows: a) mammary epithelial, astrocytic and oligodendrocytic 3D cultures are faithful models of cell polarity, where b) LKB1 and Smad4 will be knocked out using the CRISPR-Cas9 gene editing system, and impact on c) 3D architecture and d) lncRNA expression profiles will be analyzed; e) selected lncRNAs will be functionally linked to downstream targets that control cell polarity. Our end goal is to understand coordinate control of cell polarity at the nuclear and cytoplasmic level.