*EASTBIO* Regulation of scaling in nuclear and organelle size

Scaling in cell and organelle size has long been observed, but is little understood. Moreover, loss of such scaling controls and defects in organelle size have been observed in human ageing. Interestingly, for such changes in ageing and ageing-related disorders the direction of nuclear size effects depends on the tissue type. This tissue-specificity suggested to us that nuclear size and organelle scaling in general might be directed by as yet unidentified tissue-specific mechanisms/ proteins in the nuclear envelope and that such proteins might be taken advantage of for synthetic and industrial biotechnology applications. We have performed proteomics on nuclear envelopes isolated from different cell types, identifying many novel uncharacterized proteins and finding that the majority of nuclear envelope proteins are in fact tissue-restricted or tissue-specific. In screening roughly 100 of these for functional groupings, we observed that roughly a dozen yield effects on nuclear size. Such proteins might play roles in normal ageing or nuclear size defects in aging related disorders such as defects in cell migration in wound healing due to connections between the nuclear envelope and cytoskeleton. As such they could potentially also be expressed in microorganisms to increase nuclear size for increased industrial cell-based production of enzymes or to increase cell migration in a synthetically generated organism. Most certainly they could be used in mammalian protein expression systems for the many proteins that require specific post-translational modifications only found in mammals for their function. Such nuclear size-regulating proteins could thus be used in biotech production of proteins for therapies as well as supplements of hormones etc in food production.

The project will be to take the proteins we have identified and screen in vitro for small molecule inhibitors of their interactions or aptamers to better mediate their interactions using the robots platforms and high-throughput screening OPERA system in the Auer lab. The compounds identified will be tested in both mammalian cells and yeast to determine effects on nuclear and other organelle (such as endoplasmic reticulum) size and the production of specifically expressed proteins. Separately, we have designed a very complex reporter system that could allow simultaneous measurement of nuclear, nucleolar, ER, and mitochondrial size and if the student can generate this reporter further screens will be undertaken for general small molecule regulators of size for these various organelles, all of which could benefit for cultured protein production. This project will enable the student to develop skill sets in both basic biology study of organelle scale regulation in human cells and microorganisms and high throughput screening approaches.

Lab web site url: http://www.wcb.ed.ac.uk/research/schirmer

Lab web site url: http://www.ed.ac.uk/pathway-medicine/our-staff/staff-profiles/manfredauerprofile