Mapping the nanoscale organisation of cellular proteins across complex topographies

Summary

Super-resolution fluorescence microscopy techniques make it possible to visualise nanoscale structures in cells, by going beyond the capabilities of conventional microscopy. Over the past decade, this has led to a series of new biological discoveries such as revealing the molecular organisation of the genome and how proteins interact to fulfil vital cellular processes. However, there are major challenges when it comes to imaging nanoscale structures within the cell membrane due to its complex topography. There is a need for techniques that can image nanoscopic structures over large spatial scales as well as novel analysis tools that can unravel the interplay between subcellular organisation and biological processes.

In this project, you will apply point-spread-function engineering [1] and light-sheet microscopy [2] to optimise and develop novel large depth-of-field super-resolution microscopy methodologies. This will be used for nanoscopic mapping of protein organisation in entire cells that is vital e.g. for understanding the basic mechanisms involved in the immune response [3] and the influence of DNA folding on genomic processing [4].

This interdisciplinary work spans multiple research areas including: optical engineering, computational analysis (including deep learning approaches), fluorescent probe optimisation and biophysics (applying super-resolution microscopy to understand cellular processes, particularly within immunology). This offers flexibility in terms of tailoring the research direction to your interests.

This project will take place in the Molecular and Nanoscale Physics Group within the School of Physics and Astronomy, under joint supervision with Dr Ralf Richter and with external collaborators in the Schools of Engineering, Biology and Medicine. Candidates should have a background in physics, engineering, chemistry or a closely related field and a keen interest in method development.

References:
1 Carr, A.R., Ponjavic, A. et al. 2017. Three-dimensional super-resolution in eukaryotic cells using the double-helix point spread function. Biophysical journal, 112(7), pp.1444-1454.
2 Ponjavic, A., McColl, J. et al. 2018. Single-molecule light-sheet imaging of suspended T cells. Biophysical journal, 114(9), pp.2200-2211.
3 Santos, A. M., Ponjavic, A. et al. 2018. Capturing resting T cells: the perils of PLL. Nature immunology, 19(3), 203-205.
4 Di Antonio, M., Ponjavic, A. et al. 2020. Single-molecule visualization of DNA G-quadruplex formation in live cells. Nature chemistry, 12(9), 832-837.

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