A new microscope will let scientists watch the inner workings of living cells in unprecedented detail, tracking how proteins switch on and off in three dimensions over time. Cells rely on chemical signals—protein phosphorylation and ubiquitylation—to control everything from growth to DNA repair. When these signals go wrong, the result can be cancer or neurodegeneration. Current microscopes at the University of Dundee cannot capture these events at the required speed and resolution. The new Zeiss LSM980 with Airyscan 2 will image tiny cellular substructures within large tissue samples, using machine learning to automatically find and focus on areas of interest. This cuts imaging time from weeks to hours. The impact is primarily on fundamental science. Understanding how signalling pathways are turned on and off in the right place at the right time could reveal new drug targets. Past fundamental research into protein phosphorylation led directly to the development of kinase inhibitor drugs, now used to treat multiple cancers. This microscope will also replace several aging systems, making advanced imaging available to the entire university and helping maintain Dundee’s position as a top biomedical research centre.
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This proposal is led by four groups located within the MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU) and the Dundee Imaging Facility (DIF), which are all situated within the same building complex and part of the School of Life Sciences and University of Dundee. Work in the MRC PPU focusses on protein phosphorylation and ubiquitylation as essential mediators of intracellular signalling. Dysregulation of these events and disruption of intracellular signalling leads to numerous diseases, including cancer and neurodegeneration. Therefore, it is vitally important that we understand the molecular nature of intracellular signalling in the hopes of not only understanding what happens in disease states but to also identify new drug targets and therapeutic approaches. A key aspect of signalling pathways is that they are turned on and off at the right time and in the right place. It is in studying the latter that requires advanced imaging capabilities provided by the microscope system requested in this application. We are a diverse team studying multiple aspects of cellular signalling at the molecular level, both within cell culture and tissues such as the brain. To decipher these signalling pathways and determine their cellular impacts, we need to be able to image at super-resolution scale over 3 dimensions, with multiple fluorophores in both live and fixed samples. Given that our work, as detailed in the Vision Section, will involve analysing specific cellular substructures within distinct and small populations of cell types within large tissue sections, we need a way to do this this that will take hours and days and not weeks and months. The ability to take advantage of machine learning and artificial intelligence, to train the microscope to automatically and rapidly search, identify and image areas of interest will allow this vast improvement in efficiency. The capacity to allow seamless integration with current equipment within the Dundee Imaging Facility, such as the Zeiss Axioscan 7 Microscope Slide Scanner, will facilitate this. Finally, we need the capability to undertake precise micro-irradiation of subcellular structures to trigger intracellular signalling and DNA repair mechanisms. Currently, The University of Dundee does not possess microscope systems that can come close to satisfactorily addressing all these requirements. After careful assessment of potential systems we have identified a Zeiss LSM980 with Airyscan 2 confocal microscope setup that will be able to address all these requirements. Importantly, the new microscope will be situated and maintained within the DIF ensuring the microscope will be accessible to not just MRC PPU scientists, but also to those in the School of Life Sciences and University as a whole. Additionally, the enhanced capability of this new system is such that it will be able to replace multiple aging systems that are currently housed within DIF and reaching ‘end-of-life'. This will greatly increase efficiency and value for money moving forward. Given this, the proposed system will maximise benefit and enrich the scientific capability of as many Dundee groups as possible: we hope this will help Dundee maintain its position as the top biomedical sciences university in the UK (REF 2021). Together, we believe the proposed Zeiss LSM980 with Airyscan 2, as requested, will be transformative for all our research.
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