Award details

Mechanistic and single molecule studies of biological systems using fluorescence-force and label-free hybrid imaging at the University of Edinburgh

Reference	BB/W020238/1
Principal Investigator / Supervisor	Dr Julie Welburn
Co-Investigators / Co-Supervisors	Dr Aidan Brown, Dr Owen Davies, Dr David Kelly, Professor Vasileios Koutsos, Professor Adele Marston, Dr Toni McHugh, Dr Davide Michieletto, Professor Lynne Regan, Dr Marcus Wilson
Institution	University of Edinburgh
Department	Sch of Biological Sciences
Funding type	Research
Value (£)	447,323
Status	Current
Type	Research Grant
Start date	01/08/2022
End date	31/07/2023
Duration	12 months

Abstract

Many biological processes involve molecular machines, in which the response of protein assemblies to forces - including translocation, resistance, stretch, signalling and conformational change - are critical to their function. However, such mechanisms are notorious difficult to elucidate. Optical traps provide a unique opportunity to manipulate single biomolecules to study their mechanical and dynamic properties, and uncover the molecular mechanisms that underlie their function. As a consortium of researchers from the Schools of Biological Sciences, Physics and Engineering, University of Edinburgh (UoE), we request an optical tweezers with fluorescence and label-free microscopy system, the c-Trap G2 microscope, manufactured by Lumicks. This unique integrated system, combined with state-of-the-art microfluidics, will provide a timely opportunity for us to harness this transformative technology to capitalize on our ground-breaking and innovative research portfolio and advance the frontiers of bioscience discovery. The c-Trap G2 microscope is user-friendly and ideal for multi-user base in a facility and will be housed in our outstanding microscopy facility COIL, located in the School of Biology (SBS), in close proximity to co-applicants and users from other Schools. The COIL facility is managed by two highly experienced technologists (COIL Manager and Assistant) who will provide training and support to users for this microscope. Subsidised access for groups across Edinburgh and Scotland will be provided, with a priority access to BBSRC-funded researchers. In the longer term, we will explore biomedical applications and develop interactions with other groups in both industry and academia, thereby enhancing UK capabilities, with direct relevance to BBSRC priorities. In this proposal, we present showcases for the use of this revolutionary technology that would catalyze discoveries and collaborations at the University of Edinburgh with international impact.

Summary

The possibility of holding onto individual cells, microbes or even single proteins opens the road for a small-scale understanding and quantification of forces, torques and mechanics of vital processes such as cell division. Thanks to so-called "optical traps" (synonymous to tweezers we can now use light to grab and manipulate cells and biomolecules using a non-contact force. This revolutionary technology has proved essential in medical applications (eg. sperm manipulation and in vitro fertilization, tissue regeneration), biomedical research (eg. single molecule and single cell manipulation) and studying and engineering biomaterials (eg. hydrogels). Optical tweezers are not limited to what we can see using normal microscopes, can "feel" forces a billion time smaller than weighing an ant on your finger and perform measurements at a temporal resolution that is 100 times faster than you can blink. This unimaginable "super-resolved" information is therefore able to yield unique information on the behavior of single molecules and reveal how they work. This proposal requests funds to purchase the first optical tweezers with fluorescence and label-free microscope in Scotland, to be hosted in the School of Biological Sciences at the University of Edinburgh. This will enable us to: 1) manipulate single cells, bacteria, biomolecules and even viruses; 2) measure forces generated during the interaction of, and reactions between, these entities; 3) understand their dynamic and mechanical properties in real time with high spatial resolution. This instrument perfectly sits at the interface between engineering, physical and biological sciences and will allow many groups working on a great diversity of projects to address outstanding questions in their field of research. The optical tweezers with fluorescence/label-free microscope will be housed in a state-of-the-art facility called the Centre Optical Imaging Laboratory (COIL) and will be made available to the wider community of researchers in Edinburgh and Scotland. Researchers at the University of Edinburgh will use this instrument across a broad range of projects such as cell division, cellular transport and organization, bacteria swimming, strength of bacteria biofilms, material properties of DNA hydrogels, formation and stability of proteins and protein condensates that are relevant for cell regeneration and neurodegenerative diseases, folding/unfolding of DNA origami, chromatin organization, genome editing and off-target CRISPR mutations, and others. The acquisition of this technology represents a major step forward as it is currently not available anywhere in Scotland but the demand is increasing rapidly and attracts interest from researchers in diverse fields across STEM. Beyond the academic interest, this instrument will also be used to study industrial and societal problems, such as the interaction between bacteria in water purification systems. Optical tweezers with fluorescence and label-free technology is thus an unparalleled opportunity to advance imaging in Scotland and also in the whole of the UK, where only other 3 similar instruments exist. The outstanding track record of biomolecular research across the various schools in College of Science and Engineering and the expertise in imaging focused in the Edinburgh Super-Resolution Imaging Consortium (ESRIC) and Centre for Optical characteriSation, control and iMagIng of Complex materials (COSMIC) makes Edinburgh University the ideal place where to host it.

Committee	Not funded via Committee
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	Advanced Life Sciences Research Technology Initiative (ALERT) [2013-2014]
Funding Scheme	X – not Funded via a specific Funding Scheme

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