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How do membrane channels sense and react to forces?

Faculty of Engineering and Physical Sciences

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Dr G Heath , Dr C Pliotas No more applications being accepted Funded PhD Project (Students Worldwide)
Leeds United Kingdom Acoustics Biomedical Engineering Biophysics Medical Physics Other Other Physiology Radiology Structural Biology Zoology

About the Project

Mechanosensitive channels are found throughout all kingdoms of life acting as sensors for a number of systems including touch, hearing, gravity, osmotic pressure and cardiovascular regulation. Embedded within lipid membranes, these pressure sensitive channels sense and open upon specific mechanical stimuli allowing certain molecules to enter or exit the cells. In humans they are vital for many physiological functions and a number of specific genetic mutations within these channels have been implicated in several diseases. On the other hand, bacteria use this class of channels to regulate their internal turgor pressure in response to rapid changes in osmotic pressure. Despite their fundamental importance, the molecular mechanism of how these channels respond to membrane tension is not well understood. Developing an understanding of these mechanisms will help resolve the molecular basis of mechanical sensing and its role in ion channel regulation and cell physiology. Targeting these channels will provide us with essential molecular and mechanical tools to fight antimicrobial resistant bacteria and channel associated diseases in humans.

This PhD will utilise and develop world leading high-speed atomic force microscopy (HS-AFM) techniques to probe mechanically sensitive proteins at previously inaccessible time and length scales. HS-AFM allows simultaneous sub-nanometre video rate imaging whilst varying forces and environmental conditions. We have recently developed HS-AFM to increase the already pioneering 100ms time resolution (only available to a handful of groups worldwide) to 10 microseconds. This 10,000-fold leap in acquisition rate is achieved by no longer scanning the surface with a tip, but by holding it at a single point of interest and studying the dynamics of molecules underneath. This study will use HS-AFM to monitor conformational dynamics of single membrane protein channels in real-time at the nanoscale and in response to different forces. As a newly developed technique this study has a wide scope to develop new algorithms and analysis methods. Experiments will focus on understanding the structural dynamics to develop physical models of how different molecules sense and respond to force.

Funding Notes

A highly competitive EPSRC Bragg Centre Doctoral Training Partnership Studentship consisting of the award of fees with a maintenance grant of £15,285 (currently for session 2020/21) for 3.5 years.
This opportunity is open to all applicants, with a small number of awards for Non-UK applicants limited by UKRI to 1. All candidates will be placed into the EPSRC Bragg Centre Doctoral Training Partnership Studentship Competition and selection is based on academic merit.
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