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How do membrane channels sense and respond to forces?


Project Description

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 10μs. 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.

This project is available as one of five PhD studentships with the Bragg Centre to tackle fundamental and applied problems to create new and improve existing materials. These will address fundamental and applied problems across design, characterisation, fabrication and modelling. The Centre comprises around 150 members from over ten Schools and has had continued investment in excellent facilities and infrastructure, including a new building opening in 2020, to ensure that our staff and students benefit from state-of-the-art, high quality equipment and laboratories. We are a founding partner of the Henry Royce Institute, the UK’s Institute for Advanced Materials

Funding Notes

Funding is available from the Bragg Centre for Materials Research for 3.5 years and covers the cost of academic fees at the UK/EU rate (currently £4,500 per year for 2019/20) and provides a stipend at EPSRC rates (currently £15,009 per year for 2019/20).

How good is research at University of Leeds in Physics?

FTE Category A staff submitted: 24.00

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