EASTBIO: Understanding touch – why is calcium so important?

Supervisors:

Dr Guy Bewick (University of Aberdeen) https://www.abdn.ac.uk/people/g.s.bewick

Professor Andrew Jarman (University of Edinburgh) https://www.ed.ac.uk/discovery-brain-sciences/our-staff/research-groups/andrew-jarman

Dr Antonio Gonzalez Sanchez (Rowett Institute, University of Aberdeen) https://www.abdn.ac.uk/people/antonio.gonzalez/

Dr Ekkehard Ullner (University of Aberdeen) https://www.abdn.ac.uk/people/e.ullner

Mechanosensation is the least understood of all the senses. Yet, mechanical senses such as touch, blood pressure regulation and co-ordinated motor control (proprioception) are essential for normal life. Thus, almost any everyday task relies on touch, while brain function requires adequate blood pressure, and motor co-ordination is crucial for walking, driving, texting, even chewing and swallowing. A better understanding is essential, both for knowledge of ourselves and for identifying new therapeutic targets for treating unmet needs in related diseases, such as high blood pressure (the world’s biggest killer), spasticity (e.g. cerebral palsy) and muscle spasm after spinal cord injury. All major unmet clinical needs.

We have shown that calcium is essential for these nerve terminals to function1, despite calcium being entirely omitted from the classical model. The proposed project will identify where calcium works, the channel protein(s) concerned, their mechanism of action and its evolutionary conservation. Together, this knowledge will transform our understanding of how mechanically sensitive nerve terminals work.

The successful candidate will combine proteomics, live-cell imaging of calcium-sensitive proteins, electrophysiology and mathematical modelling of calcium regulation of nerve firing rates. Experience in any of these techniques will be an advantage, but training will be supplied otherwise. You will work between Aberdeen (mouse neurones – Dr Bewick1) and Edinburgh (Drosophila neurones – Prof Jarman2), under the supervision of experts in these experimental systems. Comparing proteomics and electrical response pharmacology across species will reveal the conservation of calcium-associated proteins and their effect on nerve terminal responsiveness and nerve output. Live cell imaging during movement of Ca-sensing fluorescent protein expression (Drosophila – Prof Jarman, mouse - Dr Gonzalez) will validate these findings and identify where calcium accumulates in the neurones. Finally, the kinetic and electrical parameters of the proteins identified, known from other studies, will be incorporated into a mathematical model (Dr Ullner3) to see how well the model replicates the output observed, and hence test our understanding of the functional role of calcium. Deviations from experimental observations will inform further experiments, whose outcomes will successively refine the model, greatly increasing our understanding of how such endings work.

Both institutions have comprehensive postgraduate programmes for professional development and research training, equipping you with essential generic skills and knowledge; from research ethics and integrity to project management, leadership, communication, public engagement, enterprise and research impact.

Supervised by experts in these disciplines, this unique cross-institutional, interdisciplinary collaboration will use mathematical systems modelling, proteomics, pharmacology, electrophysiology and cutting-edge gene expression techniques across the evolutionary divide to unravel the secrets of this most enigmatic of the senses. It will provide insights into its fundamental biology. And, by doing so, may uncover novel therapeutic targets for treating associated conditions, as diverse as high blood pressure, spasticity, tremor, loss of motor control in the elderly and diabetic populations, and painful muscle spasm after spinal cord injury – to name a few.