A biophysical and biomathematical analysis of the effects of clustering on receptor responses in Ca2+ signalling
This project is one of a number which are funded within the Carlota Palmer PhD programme. This four-year programme, run under the auspices of the Centre for Biomedical Modelling and Analysis, will commence in September 2016. The studentships will provide funding for a stipend (currently £16,165 per annum), research costs and UK/EU tuition fees for four years. Further details can be found here: http://www.exeter.ac.uk/bma/phd/
Location: Streatham Campus, University of Exeter, EX4 4QJ
Academic Supervisors: Professor Christian Soeller, Physics and Astronomy, University of Exeter, Professor Peter Ashwin, Mathematics, University of Exeter, Dr Jacopo Bertolotti, Physics and Astronomy, University of Exeter
Biological systems rely on the exchange of information between parts of a cell and its environment. This is often achieved by chemical and electrical signals that are processed by receptors, a large family of proteins. The heart, for example, relies on electrical signals to activate the > 1billion heart muscle cells to contract. Within each cell this is achieved by a transient increase in the calcium concentration. We now know that the function of key receptors is impaired in many types of cardiac disease resulting in less calcium being released and weaker contraction, often leading to heart failure with fatal consequences. Molecular data shows that the receptors are unchanged, it is their spatial arrangement or ‘clustering’ that changes with major consequences for biophysical behaviour.
In this project we will use mathematical methods to reveal how the molecular scale spatial arrangement of receptors can greatly affect biophysical properties, for example the movement of calcium from intracellular stores into the cell, by exploiting the strength of mathematical approaches to connect seemingly unrelated areas. Theoretical tools to understand “random walks” on networks have been used to understand molecular transport (diffusion), the spread of disease and computer viruses and the scattering of light. The supervisory team has previously used these approaches to see clearly through strongly scattering media.
We will model the activation of receptor clusters as random walks on networks to develop a detailed understanding of receptor cluster gating, an approach that has only recently been used in this area for the first time, and establish a direct link between spatial arrangement and responsiveness of clusters. We will extend this approach, allowing for non-‐uniform spacing between receptors, and use our novel (as yet unpublished) data which provides receptor distributions with molecular resolution for the first time. In addition, we will construct numerical stochastic process and deterministic (reaction-‐diffusion) models to connect the semi-‐analytical results with detailed numerical models of Ca2+ signalling in cardiac muscle cells.
A particular task for the student will be to use quantitative and spatial statistics tools to generate mathematical models from new image data. The supervisory team has developed approaches to automate this process as recently published.
The resulting insight into receptor gating will be directly applicable to improve understanding of cardiac diseases. It will provide a new theoretical framework to derive emergence of physiological function of receptor clusters directly from structural information with broad applications to general signalling.
Applicants should have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science or technology. Applicants with a Lower Second Class degree will be considered if they also have Master’s degree or have significant relevant non-academic experience. If English is not your first language you will need to have achieved at least 6.5 in IELTS (and no less than 6.0 in any section) by the start of the project (alternative tests may be acceptable, see http://www.exeter.ac.uk/postgraduate/apply/english/).
£16,165 per annum plus UK/EU fees for eligible students (2015-16 rates)