Project description
Background: in biological systems ion channel proteins sit in cell membranes and selectively allow the passage of particular types of ions, creating currents. Ion currents are important for many biological processes, for instance: regulating ionic concentrations within cells; passing signals (such as nerve impulses); or coordinating contraction of muscle (skeletal muscle and also the heart, diaphragm, gut, uterus etc.). Mathematical ion channel electrophysiology models have been used for thousands of studies since their development by
Hodgkin & Huxley (1952), and are the basis for whole research fields, such as cardiac modelling and mathematical neuroscience. There are problems in identifying which set of equations is most appropriate for an ion channel model. Often it appears different structures and/or parameter values could fit the training data equally well, but may make different predictions in new situations.
Aim: we have been developing novel experimental designs to provide more information about ion channel and drug binding behaviour from short experiments. We would like to improve our techniques – to describe the ion current and also to characterise drug binding to ion channels (which can physically block them and reduce the current that flows to zero, sometimes leading to fatal heart rhythm changes). It is difficult to measure the rate at which drug/ion channel binding occurs and whether it occurs when the channels are open, closed, or both. These factors may be crucial in determining whether novel pharmaceutical compounds are likely to have side effects or not, and there is a need to develop efficient ways to measure these properties.
Approach: this project will involve computational biophysical modelling; the application of statistical techniques to quantify our uncertainty in model parameters and model equations/structure; and some wet-lab laboratory electrophysiology experiments. We will design more information-rich experiments to reduce the uncertainty in the models we develop and work closely with Teun de Boer of University Medical Center, Utrecht in the Netherlands, Adam Hill in Sydney, and Nanion Technologies (manufacturers of automated ion channel screening technologies,
www.nanion.de) to test out experiments we design and improve them, with the aim of generating a fully-automated model selection, parameterisation and evaluation pipeline.
Other Information:
Eligibility/Entry Requirements: this PhD will suit a graduate with a 1st class degree in Mathematics (or other highly mathematical field such as Physics), ideally at the MMath/MSc level, or an equivalent overseas degree.