PhD PROJECT TITLES

Project Supervisor: Dr Krasimira Tsaneva-Atanasova, email K.Tsaneva-Atanasova@bristol.ac.uk 

DEPARTMENT OF ENGINEERING MATHEMATICS

Cardiac cells physiology - Modelling ionic fluxes across the SR

Cardiac excitation-contraction coupling depends on the controlled release of calcium from the sarcoplasmic reticulum (SR) through specialised calcium-release channels called ryanodine receptors (RyR2). Dysregulation of this process, with enhanced caclium leak, is observed in arrhythmic diseases and heart failure. Since RyR2 is considered to be the only pathway for calcium release from the SR, research into irregularities in SR calcium release have focused on RyR2 channel function. However, the SR is a complex organelle, containing other ion-channels of unknown physiological role that may influence the process of SR calcium release. For example, a novel family of SR potassium channels (with subtypes TRIC-A and TRIC-B) have recently been identified. A mutation to TRIC-A is associated with arrhythmias in patients and recent investigations in Dr R Sitsapesan lab show that the mutant protein exhibits altered single-channel function. To understand how SR calcium fluxes are regulated physiologically and altered in certain disease states, we construct and analyse mathematical models of the single-channel gating and ionic fluxes through RyR2 and other SR cation channels to produce a global model of SR ion fluxes. Results from single-channel studies and isolated cardiac cell experiments will be collated in order to develop mathematical models of the ionic fluxes supporting SR Ca2+-release in cardiac cells. Briefly, the models will include: (1) Markov state models of RyR2, and  SR K+ channels based on single channel data and (2) Compartmental modelling of SR ionic currents and respective fluxes mediated by RyR2, TRIC-A, TRIC-B and SR4C channels. 
Having identified kinetic parameters that best fit single channel experimental data we will then incorporate the kinetic models of RyR2, TRIC-A, TRIC-B and SR4C into a compartmental model of global ionic fluxes across the SR membrane. One of the most interesting future applications of the model will be to predict what patterns of naturally occurring SR activity could be affected by SR K+ channels mutations. This will allow for analysis of cardiac activity recordings during pathological conditions such as arrhythmias to show where and when various SR ionic channels may have crucial impact on normal function.
SR

Hybrid testing and continuation in an electrophysiology experiment

The goal of a hybrid test is to test a critical part in the laboratory as if it were part of an overall system. This is achieved by simulating the remainder of the system on the computer, and coupling it via sensors and actuators to the tested part. The challenge is to ensure that the result of the test reflects faithfully the dynamics of the overall system. One way of achieving this is the continuation of solutions (steady-states or periodic motion) directly in the experiments by means of root finding and pathfollowing, but without actual system equations.
Excitability of cells and tissues is a basic function of life. It is the ability of cells to respond to stimuli. Excitability is necessary for the functioning of nerves, muscles, and hormones, among other things. The basis for the excitability of cells is their ion distribution, and the distribution of ions and molecules is determined by transport mechanisms associated with their plasma membrane structure.
Dynamic clamp, a real-time dynamic sub-structured testing in its essence, is an electrophysiology method, developed in parallel in two fields that deal with excitable cells, neurophysiology and cardiac physiology. It uses a real-time interface between one or several living cells and a computer or analogue device to simulate dynamic processes such as membrane currents in living cells.
In collaboration with Dr Helen Kennedy we take such a combined experimental and theoretical approach to study the dynamical behaviour of excitable cells. 
DC

Decoding pulsatile hormonal signals at gene regulatory level

Cells communicate with one-another using chemical messages (e.g. hormones) that bind to receptor proteins and stimulate a cascade of biochemical responses within the target cell. The importance of such communication is illustrated by the fact that such receptors are targets for most current therapeutics. The intracellular signalling cascades can also be targeted for therapeutic benefit and great progress has been made in defining the signalling pathways activated by various receptors.  For example, specialised enzymes, termed kinases (that add phosphate groups) are now the most studied class of drug target in the human genome, and intensive research has lead to high profile successes in kinase targeting in disease treatment. Many chemical messages are released in brief pulses and hence act in a pulsatile manner. This research focuses on the study of how cells interpret pulsatile input signals and translate them into oscillatory functional output messages. The overall goal is spatiotemporal modelling of both metabolic activity and processes such as gene expression. The model validation is based on data from Prof Craig McArdle (Henry Wellcome Laboratories for Integrative Neuroscience and endocrinology (LINE), University of Bristol).
pulses

Modelling plants guard cells  and stomata aperture

Stomata are structures which allow effective gas exchange and water exchange between the plant and the atmosphere. They are flanked by two guard cells which show changes in turgor in order to alter pore size, they can respond to external signals such as light, water and CO2 and internal signals. The aperture of the stomatal pore is controlled by the two guard cells. Opening is associated with water entering the guard cells that causes them to swell. Thickenings in the cell wall cause the guard cells to bow open causing the pore to open. Conversely a loss of water causes the cells to shrink and the pore closes. In this way guard cells integrate information from environmental signals to “set” the most appropriate stomatal aperture to suit the prevailing conditions. Plant cells are surrounded by a cell wall that restricts the expansion of the cell. The cell wall is made of (among other things) cellulose. The mechanical properties of the stomata are central to their performance in gas-exchange regulation, but relatively little is known about these properties. In collaboration with Dr Fabrizio Scarpa we use Finite Element Method modelling approach that allows us to capture the complex geometry of the guard cells and stomatal pore.
Calcium signals are a core regulator of plant cell physiology and cellular responses to the environment. The channels, pumps and carriers that underlie calcium homeostasis provide the mechanistic basis for generation of calcium signals by regulating movement of calcium ions between subcellular compartments and between the cell and its extracellular medium. In order to understand the biological significance of the spatial distribution of calcium signals within single plant cells we aim to develop predictive models for calcium signals that incorporate the kinetics and regulation of their specific mediators. This will help to uncover the functional interconnections between the systems that decode calcium signals and other signaling systems present in guard cells.
This research is carried out in close collaboration with Prof Alistair M Hetherington from the School of Biological Sciences, University of Bristol.
stomata