MRC Research Associate Physiological Laboratory, University of Cambridge
Junior Research Fellow Christ's College, Cambridge
Lecturer in Physiology School of Biological Sciences, University of Manchester
Nuffield Research Fellow University of Manchester
Visiting Research Fellow National Institute for Physiological Sciences, Okazaki, Japan
Visiting Scholar University of Sydney, Australia
Senior Lecturer in Biological Sciences School of Biological Sciences, University of Manchester
Epithelia are sheets of cells that act as barriers between different fluid compartments in multicellular organisms. Examples include the cells lining the gastrointestinal tract, kidney tubules and airways. As well as their barrier function, epithelia mediate active transport of solutes and water between body fluid compartments and play a crucial role in salt/water and acid/base balance, exocrine secretion, intestinal absorption etc.
Systems biology brings together computational modelling, experimental cell physiology and proteomics with the aim of understanding better how the many individual transport proteins in epithelial cells interact and work together to achieve the overall physiological function of the tissue.
Solute transport across an epithelium is achieved through the combined activity of numerous transport proteins (channels, symporters, antiporters and pumps) distributed asymmetrically between the apical and basolateral membrane domains. We are using MATLAB to build modular, user-friendly computational models of epithelia which enable physiologists to explore their system’s behaviour in imaginary experiments.
By comparing the predictions of the models with real experimental data, using the powerful new tools of systems biology, both the models and the experimental strategy are progressively improved, and the details of the mechanisms and interactions gradually fall into place.
The epithelial cells lining the pancreatic ducts, airways and intestine secrete fluids that are particularly rich in bicarbonate ions. This process fails in cystic fibrosis, eventually with fatal consequences. We are using microfluorometry and electrophysiology, in parallel with modelling studies, to identify the transport mechanisms and interactions that are involved in bicarbonate secretion in cultured human epithelial cells. Our interest currently focuses on the role of the SLC26 family of anion exchangers and their interactions with CFTR, the chloride channel that is defective in cystic fibrosis. The ultimate goal is to identify novel therapeutic strategies that will circumvent the defect.