Characterisation, modelling and prediction of organelle membrane dynamics in health and disease
This multi-disciplinary project combines cutting-edge biological, biophysical and modelling approaches to understand the mechanisms, principles and functions of organelle membrane dynamics in health and disease. This work will help to predict alterations in membrane dynamics and to propose treatments for patients with defects in organelle dynamics and related dysfunctions.
Research on organelle membrane dynamics represents an exciting new field in modern cell biology and biomedical sciences because of its close relation to organelle functionality and its impact on developmental and physiological processes. Peroxisomes represent ideal model organelles as they have only one limiting membrane, can be easily labelled and are biochemically accessible. Vital, protective roles of peroxisomes in lipid metabolism, signalling, the combat of oxidative stress and ageing have emerged recently (Islinger & Schrader 2011, Curr Biol. 21:R800; Schrader et al. 2015, J Inherit Metab Dis 38:681). Our work has revealed that peroxisomes are extremely dynamic and can be formed from pre-existing organelles by membrane growth and division, a model which is now generally accepted (Schrader et al. 2012, BBA 1822:1343). This requires remodelling of the peroxisomal membrane, the formation of tubular membrane extensions which subsequently constrict and divide into several new peroxisomes. Defects in membrane dynamics and multiplication of peroxisomes have been linked to novel disorders involving neurodegeneration, loss of sight and deafness (Delmaghani et al. 2015, Cell 163:894). Very recently, it was discovered that peroxisome interaction with other organelles, which depends on peroxisome number and membrane protrusion, is crucial for the distribution of cholesterol within the cell, as well as for lipid breakdown and protein exchange (Chu et al. 2015, Cell 161:291; Thazar et al. 2015, PNAS 112:4158). Overall, this highlights the importance of peroxisome dynamics for cell viability and human health. Despite their importance for cell physiology and homeostasis, the membrane dynamics of peroxisomes are not well understood and a biophysical model is missing.
This project will therefore combine molecular cell biology approaches (M. Schrader, Biosciences) with expertise in mathematic modelling of organelle dynamics (P. Ashwin, Mathematics) and membrane biophysics approaches (P. Petrov, Physics). We will use molecular cell biology and high-resolution microscopy to generate ultrastructural, imaging, and live cell data on molecular components of the growth and division machinery and their impact on organelle dynamics. These data will be combined with approaches to determine biophysical forces that modulate membrane dynamics with the aim of ultimately generating a mathematical biophysical model on peroxisomal (organelle) membrane dynamics. With this multi-disciplinary approach we aim to unravel new basic biological and biophysical principles, to understand the mechanisms of peroxisomal (organelle) membrane remodelling in health and disease, and to be able to predict membrane alterations that can be verified in established cell models and patient cells.
Dr Michael Schrader, Bioscience (University of Exeter)
Professor Peter Ashwin, Mathematics (University of Exeter)
Dr Peter Petroc, Physics (University of Exeter)
Professor Peter Winlove, Biophysics (University of Exeter)
Location: University of Exeter, Streatham Campus, Exeter
About the award:
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/
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/).