Developing a Drosophila melanogaster model of the cardiac myocyte action potential to investigate function and performance

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Even when separated by millions of years of evolution, as are humans and flies, the molecular mechanisms through whichanimal cells, tissues and organs perform their basic functions often possess remarkable similarities. This is certainly truefor the hearts of flies and humans, which despite being rather different in size and shape, share remarkable similarities interms of the genes controlling its development and the molecular components found within the cells. With such strongsimilarities, the study of the heart of flies has potential as an important source of information about the vertebrate heart thatis so important for preventing heart disease, which is a major source of human mortality.Studies in the fruit fly, Drosophila melanogaster, have demonstrated remarkable molecular and developmental similaritiesbetween the two. Key genes in heart development are homologous between insects and mammals (e.g. tinman), as arekey components of cardiac myocyte physiology, including ion channels, pumps and exchangers. Surprisingly, however, thedetailed physiology of the fruit fly adult heart has been little explored, despite potential boons in terms of understanding thebasic biology of heart cells that can be applied to vertebrates, and for reducing/replacing the need for experimentation onvertebrates.Investigations of the Drosophila heart have focussed almost exclusively on the output of the larval heart measured throughthe electrocardiogram (ECG), ignoring the cellular level. Yet, heart cells are capable of showing substantial plasticity andredundancy so knowing the overall output is insufficient to characterise the impact of changes in molecular networks thatare the targets of drugs. Thus, to realise the potential of the Drosophila heart for genetic screens and drug discovery it isessential to characterise all levels from molecular and cellular to organ/system.This studentship aims to rectify this deficiency by developing techniques to permit recording the activity of heart cells in liveadult fruit flies. These techniques will provide an unprecedented level of information on the fruit fly heart cells that can beincorporated into a computer model of how the heart cells function individually and together. The combination ofexperiment and computer model will be essential in identifying the effects of drugs or mutations.The aim of the studentship is to characterise and produce a model of the cardiac myocyte action potential through applyingexisting techniques (e.g. sharp intracellular recordings, computational modelling) as well as the development of newtechniques (e.g. whole-cell patch). With such a model based on a detailed electrical characterisation it would be possible touse large-scale genetic screens to make crucial insights into heart function and the possible impact of candidate drugsreplacing the need for vertebrates. These insights can be used to inform subsequent vertebrate research leading to areduction in the number of animals used in such studies.Such an approach is will produce a system that can be used to study the basic molecular biology of heart cells but also forscreening drugs for their potential value in altering heart cell activity. This will be invaluable, reducing the numbers ofvertebrates that need to be used in basic research and the early stages of drug discovery but also reducing research costs.