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

Even when separated by millions of years of evolution, as are humans and flies, the molecular mechanisms through which
animal cells, tissues and organs perform their basic functions often possess remarkable similarities. This is certainly true
for the hearts of flies and humans, which despite being rather different in size and shape, share remarkable similarities in
terms of the genes controlling its development and the molecular components found within the cells. With such strong
similarities, the study of the heart of flies has potential as an important source of information about the vertebrate heart that
is 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 similarities
between the two. Key genes in heart development are homologous between insects and mammals (e.g. tinman), as are
key components of cardiac myocyte physiology, including ion channels, pumps and exchangers. Surprisingly, however, the
detailed physiology of the fruit fly adult heart has been little explored, despite potential boons in terms of understanding the
basic biology of heart cells that can be applied to vertebrates, and for reducing/replacing the need for experimentation on
vertebrates.
Investigations of the Drosophila heart have focussed almost exclusively on the output of the larval heart measured through
the electrocardiogram (ECG), ignoring the cellular level. Yet, heart cells are capable of showing substantial plasticity and
redundancy so knowing the overall output is insufficient to characterise the impact of changes in molecular networks that
are the targets of drugs. Thus, to realise the potential of the Drosophila heart for genetic screens and drug discovery it is
essential 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 live
adult fruit flies. These techniques will provide an unprecedented level of information on the fruit fly heart cells that can be
incorporated into a computer model of how the heart cells function individually and together. The combination of
experiment 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 applying
existing techniques (e.g. sharp intracellular recordings, computational modelling) as well as the development of new
techniques (e.g. whole-cell patch). With such a model based on a detailed electrical characterisation it would be possible to
use large-scale genetic screens to make crucial insights into heart function and the possible impact of candidate drugs
replacing the need for vertebrates. These insights can be used to inform subsequent vertebrate research leading to a
reduction 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 for
screening drugs for their potential value in altering heart cell activity. This will be invaluable, reducing the numbers of
vertebrates that need to be used in basic research and the early stages of drug discovery but also reducing research costs.