Homeostatic maintenance of the auditory system and its relation to age-dependent hearing loss: A Drosophila model organ study

In the UK, some 70% of people over 70 suffer from decline of hearing. Yet, we have acquiesced into this age-related decay of our senses almost as tacitly as we take their faultless operation for granted for most of our lives. Scientifically, both of these phenomena are equally remarkable. Our eyes and ears are parts of the living world and as such they are in constant need of metabolic energy and permanently exposed to countless environmental challenges. In contrast to a granite rock, a biological system that retains constant properties over periods of days, months, or even years, needs an explanation. If then at some point, and without any obvious external cause, system performance eventually declines, a second explanation is required. This research project will study both of these phenomena and test the hypothesis that they are mechanistically interlinked. In other words, what are the cellular mechanisms that maintain our sense of hearing and how do these mechanisms deteriorate over time? Using the antennal ears of the fruit fly Drosophila melanogaster as a model sensory organ, we will (i) dissect the molecular network that maintains sensitive hearing throughout the fly's life course and (ii) study how this maintenance, or homeostasis, changes during ageing. We will specifically test the hypothesis that the same molecular networks that direct the construction of the ear in the growing fly (about which we already know quite a lot) also contribute to its homeostatic control during adult life (about which we know very little). Importantly, the molecular networks of ear construction are known to have much in common between flies and humans, and we expect our research will provide a relevant model to understand decline of hearing in humans.

Knowledge about the homeostatic equilibria that maintain sensory systems throughout their life courses is scarce, contrasting starkly with the wealth of information available for the cellular, and molecular, processes that bring about their development. This project will test sets of candidate genes for their contributions to the homeostasis of Johnston's Organ (JO) in the antennal ears of adult fruit flies (Drosophila melanogaster). Specific focus will be given to the post-developmental roles of classic 'regulatory' genes, such as proneural transcription factors, developmental assembly genes, or genes contributing to transport or chaperone pathways. Preliminary evidence suggests that vast parts of the adult JO transcriptome fall into such regulatory categories, but their specific non-developmental functions in the adult ear have remained unknown. We will probe the genes' homeostatic roles in three different ways. First, we will check the expression of candidate genes in JO. Second, we will use the constant turnover of auditory transducer modules as background paradigm. JO mechanotransducer function can be measured in vivo and we will thus use RNAi-mediated gene knockdown strategies to quantify the effects of adult-specific gene knockdowns on the integrity and specific properties of JO transducer modules. We will also use photo-bleaching of fluorescent transducer modules to directly compare turnover rates in between ears expressing knockdown constructs and their respective controls. Third, we will probe the homeostasis, and possible breakdowns thereof, in the ageing auditory system. In biophysical assays (e.g. gating compliance analyses, nerve recordings), we will quantify auditory transducer function in flies of different ages; in molecular assays (e.g. by RNASeq) we will explore age-related changes in the JO transcriptome. Based on these data, we will finally test individual genes for their ability to accelerate, or slow down, age-related hearing loss in flies.

Commercial benefits

Biomedical drug companies may be interested in the targets identified in this research and in the in vivo screening skills we develop during the project. For instance, our screening strategy can be more generally applied to identify genes required for mechanosensory function, and therefore may be new therapeutic targets for deafness.

Insects are major pests of agriculture and are vectors of disease. Our research has potential benefits for agrochemical and insect control research. Chordotonal auditory and proprioceptive neurons (the subject of this proposal) are the reported targets of action for some well-known insecticides whose molecular mode of action is uncharacterised. It is highly possible that functional homeostasis is itself the insecticide target. The identification of genes required for chordotonal neuron homeostasis will provide excellent targets for understanding the modes of action of such pesticides, and may allow more specific pesticide intervention. Syngenta?

Charity interest

Although this is a basic science proposal, there are several medical charities that are likely to be interested in the research in this proposal for its long term potential to help understand deafness. Implications for hearing research should be of interest to Action on Hearing Loss. Potential impacts would be the identification of molecular targets for possible therapeutic intervention to prevent age-related inner ear hair cell degeneration or to promote regeneration.

Skills/training

The PDRAs to be recruited to this programme will benefit from training in the wide range of molecular and biophysical techniques involved. This will increase their long-term employability in laboratory research.

Public engagement

The wider public is likely to be interested in this research from several points of view. The use of an insect to understand hearing is a fascinating and unexpected concept to many, and it is essential to communicate this as an important aspect of BBSRC's remit.