PhD Studentship: Understanding Motor Neuron Disease Using a Powerful Combination of Model Systems

About the GW4 BioMed2 Doctoral Training Partnership

The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and 'team science'. The DTP already has over 90 studentships over 6 cohorts in its first phase, along with 58 students over 3 cohorts in its second phase.

Research Theme: Neuroscience & Mental Health

Project Summary: The aim of this project is to understand the mechanisms that cause motor neuron disease (MND) so that new treatments can be developed. This is important because MND is a devastating disease that results in death only three years after diagnosis. There are no cures and our understanding of why people develop the disease is limited. This project will use cutting edge techniques to investigate the mechanisms underlying MND, leading to effective therapies in the future.

Project Description: The aim of this project is to investigate the cellular mechanisms underlying motor neurone disease (MND) to facilitate the development of new therapies in the future. This is important because MND has a short life expectancy (3 years from diagnosis), the impact on quality of life is severe and there are currently no effective treatments. There is a clear need to gain a better understanding of the disease to inform the development of effective therapies.

Our approach to uncovering mechanisms of MND is to use genetic interaction analysis to gain insight into the genes and pathways that are involved in loss of viability in MND cells. We have developed Drosophila cell culture models expressing mutant version of human proteins known to be associated with MND (SOD1, FUS and TDP43) and have demonstrated that these models share characteristics with human models of the disease (e.g. alterations in cell viability and protein localisation). Using these new models, we have screened for genetic interactions between two mutant forms of TDP43 and approximately 350 kinases. This has resulted in the identification of several candidate genetic interactions that are now being validated. In addition, we have profiled transcriptional changes that occur when mutant forms of TDP43 are expressed. These datasets provide a powerful basis for mechanistic analysis.

A major problem in determining mechanisms of human disease is that knowledge and candidate therapies identified in cell culture systems are not always relevant in patients. We have developed methods to overcome this issue by cross comparing between cell models derived from distant genetic backgrounds. Specifically, by comparing Drosophila cells to human cells modelling the same disease, it is possible to distinguish mechanisms and drug targets that are relevant across diverse systems from those that are specific to one system. This results in mechanistic understanding and candidate drug targets with a high chance of relevance in the clinic. In this project, the student will compare results between Drosophila cells, Drosophila in vivo models and human iPSC models of MND to gain new knowledge of the underlying mechanisms that are likely to be relevant to patients.

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