Housden Group

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Available PhD Opportunities

Funded PhD positions

Project 1: Investigating novel interactions of the Merlin gene in cell behaviour

Supervisors: Associate Prof Benjamin Housden, Prof David Parkinson

The aim of this project is to investigate the functions of the Merlin/NF2 protein using a
combination of Drosophila, mouse and human resources and approaches, giving the student on this project
a huge range of expertise with many different techniques and model organisms. This project is important
because the Merlin protein is a key scaffolding protein, which controls many aspects of cell growth, adhesion,
proliferation, differentiation and migration as well as being dysregulated in many tumour types and tumour
syndromes. While the function of NF2/Merlin in regulating Hippo signalling is relatively well characterised,
there is evidence that the protein has multiple other functions that have not been fully explored.
Understanding these alternate roles of the protein as well as completely unknown functions will lead to a
better understanding of how basic cell behaviour is controlled during tissue development and disease. The
wide range of mutations within the NF2/Merlin gene in disease also gives us ideal models to track such new
interactions. In this project, the student will use a combination of Drosophila, mouse and human model
systems to investigate novel functions of the NF2/Merlin protein. We will start by investigating the genetic
interactions of the NF2/Merlin gene in Drosophila cells, which will provide insight into gene function. This
will identify genes that depend on NF2/Merlin to fulfil their own functions and, combined with statistical
enrichment analysis of the genetic interactions, will provide new knowledge into the various biological
pathways that are dysregulated by NF2/Merlin loss. Next, the identified pathways will be investigated in
human cell lines and primary cells to assess the conservation of the newly identified functions of NF2/Merlin.
Finally, mouse models will be used to test the new functions of NF2/Merlin using an in vivo system. By the
end of the project, we expect to have uncovered new functions of the NF2/Merlin gene that will improve our
understanding of how cells control their growth, proliferation and behaviour. Given the important role of this
gene in disease, we expect that this new knowledge will lead to the discovery of new therapies for NF2/Merlin
related tumours in the future. This project will combine cell culture, molecular biology, biochemistry,
statistical analysis and in vivo experiments. This broad range of experience and skills will provide a strong
basis for the successful candidate’s future career development

Self-funded PhD positions

Project 2: Developing a preventative therapy for Neurofibromatosis type 1 tumours.

Supervisors: Associate Prof Benjamin Housden, Dr. Kirsty Wan and Prof Steven West

The aim of this project is to investigate the possibility of developing a preventative treatment for tumours associated with Neurofibromatosis type 1 (NF1). This is important because patients live with the constant fear of developing disfiguring and potentially life threatening tumours throughout their lives and there are currently no effective treatments available. A preventative drug would allow patients to live without this fear and without the disfigurements caused by skin tumours. This project therefore has the potential to result in significant benefits to the quality of life of people with NF1.

NF1 tumours form when the NF1 gene is mutated in a single cell within the patient’s body. This mutation stimulates the cell to grow and divide, resulting in a tumour. Our previous work suggests that cells contain mechanisms that allow them to adapt and survive following mutation of a gene like NF1. During this project, we will look at how gene expression changes over time following loss of NF1 gene function. This approach will allow us to investigate the adaptive mechanisms to identify the genes and molecular pathways that are altered immediately following mutation of the NF1 gene. We will then test whether existing drugs, that are known to be safe for use in humans, can be repurposed to target these mechanisms. Our hypothesis is that by inhibiting these adaptive mechanisms, cells will no longer be able to survive mutation of the NF1 gene and will therefore be killed before a tumour forms.

By the end of this project, we expect to have mapped the mechanisms by which cells adapt to loss of the NF1 gene. In addition, we expect to identify existing drugs that have potential to be repurposed as a preventative therapy for NF1 tumours. By focusing on existing drugs, our results can be rapidly developed for clinical use, resulting in benefits to NF1 patients as soon as possible.

Email b.housden@exeter.ac.uk to apply

Project 3: Development of novel drug treatments for prostate cancer

Supervisor: Professor Benjamin Housden, Professor Mike Weedon, Professor Seb Oltean and Professor Nic Harmer

Prostate cancer is one of the most common forms of cancer and despite available treatments, over 300,000 men die from this disease each year globally. It is therefore vital that we identify new therapies to treat this disease.

In our previous work, we have shown that by combining human genomic analysis with genetic screens in cultured cells, it is possible to identify genes associated with prostate cancer that were missed by either approach alone. Using this method, we have already identified two new prostate cancer-associated genes.

So far, we have only applied this approach on a small scale. In this project, the student will first analyse human genome data to identify genes involved in prostate cancer. Next, the candidate genes will be screened in cell culture models to validate those that selectively kill prostate cancer cells. Finally, the student will learn how to apply in silico drug screening methods to prioritise candidate targets for drug development.

Email b.housden@exeter.ac.uk to apply

Project 4: Understanding motor neuron disease using a powerful combination of model systems

Supervisors: Professor Benjamin Housden, Professor James Hodge and Professor Krasimira Tsaneva-Atanasova

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.

Email b.housden@exeter.ac.uk to apply