Identification of Therapeutic Drugs for Amyotrophic Lateral Sclerosis Using a Cross-Species Screening Approach - Biomedicine, PhD (GW4 BioMed MRC DTP)

About
Supervisory Team: Dr Ben Housden
Location: Exeter, Streatham Campus

Project
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that causes the death of motor neurons, leading to a loss of muscle function and eventually death due to respiratory paralysis. There are currently no treatments to cure or significantly slow progression of ALS. It is therefore vital to identify new drugs for the treatment of this disease. Approximately 10% of ALS cases are familial with mutations identified in genes with diverse functions such as SOD1 and FUS, the aggregation of which in motor neurons eventually leads to cell death. In this project, the student will use a variety of cutting-edge techniques to identify candidate drug targets to reverse the toxicity caused by SOD1 and FUS protein aggregation.

We recently developed new high-throughput screening technologies that allow sensitive detection of changes in cell survival caused by disruption of individual genes. This RNAi-based technology represents a significant advance over previous methods and has proven effective in the identification of drugs to treat two types of cancer. Therefore, in the first stage of the project, the student will use this method to perform high-throughput screens in a Drosophila cell based model of ALS. Results will be analysed using a network-based approach to identify genes that reverse the toxicity caused by mutant SOD1 and FUS expression. By screening in Drosophila and then assessing the conservation of identified gene effects in mammalian systems, we will identify the most robust candidate drug targets. In the second stage, the student will use imaging and other assays to further investigate genes that were identified in the screens. This will involve working with mouse cell culture models of ALS as well as patient derived human induced pluripotent stem cells (iPSCs) to assess whether disruption of the genes identified in the screen reduces mutant protein aggregation and improves disease outcome. We will attempt to identify existing drugs that inhibit promising genes and will test these in parallel to the genes themselves. In the final stage, the student will work in Dr. Buchman’s lab at Cardiff University for twelve months in order to assess the effects of identified drugs and drug targets using in vivo mouse models of ALS.

This project adopts a systems biology approach to understanding ALS and deliver potential therapeutics. The methodology takes advantage of the diverse expertise of the three supervisors and will provide training in multiple cutting-edge methods in the areas of high-throughput screening, disease modelling using iPSCs, high-content imaging and in vivo analysis. In addition, we are discussing a collaboration with a leading pharmaceutical company which will allow us to drive candidate drugs identified in this project into future translational and clinical studies. We therefore expect this project to result in the development of improved treatments for ALS with a clear route for translation to clinical use.

Start date: October 2018

Most studentships will be 3.5 years full time or up to 7 years part-time, and can be longer where additional training is undertaken.


How to apply
APPLICATIONS OPEN ON 25 SEPTEMBER AND CLOSE AT 17:00 ON 24 NOVEMBER 2017.

IMPORTANT: In order to apply for this project, you should apply using the DTP’s online application form. More information on the application process may be found here: http://www.gw4biomed.ac.uk/projects-2/for-students/

You do NOT need to apply to the University of Exeter at this stage – only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application to study at Exeter.