Developing unbiased fluxomics tools to identify and validate novel therapeutic agents in models of Amyotrophic lateral sclerosis (ALS).

Amyotrophic lateral sclerosis (ALS) is a neurological disease that primarily affects the neurons responsible for controlling voluntary muscle movement. Disease-modifying therapies for ALS remain restricted to a small number of drugs that provide only modest clinical benefits. We have previously shown that metabolism plays a major role in the pathogenesis of ALS, and we are working to identify novel therapeutic strategies and molecular targets to ameliorate this dysregulation and improve treatment options.

Metabolomics simultaneously measure the abundance of thousands of metabolites providing comprehensive insight into metabolism, and has played a significant role in bridging the gap between genotype and phenotype. Metabolic architecture (i.e., the order of reactions in a metabolic pathway) is well known and highly conserved even between disparate phenotypes. However, metabolism is highly dynamic, and it is the flow of substrate through metabolic pathways that is responsible for determining metabolic function, and thus the final observed phenotype. Fluxomics approaches provide a dynamic readout of functional metabolism by introducing an isotopically labelled substrate into a system and mapping the ‘diffusion’ of isotopic label through the metabolic network. Traditionally, these approaches have used ¹³C-labelled glucose as a primary metabolic substrate however this is expensive limiting the utility of these approaches.

In this project we will develop new fluxomics methods utilizing deuterium oxide (which is far cheaper than ¹³C-glucose) as these approaches will have far wider utility than their ¹³C counterparts. Once these tools have been established, we will take advantage of the fruit-fly Drosophila to comprehensively map functional metabolism to identify novel targets for therapeutic intervention in C9orf72 drosophila melanogaster which is a common genetic cause of Amyotrophic lateral sclerosis (ALS).

Research objectives:

1)     Develop and validate tools for performing unbiased fluxomics analysis using deuterium oxide in Drosophila models of ALS, including establishing:

a.      Protocols for preparation and supplementation of D₂O to flies.

b.      Methods for LC-MS analysis of whole flies and specific tissues

c.      Implement semi-automated pipelines for analysing unbiased fluxomics data.

2)     Use the methods generated in objective 1 to perform an unbiased metabolic screen in the C9orf72 Drosophila model of ALS to identify potential therapeutic targets.

3)     Determine if the metabolic effect of the targets identified in objective 2 can be ameliorated using a range of therapeutic agents.  

We are looking for candidates with a BSc, MSc or MRes in biological sciences, biochemistry or equivalent, with basic knowledge in molecular biology, with interest in neurodegeneration or drug discovery. Basic knowledge in analytical chemistry, mass spectrometry or bioinformatics is desirable but not essential.

For informal enquiries please contact Dr Stuart Snowden via [Email Address Removed]

To apply follow link and instructions at https://www.royalholloway.ac.uk/studying-here/applying/postgraduate/how-to-apply/. Please indicate "Snowden" in your application. Application deadline 12 March 2023