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A personalised medicine approach to the treatment of low dose interleukin-2 in amyotrophic lateral sclerosis: predicting patients’ response through blood transcriptomics

  • Full or part time
  • Application Deadline
    Wednesday, January 29, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Background: The Horizon 2020 funded project, MIROCALS, is a clinical trial of low-dose interleukin-2 (IL-2) in patients with amyotrophic lateral sclerosis (ALS), an adult onset neurodegenerative disorder. Disease duration is 2-3 years from symptom onset and death is usually due to respiratory failure. Riluzole is currently the only approved drug in the UK and is estimated to extend life by 3-6 months. Patients with high T regulatory cells (Tregs) levels live longer than those with low Treg levels. Therefore, the clinical trial aims to increase Treg levels though treatment with a low-dose of IL-2, as used previously in type 1 diabetes. Longitudinal blood samples are being taken, white cells isolated and the cells sent to Sheffield for transcriptomic analysis.

Objectives: The primary aim is to establish the changes in transcriptomic profiles in response to both riluzole and IL-2 treatment. Secondary objectives are to establish the gene expression profiles associated with high and low levels of phosphorylated neurofilament heavy protein (pNFH), a proposed biomarker of ALS, and those profiles associated with responders and non-responders to IL2.

Novelty: The clinical trial is novel because of the science being carried out alongside; blood (serum/plasma/PBMCs/DNA/RNA) and CSF samples are being collected throughout the trial and transcriptomic analysis will be linked with genomic and immunological data being generated by our collaborators. This project is unique in providing a large cohort of longitudinal biosamples from ALS patients treated with riluzole or riluzole and IL2.

Timeliness: The clinical trial is underway and the majority of patients have been recruited. Microarray analysis has already begun. Therefore, by October 2020, data will be available for the student to begin to analyse to establish the primary objectives. Once pNFH and Treg levels are generated from our collaborators, further analysis and correlations will be determined to complete the secondary objectives.

Experimental Approach: Gene expression profiles are being generated using Clariom D arrays (Affymetrix), which allow us to distinguish not only differential expression of genes but also detect alternatively spliced exons, using the Transcriptome Analysis Console (TAC) (Affymetrix). Weighted gene co-expression network analysis (WGCNA) will be used to identify genes behaving similarly following treatment and software such as DAVID and EnrichR will be used to identify significantly enriched biological pathways. The secondary supervisor will input directly into the bioinformatics analysis and teach the student how to write their own scripts in R to analyse the data using known and bespoke software.

Funding Notes

Funding:
These studentships will be 42 months in duration, and include home fee and stipend at UKRI rate.

Eligibility:
Candidates must have a first or upper second class honors degree or significant research experience.

Enquiries:
Interested candidates should in the first instance contact Dr Janine Kirby ()

References

How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select 'Neuroscience' as the department.

Deadline for applications is 5pm on Wednesday 29th January 2020. Late applications will not be accepted. Interviews are scheduled to be held on Tuesday 25th February 2020.

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