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MRC DiMeN Doctoral Training Partnership: Using patient-derived stem cells for precision medicine approaches


MRC DiMeN Doctoral Training Partnership

Sheffield United Kingdom Bioinformatics Cell Biology Data Analysis Molecular Biology Neurology Neuroscience Pharmacology Toxicology

About the Project

Motor Neurone Disease (MND) is a neurodegenerative disease resulting in the death of the neurons that control muscle movement, thus resulting in muscle atrophy and paralysis and eventually death by respiratory failure.

Therapeutic approaches towards MND have always proven difficult due to the impressive genetic and phenotypic heterogeneity of the disease, thus leaving patients without any effective drug. Through previous drug screening using patient-derived stem cells, we have discovered that no single drug is neuroprotective in all patient-derived neurons, similarly to how individuals do not all benefit from the same therapy. 

We have used gene expression profiling of patient neurons before and after drug treatment to identify what genes discriminate between patient responders or non-responders to a specific drug. This transcriptional signature is successful in discriminating patient responders and non-responders, but the main limitation of this approach is the feasibility of reprogramming skin fibroblasts into stem cells to assess the neuroprotective effect of specific drugs on patient-derived neurons. This approach would not be feasible in a real-life clinical setting; hence we aim to determine whether the responder gene signature identified in stem cells can be also identified in blood cells.

For this project we will focus specifically on a new neuroprotective drug identified at the Sheffield Institute for Translational Neuroscience (SITraN) that is due to enter clinical trial in the next 2-3 years.

We aim to: 1. Test the neuroprotective drug on patient-derived neurons and identify patient responders and non-responders; 2. Perform RNA-Seq and corroborate the RNA signature biomarker of responders vs non-responders based on the culture results; 3: Determine the presence of a peripheral transcriptional signature that identifies responders in blood cells isolated from the same donors. 

The student will have the chance to be embedded in a very dynamic team, including other PhD students, Post-doctoral researchers and technicians (for more information on the team visit https://theferraiuololab.com/ or on Twitter @FerraiuoloLab). The successful candidate will learn fibroblast reprogramming into induced stem cells, will perform drug screening in the high-throughput screening facility at SITraN, will learn how to master and analyse RNA-sequencing data, will handle precious human biosamples and will learn how to integrate large datasets to obtain high-quality data that can be directly translated into findings that are likely to inform patient treatment.

This project is potentially a game changer in translational neuroscience. Patient stratification approaches for neurodegenerative diseases are not established, although greatly needed. This study is novel in its approach, as it combines a novel methodology for cell reprogramming, which models more reliably patient phenotypes, transcriptomics and patient biosamples such as blood cells.

With a clinical trial due to start in the next few years, understanding the real potential of patient stratification through the analysis of transcriptomics of peripheral biosamples, such as blood, is of primary importance, as it will support a future platform for patient stratification.

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

https://bit.ly/3lQXR8A 


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2021
Good luck!

References

1. Stopford MJ, Allen SP, Ferraiuolo L. A High-throughput and Pathophysiologically Relevant Astrocyte-motor Neuron Co-culture Assay for Amyotrophic Lateral Sclerosis Therapeutic Discovery. Bio Protoc. 2019 Sep 5;9(17). pii: e3353. doi: 10.21769/BioProtoc.3353.
2. K Meyer, L Ferraiuolo, CJ Miranda, S Likhite, S McElroy, S Renusch, D Ditsworth, C Lagier-Tourenne, RA Smith, J Ravits, AH Burghes, PJ Shaw, DW Cleveland, SJ Kolb, BK Kaspar. Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. PNAS. 2014 Jan 14;111(2):829-32
3. Delcoigne B, Manouchehrinia A, Barro C, Benkert P, Michalak Z, Kappos L, Leppert D, Tsai JA, Plavina T, Kieseier BC, Lycke J, Alfredsson L, Kockum I, Kuhle J, Olsson T, Piehl F. Blood neurofilament light levels segregate treatment effects in multiple sclerosis. Neurology. 2020 Mar 17;94(11):e1201-e1212.

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