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MRC DiMeN Doctoral Training Partnership: Treating the untreatable; defining the role of fibro-adipogenic precursor cells in the process of muscle degeneration in Duchenne muscular dystrophy to identify novel therapeutic approaches


   MRC DiMeN Doctoral Training Partnership


Newcastle United Kingdom Biochemistry Bioinformatics Biotechnology Cell Biology Developmental Biology Molecular Biology Neurology

About the Project

Duchenne muscular dystrophy is a genetic disease characterized by severe disability including loss of ambulation and cardiorespiratory problems leading to death before patients reach 30 years. As it stands there is no cure, nor effective treatment. In this work you will study the process of muscle degeneration, with an aim to find novel therapeutics to slow this process, and therefore slow disease progression.

In particular you will investigate the role of fibroadipogenic progenitors (FAPs), recently discovered mesenchymal stem cells responsible for the expansion of fibrotic and fat tissue that replace muscle fibers. The focus of this will be to unravel and target the molecular pathways that are differentially enhanced in DMD FAPs compared to control muscles.

You will use a wide range of lab techniques to carry out this work, including common ones such as immunofluorescence or western-blot but also cutting-edge technologies such as single-nuclei RNA sequencing or spatial transcriptomics. You will isolate cells from human muscle samples, culture them and explore different cell functions such as proliferation, migration or differentiation. You will study gene expression in muscle DMD and control samples using new approaches in collaboration with bioinformaticians expert in the field. You will also study the changes in epigenetics that influence cell fate. You will learn how to perform a high-through put drug screening to identify new drugs and all the steps needed to identify the optimal dose to be used in experiments, exploring the consequences on cell function as well as its potential cytotoxicity. This will inform testing the drug on preclinical animal models, which you will be involved in, and therefore you will learn how to assess animal wellbeing and muscle function, and how to isolate tissue for analysis.

You will work in a multidisciplinary team specialized in muscular dystrophies based in an international centre of excellence where clinicians and basic researchers interact on a daily basis. This will give you a holistic view of what muscular dystrophies are, from the very basic fundamentals of the pathomechanisms behind these diseases, to the latest results of clinical trials.

This project uses state-of-the art technology and addresses disease progression and therapeutic approaches, providing a research opportunity to interlink concepts at the molecular, cellular, tissue and organismal level. Upon completion you will have attained a large technological skill set and knowledge and you will have contributed to meaningful and crucial progress in the field.

If you would like to know more about our research institute please follow this link https://newcastle-muscle.org or follow us in twitter: @jwmdrc

Benefits of being in the DiMeN DTP:

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, York 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:

http://www.dimen.org.uk/how-to-apply/application-overview


Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover UK tuition fees, stipend and project costs as standard. We also 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 be awarded to exceptional candidates only, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2022
Good luck!

References

1) RhoA/ROCK2 signalling is enhanced by PDGF-AA in fibro-adipogenic progenitor cells in DMD https://www.biorxiv.org/content/10.1101/2021.04.12.439417v1
2) Isolation of human fibroadipogenic progenitors and satellite cells from frozen muscle biopsies.FASEB J. 2021 Sep;35(9):e21819 (https://pubmed.ncbi.nlm.nih.gov/34405910/)
3) Proteasome inhibitors reduce thrombospondin-1 release in human dysferlin-deficient myotubes. BMC Musculoskelet Disord. 2020 Nov 27;21(1):784. (https://bmcmusculoskeletdisord.biomedcentral.com/articles/10.1186/s12891-020-03756-7)
4) Fibroadipogenic progenitors are responsible for muscle loss in limb girdle muscular dystrophy 2B. Nat Commun. 2019 Jun 3;10(1):2430 (https://www.nature.com/articles/s41467-019-10438-z)
5) Nintedanib decreases muscle fibrosis and improves muscle function in a murine model of dystrophinopathy. Cell Death Dis. 2018 Jul 10;9(7):776 (https://www.nature.com/articles/s41419-018-0792-6)

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