MRes - Extended cardiorespiratory phenotyping in the DE50-MD canine model of Duchenne Muscular Dystrophy

Supervisors: Professor Richard Piercy and Professor Dominic Wells

Department: Clinical Science and Services

Project Details

Duchenne muscular dystrophy (DMD) is an invariably fatal, X-linked muscle wasting disease affecting 1 in 5000 boys. Lack of dystrophin protein results in myofibre degeneration, leading to infiltration or replacement of muscle with adipose or connective tissue (fibrosis). Progressive skeletal muscle dysfunction results in loss of ambulation by adolescence and ultimately, respiratory muscle failure. Similarly, in cardiac muscle, progressive left ventricular (LV) fibrosis leads to wall motion abnormalities and later, acute deterioration due to overt systolic failure usually between 13 and 16 years of age. Advances in supportive management and the use of palliative steroid treatment have increased longevity for DMD patients such that cardiomyopathy and respiratory muscle (primarily diaphragm) failure have emerged as the leading causes of death. Dogs are susceptible to an equivalent disorder that closely mimics the human condition.  

In this project the student will examine specific aspects of the cardiorespiratory phenotype in a canine model of DMD -  the DE50-MD model -  using historical plethysmography data acquired longitudinally from affected and control dogs as they age and cardiac, intercostal and diaphragm muscle tissues histologically. The student will attempt to explain our previous finding that affected animals have smaller hearts than control animals, by comparing cardiomyocyte size in affected dogs compared with controls and validate the use of plethysmography and thoracic computed tomography as suitable non-invasive biomarkers for translational treatment trials. The output will be a detailed characterisation of the cardiorespiratory phenotype of this DMD model.

References

  1. Hildyard JCW, Riddell DO, Harron RCM, Rawson F, Foster EMA, Massey C, Taylor-Brown F, Wells DJ, Piercy RJ. The skeletal muscle phenotype of the DE50-MD dog model of Duchenne muscular dystrophy. Wellcome Open Res. 2022 Sep 23;7:238. doi: 10.12688/wellcomeopenres.18251.1. PMID: 36865375; PMCID: PMC9971692.
  2. Hawkins EC, Bettis AK, Kornegay JN. Expiratory dysfunction in young dogs with golden retriever muscular dystrophy. Neuromuscul Disord. 2020 Nov;30(11):930-937. doi: 10.1016/j.nmd.2020.09.027. Epub 2020 Sep 20. PMID: 33071066; PMCID: PMC7680419.
  3. Amoasii L, Hildyard JCW, Li H, Sanchez-Ortiz E, Mireault A, Caballero D, Harron R, Stathopoulou TR, Massey C, Shelton JM, Bassel-Duby R, Piercy RJ, Olson EN. Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Science. 2018 Oct 5;362(6410):86-91. doi: 10.1126/science.aau1549. Epub 2018 Aug 30. PMID: 30166439; PMCID: PMC6205228.

Requirements

Essential:

Desirable:

  • Prior wet-lab research experience in histology or immunohistochemistry
  • Clinical experience and interest in canine medicine or neurology  

This can be taken full-time (12months FTE), project commencing in October 2024, based at RVC's Camden campus, with occasional requirement to visit the Hawkshead campus.

Funding

This is a fully funded project that will cover tuition fees, stipend  and research costs.

International applicants are welcome to apply but must be able to fund the difference between "Home" and "Overseas" tuition fees. Please note that EU/EEA and Swiss national students may no longer be eligible for the “Home” rate of tuition fees, dependent on personal circumstances (including immigration status and residence history in the UK) and UK government rules which are currently being developed. For up-to-date information on fees for EU/EEA and Swiss national students following Brexit please see our fees and funding page.

How to Apply

For more information on the application process and English Language requirements see How to Apply.

Deadline: Sunday 14th July 2024

We welcome informal enquiries - these should be directed to Prof Richard Piercy  (rpiercy@rvc.ac.uk)

Interview date and location: TBC

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