Summary

This project will improve our understanding of ALS physiopathology and open new routes toward therapies. The student will be part of a dynamic team that collaborates with an international network (London, Washington DC, Montpellier, Paris).

Rationale: Studies in animal models and ALS patients show that motor neuron degeneration starts at the neuromuscular junction and that post-synaptic muscle changes may play an active role1,2. This axonopathy could be due to the secretion of toxic elements from the muscle. In our lab, we have already shown that ALS muscle cells release toxic exosomes. The purpose of the current project is to explore the in vivo capacity of the muscle exosomes to be transmitted to motor neurons.

Aim1 - Retrograde transport of murine exosomes in vivo: We will express exosomes tagged with a fluorescent marker in murine muscle and track them in vivo. At 5, 10, and 20 days post-injection, the muscles, sciatic nerves and central nervous system will be harvested for immunostaining. This experiment will allow us to determine the speed of diffusion of muscle exosomes in vivo.

Aim2 - Tracking ALS exosomes in vivo: We will track ALS muscle exosomes in vivo and determine whether they preserve their toxic properties.

Aim2a: Exosomal suspensions extracted from muscle cells of ALS patients and healthy subjects will be injected into muscles of immunodeficient mice. Similarly to aim1, various tissues will be harvested post-injection for immunostaining. This experiment will allow us to determine whether ALS muscle exosomes induce motor neuron death in vivo.

Aim2b: The sciatic nerves of mice of several ALS murine models will be harvested at pre-symptomatic ages and tested for muscle exosome markers. This experiment will allow us to determine whether ALS murine models are good models to study the retrograde transport of muscle exosomes. Aim3 - Correcting the toxicity of ALS exosomes in vivo: For this purpose, we will knockdown the expression of mutated SOD1 or FUS or TDP43 in vitro using an siRNA strategy. We will then extract the exosomes from these cells and inject them in vivo as described in Aim2a, to determine whether their toxic effect is abolished. This experiment will be a proof of concept to demonstrate whether targeting the secretion of toxic elements through exosomes could be a good therapeutic strategy.

Skills required: The successful candidate should have some familiarity with technical skills such as immunostaining and cell culture, should have good organizational and planning skills, a rigorous and methodical approach to lab-work, be capable of both independent and team work, and have good skills in writing and presenting data. Experience of the following would be advantageous: PCR and RT-qPCR, and RNA extractions.

References:

1.Fischer, L. R. et al. Exp. Neurol. 185, 232–40 (2004).

2.Tallon, C., Russell, K. A., Sakhalkar, S., Andrapallayal, N. & Farah, M. H. Neuroscience 312, 179–89 (2016).

3. Pradat, P.-F., Kabashi, E. & Desnuelle, C. Curr. Opin. Neurol. 28, 455–61 (2015).

4.  Duguez, S. et al. Cell. Mol. Life Sci. (2013).


Essential criteria

  • To hold, or expect to achieve by 15 August, an Upper Second Class Honours (2:1) Degree or equivalent from a UK institution (or overseas award deemed to be equivalent via UK NARIC) in a related or cognate field.
  • Sound understanding of subject area as evidenced by a comprehensive research proposal
  • A comprehensive and articulate personal statement

Desirable Criteria

If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.

  • First Class Honours (1st) Degree
  • Masters at 65%
  • Completion of Masters at a level equivalent to commendation or distinction at Ulster
  • Research project completion within taught Masters degree or MRES
  • Experience using research methods or other approaches relevant to the subject domain
  • Sound understanding of subject area as evidenced by a comprehensive research proposal
  • Work experience relevant to the proposed project
  • Publications - peer-reviewed
  • Experience of presentation of research findings
  • A comprehensive and articulate personal statement

Funding

    The University offers the following awards to support PhD study and applications are invited from UK, EU and overseas for the following levels of support:

    Vice Chancellors Research Studentship (VCRS)

    Full award (full-time PhD fees + DfE level of maintenance grant + RTSG for 3 years).

    This scholarship will cover full-time PhD tuition fees and provide the recipient with £15,000 maintenance grant per annum for three years (subject to satisfactory academic performance). This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

    Vice-Chancellor’s Research Bursary (VCRB)

    Part award (full-time PhD fees + 50% DfE level of maintenance grant + RTSG for 3 years).

    This scholarship will cover full-time PhD tuition fees and provide the recipient with £7,500 maintenance grant per annum for three years (subject to satisfactory academic performance). This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

    Vice-Chancellor’s Research Fees Bursary (VCRFB)

    Fees only award (PhD fees + RTSG for 3 years).

    This scholarship will cover full-time PhD tuition fees for three years (subject to satisfactory academic performance). This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

    Department for the Economy (DFE)

    The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £ 15,009 per annum for three years. EU applicants will only be eligible for the fee’s component of the studentship (no maintenance award is provided). For Non-EU nationals the candidate must be "settled" in the UK. This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

    Due consideration should be given to financing your studies; for further information on cost of living etc. please refer to: www.ulster.ac.uk/doctoralcollege/postgraduate-research/fees-and-funding/financing-your-studies


Other information


The Doctoral College at Ulster University


Reviews

Profile picture of Kieran O'Donnell

My experience has been great and the people that I have worked with have been amazing

Kieran O'Donnell - 3D printing of biological cells for tissue engineering applications

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Profile picture of Michelle Clements Clements

Completing the MRes provided me with a lot of different skills, particularly in research methods and lab skills.

Michelle Clements Clements - MRes - Life and Health Sciences

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Profile picture of William Crowe

Throughout my PhD I’ve been provided with continuous support and guidance by my supervisors and the staff at the University.I’ve also received many opportunities to further enhance my professional development in the form of teaching experience and presenting my work at conferences which will aid in my pursuit of a career in academia or industry.

William Crowe