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Investigating the role of adenosine deaminase in motor neuron disease

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

In a recent study published in Brain (https://doi.org/10.1093/brain/awy353) and highlighted in a number of media articles (www.sheffield.ac.uk/news/nr/disrupted-pathway-motor-neurone-disease-1.830534) we have identified a novel disruption in an energy generating pathway in astrocytes (neuronal support cells) derived from motor neurone disease (MND) patients. The pathway involves the conversion of the nucleoside adenosine to inosine, which is controlled by the enzyme adenosine deaminase (ADA). We have found that ADA is reduced in astrocytes derived from patients with a mutation that causes MND and in patients with no identified mutation. Loss of ADA would reduce inosine production and cause a build-up of adenosine that can be toxic in the central nervous system. The aim of this project is to further investigate this exciting novel discovery by ascertaining whether increasing ADA levels by gene therapy in MND patient derived astrocytes;

1. Reduces adenosine mediated astrocyte toxicity.
2. Increases astrocyte bioenergetic capacity.
3. Increases astrocyte antioxidant capacity.
4. Reduced DNA damage by increasing DNA repair mechanisms in astrocytes.
5. Increases astrocyte mediated support to motor neurones in co-culture.

The project will involve extensive tissue culture of induced neuronal progenitor derived astrocytes including lentiviral delivery of ADA targeted vectors. The project will include the use of cutting edge technologies to analyse cell function including an OmniLog™ phenotypic analyser, an XF24 metabolic flux analyser, an IN Cell automated microscope and 96 well plate fluorescent readers. Furthermore, the project will involve basic biochemical techniques such as SDS-PAGE, western blot and immunofluorescence. All protocols are in place (https://doi.org/10.1093/brain/awy353), as well as the expertise to modulate the level of ADA by gene therapy.

The project will be performed at the Sheffield Institute for Translational Neuroscience (SITraN), a world class neurodegenerative disease research institute, which is part of the Sheffield Biomedical Research Centre and the newly formed Neuroscience research institute. https://www.sheffield.ac.uk/neuroscience-institute/home

Funding Notes

This project is open to self-funded students only.

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

References

Enquiries:
Interested candidates should in the first instance contact (Dr Scott Allen, [email protected])

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.

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