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PhD Studentship (4 years) - A Channel to Nerve Degeneration

Aston Pharmacy School

Location:  Aston University Main Campus
Basis:  Full Time
Closing Date:  23.59 hours GMT on Sunday 10 January 2021
Reference:  R200309
Release Date:  Tuesday 10 November 2020

Supervisor: Dr. Xuming Zhang

Associate Supervisors: Dr. Rhein Parri

Project Reference: MIBTP_Zhang_Degeneration

BBSRC Strategic Research Priority: Neuroscience and behaviour, Animal health and welfare, Ageing

Applications are invited for four year Postgraduate studentships, supported by the Midlands Integrative Biosciences Training Partnership (MIBTP) and Biotechnology and Biological Sciences Research Council (BBSRC). Up to 6 studentships are available.

The studentships are available to start in October 2021. 

Financial Support

The studentships include a fee bursary to cover the Home fees rate, plus a tax free stipend of at least £15,285 p.a (to rise in line with UKRI recommendation).

Overseas Applicants

Overseas applicants may apply for this studentship, and the home fees rate will be covered. UKRI funding will not cover the difference between UK tuition fees and international tuition fees; international tuition fee payers will be required to fund the fee difference themselves. MIBTP encourages international students with existing sources of funding (e.g. fellowships) to apply. The difference between home and international fees is £13,443 in 2020/21. Please confirm in your application how you will fund the fee difference."

Background to the Studentship

All MIBTP scholars will join a programme of skills training in year 1. Applicants are required to select an area of study (Sustainable Agriculture and Food, Understanding the Rules of Life, Renewable Resources and Clean Growth or Integrated Understanding of Health) but may join the programme with or without selecting a preferred project. Part of the skills training programme includes short rotation projects and students are able to choose a PhD project once they have experienced these differing research environments.

Potential PhD projects are provided to give applicants an idea of the breadth of research within MIBTP and specific research topics at Aston University. You can browse the other projects available here. Additional projects will become available during Year 1 and students can work with potential supervisors during their first year to develop a particular project.

Project Outline

Afferent nerve fibres carry sensory signals to the brain responsible for sensory perception and pain. They are formed by the axons of sensory neurons surrounded by myelin-forming Schwann cells (SCs). When nerve fibres are degenerated or injured, often occurring in ageing, obesity and diabetes, peripheral neuropathy (PN) will evolve causing pain, unusual sensations such as numbness and even sensation loss, leading ultimately to foot ulcer and amputations. How this damaging process occurs remains elusive. Here, we will investigate the molecules mediating PN and the roles of both sensory axons and SCs in this process. 

Oxidative stress and nerve inflammation are two hallmark processes causing demyelination and nerve degeneration in PN. They result from altered metabolism and mitochondria dysfunction during ageing and diabetes triggering excessive production of reactive oxygen species (ROS). Accumulated ROS then drives neuroinflammation by activating inflammatory signaling. Interestingly, transient receptor potential melastatin 2 (TRPM2) ion channels are both a metabolic sensor and a sensor for oxidative stress critical to oxidative-stress-induced cell and tissue damage. TRPM2 also mediates immune and inflammatory responses. These prominent functions of TRPM2 align perfectly with the pathological processes of PN, suggesting a pivotal role for TRPM2 in PN. Indeed, TRPM2 is expressed in both sensory axons and SCs, and neuropathic pain in PN was prevented by both pharmacological blockade and genetic deletion of TRPM2. We will investigate the role of TRPM2 in PN and the underlying mechanisms with three objectives. 

Firstly, we will investigate the role of TRPM2 in nerve degeneration, oxidative stress and neuroinflammation. We will generate diabetic neuropathy model in wild-type and TRPM2 knockout mice. We will then assess neuropathy behaviours of mice such as pain and gait instability. To examine nerve degeneration, we will stain nerve fibres in the skin with anti-PGP9.5. We will also isolate sciatic nerves to evaluate neuronal damage, demyelination and apoptosis of SCs using histology and apoptosis assay combined with qRT-PCR to determine changes in the expression of neuron- and myelin-specific genes. We will also examine nerve oxidative stress and neuroinflammation in sciatic nerves using lipid peroxidation assay and by staining infiltrated macrophage, respectively. Reduced nerve degeneration, oxidative stress and neuroinflammation are expected in TRPM2-lacking mice.  Secondly, we will determine the role of TRPM2 in nerve firing. Nerve function depends on their firing activities. The fact that blocking TRPM2 inhibits pain in PN suggests a key role for TRPM2 in nerve firing. We will isolate sensory neurons and use current patch clamping to record neuronal firing. We anticipate that abnormal nerve firing in diabetic neuropathy is prevented in TRPM2-lacking mice. Thirdly, we will define the separate roles of TRPM2 in neurons and in SCs in PN. We will use Cre-Lox technology to generate conditional knockout mice in which TRPM2 is selectively deleted in either sensory neurons or SCs. We will then employ the same approaches above to investigate the effect of selective TRPM2 deletion on nerve degeneration, oxidative stress, neuroinflammation and nerve firing. 

Altogether, this research will reveal the novel mechanisms by which TRPM2 mediates PN through two different cell types, and suggest that TRPM2 is an appealing drug target for the treatment of PN. 

You will be supported by experienced senior scientists to engage our cutting-edge research in a well-funded laboratory with a vibrant and stimulating environment. This is an excellent opportunity to learn multi-disciplinary knowledge (neuroscience, immunology, pharmacology and cell biology) and a range of interdisciplinary skills including gene manipulations, animal behaviour, immunohistology, electrophysiology, qPCR, imaging and cell biology assays to address a prevalent neurologic condition.

References:

1. Feldman EL et al, Nat. Rev. Dis. Primers 2019, 5, 41.

2. Yamamoto S et al, Pharmaceuticals (Basel) 2016, 9.

Person Specification

The successful applicant should have been awarded, or expect to achieve, a Masters degree in a relevant subject with a 60% or higher weighted average, and/or a First or Upper Second Class Honours degree (or an equivalent qualification from an overseas institution) in a relevant subject. Full entry requirements for Aston University can be found on our website.

Evidence of quantitative training is required. For example, AS or A level Maths, IB Standard or Higher Maths, or university level maths/statistics course. Full entry requirements for MIBTP can be found on their website.

Contact information

For further information on the advertised project, please contact Dr. Xuming Zhang at x.zhang39@aston.ac.uk

Submitting an application

In order to apply for the MIBTP PhD studentship you must:

  1. Check your eligibility. 
  2. Complete a PhD application form on the Aston University website. From the drop-down options select School of Life and Health Sciences; October; Full time; Postgraduate Research; “Research Biomedical Sciences October 2021 Entry (Full-time)”.
  3. Notify MIBTP of your application by completing the online notification form; ensuring that you upload a current CV to the form.
  4. Review the MIBTP Data Privacy Policy to understand how we process your personal data.


When completing the Aston University application form, you will need to ensure to include the following documents:

  • Copies of your academic qualifications for your Bachelor degree, and Masters degree (if studied); this should include both certificates and transcripts, and must be translated in to English.
  • A personal statement*
  • A copy of your current CV
  • Two academic references
  • Proof of your English Language proficiency for non-Native English speakers, further details can be found on our website

*Please note that a project proposal is not required, however your Personal Statement should address your ability & knowledge of the research area.  Where applying for a specific project, please include the supervisor name, project title and project reference in your Personal Statement. 

If you require further information about the application process please contact the Postgraduate Admissions team at pgr_admisssions@aston.ac.uk 

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Further particulars and application forms are available in alternative formats on request i.e. large print, Braille, tape or CD Rom.

If you have any questions, please do not hesitate to contact HR via recruitment@aston.ac.uk


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