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A Channel to Nerve Degeneration - Reference: MIBTP_Zhang_Degeneration


College of Life & Health Sciences

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Dr X Zhang , Dr R Parri No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Applications are invited for four year Postgraduate studentships, supported by the Midlands Integrative Biosciences Training Partnership (MIBTP) (URL: https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/structural_biology/activation) and Biotechnology and Biological Sciences Research Council (BBSRC) (URL: https://bbsrc.ukri.org/). Up to 6 studentships are available.

The studentships are available to start in October 2021.

Background to the Studentship
MIBTP scholars join a programme of skills training in year 1. Applicants are required to select an area of study (URL: https://warwick.ac.uk/fac/cross_fac/mibtp/areas_of_research/), but may join the programme with or without selecting a preferred project. 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 (URL: https://www.findaphd.com/phds/program/midlands-integrative-biosciences-training-partnership-mibtp-funded-phd-studentships/?i369p1045). 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 and surrounded myelin-forming Schwann cells (SCs). When nerve fibres are degenerated or damaged, often occurring in ageing, obesity and diabetes, peripheral neuropathy (PN) will evolve causing pain, unusual sensations (e.g. 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. Interestingly, transient receptor potential melastatin 2 (TRPM2) ion channels are both a metabolic sensor and a sensor for oxidative stress mediating oxidative-stress-induced tissue damage and immune-inflammatory responses. These prominent functions align perfectly with the pathological processes of PN, suggesting a pivotal role for TRPM2 in PN. Indeed, TRPM2 is found in both sensory axons and SCs, and pain in PN was prevented by blocking TRPM2. We aim to 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 and then assess neuropathy behaviours of mice such as pain and gait instability. To examine nerve degeneration, we will isolate sciatic nerves and evaluate neuronal damage, demyelination and apoptosis of SCs using histology, apoptosis assay and qRT-PCR. We will also examine nerve oxidative stress using lipid peroxidation assay and neuroinflammation by staining infiltrated macrophage. 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 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 electrophysiology to record neuronal firing. We anticipate that aberrant 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 firing.

Altogether, this research will reveal the novel mechanisms through which TRPM2 mediates PN and suggest that TRPM2 is an appealing target for the treatment of PN.
You will engage our cutting-edge research in a well-funded laboratory, and have excellent opportunities to learn interdisciplinary skills to address a prevalent neurologic condition.

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 (URL: https://www.aston.ac.uk/study/courses/phd-life-and-health-sciences).

Full entry requirements for MIBTP can be found on their website ((URL: https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/#Eligibility).

Contact information
For further information on the advertised project, contact Dr. Xuming Zhang at [Email Address Removed]

Submitting an application
Details of how to apply for the studentship can be found here (URL: https://jobs.aston.ac.uk/Vacancy.aspx?ref=R200309).

If you require further information about the application process contact the Postgraduate Admissions team [Email Address Removed]


Funding Notes

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.

References

1. Feldman EL et al, Diabetic neuropathy. Nature Reviews Disease Primers 2019 (5): 41.
2. Yamamoto S et al, Targeting TRPM2 in ROS-coupled diseases. Pharmaceuticals (Basel) 2016, 9.

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