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(BBSRC DTP) Modulating the microtubule network to improve nerve regeneration


Project Description

Axon terminals typically undergo dynamic extension and retraction processes in response to stimuli such as neurotrophic factors, physical stimuli or damage. This is essential for the normal development, function and regeneration of the nervous system. In conditions, such as diabetic neuropathy (a common and often debilitating complication of diabetes), where nerve regenerative processes are critically impaired distal axon degeneration occurs at a faster rate than regeneration and this can lead to a permanent loss of sensation. Therapeutic options are often inadequate and limited to glycaemic control and symptomatic treatment, and do not restore innervation. The molecular changes which underlie distal axonal die-back are not fully understood. Since alteration in microtubule formation, organisation and stability impacts on the degenerative/regenerative phenotype, destabilisation of microtubules (MT) is a potential key target mechanism for therapeutic approaches. Our pilot data suggests stabilisation of MTs may prevent sensory nerve degeneration and increase nerve regeneration.

This multidisciplinary project will investigate the role of MTs in distal axon degeneration in primary neuronal cell culture (rodent and Drosophila) to dissect the intricate mechanistic responses of cells to oxidative/glycative stressors, and provides new opportunities to combine the strengths of different models to investigate the potential of MTs for the treatment of diabetic neuropathies. Drosophila is a powerful genetic model, ideal to study the key roles of cytoskeletal filaments in particular actin and MTs as the essential drivers of axonal growth. State-of-the-art bioimaging approaches will be used to investigate MT networks and axon outgrowth. The student will benefit from expertise offered by the combined supervisory team: Natalie Gardiner and Adam Reid (diabetic neuropathy, nerve repair and sensory neuron cultures) as well as Andreas Prokop and Ines Hahn (axon growth, microtubule regulation, live-cell imaging, genetics, fruit fly model). Once candidate pathogenic mechanisms have been identified, the student will be able to use molecular and pharmacological tools to modulate MT organisation, enhance the stability of the neuronal cytoskeleton using in vitro models, and assess their translation potential using in vivo nerve regeneration and diabetic neuropathy models.

The multidisciplinary nature of this project provides an excellent training opportunity for the successful applicant. The student’s transferable experimental skill training opportunities will include molecular biology, genetics, neuronal cell biology, a range of imaging techniques and in vivo skills as well as insights into important concepts of the cell and neurobiology fields. In addition AP & NG are Social Responsibility leads providing further training opportunities for science communication and outreach, important for career development.

https://www.research.manchester.ac.uk/portal/natalie.gardiner.html
https://www.research.manchester.ac.uk/portal/andreas.prokop.html
https://www.research.manchester.ac.uk/portal/ines.hahn.html
https://www.research.manchester.ac.uk/portal/adam.reid.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

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