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Understanding the aetiology of diabetic neuropathy


Project Description

Diabetic neuropathy is a common secondary complication of diabetes mellitus which affects around 50% of all patients with diabetes - impacting on health, wellbeing and quality of life. Symptoms of diabetic neuropathy arise in a typical ‘glove and stocking’ distribution, with the longest axons of the body showing distal die-back of terminals from the skin of the feet and hands. Innervation of the skin is through both autonomic and sensory fibres. Sensory afferents in the skin are activated by physical touch, temperature and/or chemical stimuli and autonomic efferents regulate glandular activity and vasoregulation. Patients with diabetic neuropathy typically develop symptoms such as pain, tingling, burning or aching sensations or numbness. Loss of sensation can lead to tissue damage and an increased risk of limb amputation

The underlying origin of the disease is complex and poorly understood. Our current work uses untargeted proteomic and metabolomic analysis of various regions of the nervous system, including sciatic nerve, trigeminal and dorsal root ganglia, to identify proteins and metabolites whose levels alter in diabetes. This approach has allowed us to generate new hypotheses regarding the mechanisms underlying diabetes-associated neuropathy. This PhD project will both extend these studies into different regions of the nervous system and examine the impact of modulating key target proteins/pathways on nerve function using in vivo and in vitro models of sensory nerve regeneration. Gaining further understanding of the pathogenic changes that occur in disease and how these impact on nerve phenotype will play a major role in providing new targets for treatment of diabetic neuropathy.

This multidisciplinary project aims to improve our understanding of the contribution of lipids on distal axon degeneration of sensory neurons in diabetic neuropathy. We have established experimental models of diabetic neuropathy. The student will learn a variety of important experimental skills from working with rodents, tissue dissection and immmunohistochemisty, and in vivo behavioural assessment of sensory nerve function (thermal and mechanical sensitivity threshold, nerve conduction velocity measurement), and ‘omics analysis of tissue. These studies will be combined with in vitro experiments to investigate the axon outgrowth dynamics of sensory neurons prepared from adult rat dorsal root ganglia.

Funding Notes

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject.

This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.

References

• Freeman OJ, Unwin RD, Dowsey AW, Begley P, Ali S, Hollywood KA, Rustogi N, Petersen RS, Dunn WB, Cooper GJ & Gardiner NJ (2016) Metabolic Dysfunction is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy. Diabetes 65(1): 228-38.
• Gardiner NJ & Freeman OJ (2016) Can diabetic neuropathy be modelled in vitro? Chapter 5: Controversies in Diabetic Neuropathy. Edited by Nigel A. Calcutt and Paul Fernyhough (Elsevier). Int Rev Neurobiol 127
• Gardiner NJ (2011) Integrins and the extracellular matrix: key mediators of development and regeneration of the sensory nervous system. Developmental Neurobiol 71(11): 1054-72.
• Tomlinson DR & Gardiner NJ (2008) Glucose neurotoxicity. Nature Rev Neurosci. 9(1):36-45
• Duran-Jimenez, B, Dobler D, Moffatt S, Rabbani N, Streuli CH, Thornalley PJ, Tomlinson DR & Gardiner NJ (2009). Advanced glycation end products in extracellular matrix proteins contribute to the failure of sensory nerve regeneration in diabetes. Diabetes 58(12):2893-903

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