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Role of Transient Receptor Potential A1 in diabetic pain and neuropathy

First supervisor: David Andersson
Second supervisor: Stuart Bevan
Division: Wolfson Centre for Age-Related Diseases
Type of programme: 4 years
Project code: WCARDAnderssonD

Project description

Almost 3 million people in the UK (4.5% of the population) have been diagnosed with diabetes and the prevalence is increasing rapidly. A majority of these patients will be affected by diabetic complications, with almost a third developing nephropathy and almost 50% developing neuropathy. Diabetic complications are often life-changing and devastating for the patient. Diabetic nephropathy is the leading cause of end stage renal disease and diabetic neuropathy is the most common reason for lower limb amputations and a major cause of neuropathic pain. Successful glycaemic control may delay the onset of diabetic complications, but this is not achieved by the majority of patients. Despite the urgent need for prevention and improved treatment, the cellular mechanisms responsible for diabetic neuropathy and nephropathy remain elusive.

We have identified reactive oxygen species and methylglyoxal as key mediators responsible for the development of diabetic neuropathy. These mediators act by stimulating the ion channel TRPA1 in pain-sensing neurons, thereby producing pain and neuropathy. Methylglyoxal is a glucose metabolite that occurs at higher concentrations during hyperglycemia in diabetes. We have discovered that increased levels of methylglyoxal in vivo (in the absence of diabetes) produce a painful neuropathy in wildtype mice, but not in transgenic mice lacking TRPA1.

This project will exploit immunohistochemical, behavioural, electrophysiological and molecular techniques to determine the role of TRPA1 for the sensory and anatomical changes seen in diabetic sensory neuropathy in models of genetically and chemically induced diabetes. The project will be supported by a CASE award from Eli Lilly.

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