Pathophysiological role of TRPA1 in diabetic sensory neuropathy

Diabetes is one of the major health challenges of our time, affecting about 10% of the global population. Complications of longstanding disease affect many organ systems and are regularly serious. Diabetic neuropathy (DN) is one of the leading causes of chronic neuropathic pain, but current therapies leave patients without satisfactory pain relief. About half of all patients with diabetes develop diabetic sensory neuropathy, and many of these suffer from chronic debilitating pain that is difficult to treat. Despite that DN is an important cause of pain, its most characteristic symptom is sensory loss, which in itself contributes to foot ulcers and amputations. Like some other types of neuropathy, DN is characterized by a loss of innervation of the skin (an anatomical loss of nerve fibres), but its relationship to pain and sensory loss is unclear. 

The oxidative and metabolic stress typical of diabetes leads to production of multiple reactive metabolites, which all stimulate the ion channel TRPA1. TRPA1 is expressed in a large subset of pain sensing (nociceptive) sensory neurons and has been hotly pursued as a target for novel analgesic drugs. The supervisors have discovered that diabetic mice lacking TRPA1 are protected from the anatomical signs of neuropathy (no loss of skin innervation), and these observations suggest that TRPA1 may contribute to the onset of DN, as well as producing pain. During this project, the mechanisms responsible for DN and sensory abnormalities will be examined in isolated primary sensory neurons, and in sensory neurons derived from human induced pluripotent stem cells (hIPSCs).

Diabetic sensory neuropathy is characterized by sensory loss, small-fibre neuropathy associated with a reduced innervation of the epidermis and the cornea, and about half of affected patients suffer from pain and paraesthesias. The available therapies for diabetic neuropathic pain produce problematic side effects that limit their use, and they are typically only efficacious in a subset of patients, often only for a limited time. While diabetic neuropathic pain has received much attention, sensory loss is also an urgent health priority. Sensory loss contributes to development of foot ulcers, amputations, and is associated with increased mortality. Diabetic neuropathy has a profound impact on quality of life, and its high prevalence incurs extreme societal and healthcare costs.

Most experimental studies of diabetes and diabetic complications have been conducted in rodents treated with streptozotocin (STZ). STZ kills insulin producing pancreatic β-cells within a few days of administration, but also exerts other direct effects on sensory neurons (including activation of TRPA1), which complicates the interpretation of findings. To avoid the need to use the β-cell toxin streptozotocin to induce diabetes, we instead used the Ins2^+/Akita strain of diabetic mice in the studies leading up to this PhD project. We crossed the Ins2^+/Akita strain with Trpa1^-/- mice to generate diabetic mice lacking TRPA1 and discovered that these mice were protected from the loss of epidermal innervation that is reliably observed in diabetic Ins2^+/Akita mice as well as in patients with diabetic neuropathy. The conduction velocity (CV) of sensory afferents is reduced in diabetic neuropathy, but we further noticed that the C-fibre CV was normalised in Ins2^+/Akita/Trpa1^-/- compared to Ins2^+/Akita mice. During this studentship, we will use several approaches to elucidate the mechanisms by which TRPA1 inactivation protects against diabetic neuropathy, and how TRPA1 influences neuronal excitability and the associated pain and sensory abnormalities.

Funding Notes:

This project is fully funded for four years, with the student receiving the following support:

-         Stipend: Students will receive a tax-free stipend for each year of study, starting on £20,562 in year 1 and increasing each year with inflation.

-         Tuition fees: Students tuition fees for each year of study are fully covered. The amount of £4,596 in 2022/23, rates for subsequent years will be announced by UKRI.

-         Bench fees: a generous allowance of £6,400 each year provided towards research consumable and project costs.

-         Travel and conference allowance: £300 each year provided to support students in attending UK and international conferences.

Funding source: this project is co-funded by King’s College London and the Industry Partner Grünenthal.

Eligibility: 

To be classed as a home student, candidates must meet the following criteria: 

•Be a UK National (meeting residency requirements), or 

•Have settled status, or 

•Have pre-settled status (meeting residency requirements), or  

•Have indefinite leave to remain or enter  

Enquiries email name and address:

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Application Web Page:

Full details on how to apply here: https://kcl-mrcdtp.com/studentships/icase-studentships/icase-application-process/