Pericytes as instigators of microvascular dysfunction and neuronal hypoxic injury in diabetic ischaemia and neuropathy (360G-Wellcome-224049_Z_21_Z)

Diabetic neuropathy is the most common complication of diabetes, yet the underlying aetiology of this disorder remains poorly understood. A growing body of evidence suggests that diabetic neuropathy involves nerve injury downstream of reduced local blood flow due to capillary dysfunction. Pericytes are key regulators of capillary blood flow in other tissues, and are central to the pathophysiology of other diabetic disorders including diabetic retinopathy. Pericyte loss has been reported in patients with diabetic neuropathy, but the consequences are unexplored. We hypothesise that pericyte pathology drives reduced blood flow in diabetic neuropathy, thereby contributing to nerve injury. To test this hypothesis we will: 1) Characterise the progression and distribution of lower limb pericyte, capillary and neuronal dysfunction 2) Elucidate changes in pericyte function and how pericytes contribute to vascular dysfunction 3) Resolve whether pericyte and sensory neuron dysfunction in diabetes occur secondary to hyperglycaemia or ischaemia 4) Translate observed results to the Db/Db type 2 diabetes model and human tissue To this end, this project will use a combination of ex vivo and in vivo functional study to evaluate the time-course, mechanisms and implications of pericyte dysfunction/loss during diabetes, and how this contributes to diabetic neuropathy.