Nearly one in ten people live with neuropathic pain, yet the drugs available to treat it often fall short. This research will pinpoint which ion channels—tiny gateways that control nerve cell activity—are responsible for driving that pain, by studying genetic variants found in patients with common conditions like painful diabetic neuropathy. The problem is that current treatments were not designed for the specific molecular faults causing neuropathic pain in most patients. By linking specific genetic variants to how nerves become hyper-excitable, this work aims to reveal the exact biological mechanisms at play. If successful, the research could lead to better-targeted therapies—either by repurposing existing drugs for the right patient groups or by identifying new drug targets. It will also create a platform using human stem cells and animal models to screen potential treatments before they reach clinical trials. This is fundamental science with a clear translational path: understanding the human genetics of pain to move beyond the current trial-and-error approach to prescribing.
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Neuropathic pain (NeuP) affects almost 10% of the general population and current therapies are inadequate. Ion channels are key determinants of excitability within the sensory nervous system and so are attractive therapeutic targets. We need to understand the mechanisms by which ion channels drive hyper-excitability and NeuP in humans. Ion channel variants have been associated with rare Mendelian pain disorders; we have recently found that variants in ion channels also act as risk factors for more common NeuP disorders such as painful diabetic neuropathy. I will investigate ion channels (and their variants) identified from human genetic studies of NeuP. These will include voltage-gated sodium channels and, recently implicated targets, such as channels which maintain neuronal homeostasis in response to sodium. I will determine how these genes regulate excitability within the sensory nervous system and their interaction with environmental stressors (such as extremes of temperature) using electrophysiology, human-iPSC and animal models. These models will also provide a platform in which to screen potential treatments. I will explore the relationship between pathogenic variants, clinical and sensory phenotype. This will lead to new understanding of the pathophysiological mechanisms driving NeuP, facilitating identification of new treatment targets and better targeting of existing therapies.
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