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Neuropathic pain arises from disease or damage of the nervous system. It is a major clinical problem affecting 5-10% of the adult population, despite the use of current therapies.

Pain sensing neurons
LGI1 mRNA expression (red) in primary sensory neurons

Excessive activity in pain-sensing neurons is a key driver of neuropathic pain.Animal studies have shown that certain potassium channels (e.g. Kv1 channels) act as a brake to limit sensory neuron excitability. A significant proportion of patients who have autoantibodies directed against proteins which interact with Kv1 channels, and hence regulate their function (e.g. CASPR2, LGI1), have neuropathic pain which can be reversed with therapies that reduce antibody levels.

The goal of John Dawes' work is to better understand how autoantibodies contribute to chronic pain. He will use these patients samples to identify novel clinically relevant molecular pathways regulating sensory neuron excitability and test whether these pathways can be modulated for the treatment of neuropathic pain more generally.

The project will focus on LGI1 (leucine rich glioma inactivated 1). This protein is known to have a role in regulating excitability within the central nervous system. Recent studies have uncovered the previously unrecognised expression of LGI1 by primary sensory neurons. In collaboration with Sarosh Irani, this work will use patient LGI1 autoantibodies to generate new models of autoimmune pain and develop these alongside transgenic mouse lines to assess the impact of LGI1 disruption on regulating sensory neuron excitability and pain sensitivity. He will then develop strategies for increasing the availability of LGI1 and use preclinical models of nerve injury to assess whether this is a viable approach for the treatment of neuropathic pain.

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