Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Developing neuroprotective and repair strategies represents an urgent unmet need for treating inflammatory demyelinating disorders of the central nervous system (CNS) including multiple sclerosis (MS). Lesions in both MS patients and the MS mouse model, experimental autoimmune encephalomyelitis (EAE), involve T lymphocyte infiltration and axonal damage. However, interactions between CNS-infiltrating T cells and central neurons remain poorly understood. 4-Aminopyridine (4-AP) is an FDA-approved drug for the symptomatic treatment of MS to improve walking speed. Although it is commonly believed that 4-AP blocks Kv1 (Shaker) voltage-gated K+ (Kv) channels to enhance axonal conduction and suppress immune response, the mechanisms underlying 4-AP’s actions in treating MS are still not completely clear. Our new results have provided several lines of compelling evidence that a Kv3 (Shaw) channel, with high 4-AP sensitivity, is expressed in both CD4+ T cells and CNS neurons, and plays a key role in T cell-induced axonal injury. This channel regulates T cell activation that is required for EAE induction, shown by our active and passive EAE results using its global knockout (KO) mice. This notion is further supported by our data from T cell culture, immunostaining/confocal imaging, flow cytometry, RNAi knockdown, and conditional KO (cKO) mice. Therefore, based on our new findings, we propose a novel hypothesis that in the development and pathology of CNS autoimmunity, Kv3 channel is required for the efficient generation of encephalitogenic T cells, whereas its upregulation in axons aggravates autoimmune-induced injury via aberrant Ca2+ signaling. To test this original hypothesis, we have created a floxed mouse line for this Kv3 channel to examine the effects of its cell- type-specific cKOs on EAE. We will use a multidisciplinary approach, including active and passive EAE models, inducible cKO and transgenic mouse lines, flow cytometry, confocal and transmission electron microscopy, functional assays, in vivo RNAi, and a new myelin coculture. We will determine (Aim 1) whether deleting this Kv3 channel from CD4+ T cells suppresses EAE induction and progression via impaired T cell activation, (Aim 2) whether deleting this channel from CNS neurons ameliorates autoimmune-induced axonal injury, and (Aim 3) how this channel regulates pathogenic interactions between T cells and axons in autoimmune-induced injury. This project is innovative because this is the first study to show that a Kv channel regulates the function of both immune cells and neurons. This project is significant because the findings of this project will provide novel mechanistic insights into pathogenic interactions between T cells and neurons, and hence may contribute to a novel treatment strategy for MS through simultaneously suppressing immune response and rescuing injured axons.
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