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Principal Investigator: CHEN GU
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $521,130
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <4-Aminopyridine><4-Pyridinamine><Action Potentials><Adoptive Transfer><Affect><Assay><Auditory><Autoimmune><Autoimmune Diseases><Axon><Bioassay><Biological Assay><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CNS Injury><CNS Nervous System><CNS autoimmunity><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cells><Cellular Immune Function><Central Nervous System><Chronic><Co-culture><Cocultivation><Coculture><Coculture Techniques><Connector Neuron><Data><Degenerative Neurologic Disorders><Demyelinations><Development><Disease Progression><Disease remission><Disseminated Sclerosis><Dominantly-Inherited Spinocerebellar Ataxias><Drugs><Dysfunction><EAE><Experimental Allergic Encephalitis><Experimental Allergic Encephalomyelitis><Experimental Autoimmune Encephalitis><Experimental Autoimmune Encephalomyelitis><FDA approved><Female><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Generations><Genetic Alteration><Genetic Change><Genetic defect><Image><Imaging Procedures><Imaging Technics><Imaging Techniques><Immune><Immune infiltrates><Immune response><Immunes><Immunological response><Immunomodulation><Impairment><Inflammation><Inflammation Mediators><Inflammatory><Injury><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><Ion Channel Gating><Ion Channel Gatings><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Lesion><Link><Locomotor Activity><LoxP-flanked allele><Lymphocytic Infiltrate><MS Lesions><MS patient><MS treatment><Medication><Medulla Spinalis><Mice><Mice Mammals><Modeling><Motor Activity><Motor Cell><Motor Neurons><Multiple Sclerosis><Multiple Sclerosis Lesions><Murine><Mus><Mutation><Myelin><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Deficit><Neurologic Degenerative Conditions><Neuron Degeneration><Neuronal Injury><Neurons><Neurophysiology - biologic function><Null Mouse><Outcome><Parvalbumins><Pathogenicity><Pathology><Patients><Pharmaceutical Preparations><Physiopathology><Play><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Protein Biochemistry><Protein/Amino Acid Biochemistry><Proteins><Pymadine><QOL><Quality of life><RNA Interference><RNA Silencing><RNAi><Regulation><Relapse><Remission><Research><Role><Sequence-Specific Posttranscriptional Gene Silencing><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Spinal Cord><Spinocerebellar Ataxias><Spinocerebellar Atrophies><T cell infiltration><T-Cell Activation><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Testing><Therapeutic Effect><Transgenic Mice><Transmission Electron Microscopy><Up-Regulation><Upregulation><activate T cells><autoimmune condition><autoimmune disorder><autoimmune encephalomyelitis><autoimmunity disease><axon damage><axon injury><axonal damage><axonal injury><biological signal transduction><cell culture><cell cultures><cell type><central nervous system autoimmunity><central nervous system demyelinating disease><central nervous system demyelinating disorder><central nervous system injury><conditional knock-out><conditional knockout><confocal imaging><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><demyelinate><developmental><drug/agent><excitotoxic><excitotoxicity><flow cytophotometry><floxed><floxed allele><genome mutation><host response><imaging><immune cell infiltrate><immune function><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><in vivo><inflammatory mediator><injured CNS><injuries><injury and repair><innovate><innovation><innovative><insight><insular sclerosis><interdisciplinary approach><knock-down><knockdown><male><motoneuron><mouse model><multidisciplinary approach><multiple sclerosis patient><multiple sclerosis therapy><multiple sclerosis treatment><murine model><neural degeneration><neural function><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuron injury><neuronal><neuronal degeneration><neuroprotection><neuroprotective><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><patch clamp><pathophysiology><patients with MS><patients with multiple sclerosis><people with Multiple sclerosis><preservation><repair strategy><social role><symptom treatment><symptomatic treatment><therapeutic target><thymus derived lymphocyte><trafficking><treat symptom><treatment strategy><voltage><walking pace><walking speed>