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Principal Investigator: Junfang Wu
Organization: UNIVERSITY OF MARYLAND BALTIMORE
Fiscal Year: 2024
Award: $227,884
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary
Despite considerable research over the past 30 years, there is still no established effective treatment to
improve recovery following spinal cord injury (SCI). In part, this reflects incomplete understanding of the
complex secondary pathobiological mechanisms involved. The aim of our research is to understand the cellular
and molecular mechanisms responsible for post-injury neuroinflammation in order to allow future development
of novel therapies. The voltage-gated proton channel Hv1 is a newly discovered ion channel, highly expressed
in resting microglia of the brain. Under pathological conditions, microglial Hv1 is required for NADPH oxidase
(NOX)-dependent generation of ROS (reactive oxygen species) by providing charge compensation for
exported electrons and relieving intracellular acidosis. Thus, Hv1 is a unique target for controlling multiple NOX
activities and ROS production. However, neither the precise signaling mechanisms underlying this finding nor
critical role of Hv1 in the pathophysiology of SCI are fully understood. Based on our preliminary data, we will
test the hypothesis that microglial Hv1 functions as a key mechanism in neuroinflammation, through altered
NOX2/ROS/IFN- signaling that modulates microglia-astrocyte interaction, thus affecting long-term
neurological outcomes after SCI.
We will use systemic or microglial Hv1 KO, microglial NOX2 KO transgenic mice and in vivo and in vitro
innovatively technologies to determine the mechanisms of SCI-triggered Hv1 elevation on post-injury
neuroinflammation. Aim 1 will determine the function and mechanisms of the Hv1 in neuroinflammation
after SCI. Multiple quantitative assessments of microglia-mediated neuroinflammation will be combined with
genetic or pharmacological intervention targeting Hv1 to test the hypothesis that SCI-induced microglial Hv1
activation mediates detrimental neuroinflammation and functional deficits through altered microglial
NOX2/ROS signaling. Aim 2 will elucidate the role of microglial NOX2 in post-injury neuroinflammation.
We will utilize genetic intervention to delete Hv1-dependent up-regulation of NOX2 in microglia, and evaluate
the effects on microglial NOX2 coupling to Hv1 on neuroinflammation after SCI. Aim 3 will identify critical
role of Hv1/NOX2-derived ROS/IFN- in SCI-chronic neuroinflammation through microglia-astrocyte
interaction. Complimentary cellular, molecular, and genetic approaches will be used to test the hypothesis
that Hv1/NOX2-mediated microglial ROS activates pro-inflammatory astrocytes resulting in secreting IFN that
in turn reinforces microglial inflammation, thus contributes to astrocytes dysfunction and neuronal damage.
Our study will be the first to implicate microglial Hv1/NOX2/ROS/IFN- signaling in the pathophysiology
of SCI, leading to novel treatment approaches for SCI. Given the proposed roles for Hv1 in other inflammatory
models, Hv1 signaling represents a generic mechanism relevant to other neuroinflammatory states.
Terms: <Acidosis><Acquired brain injury><Active Oxygen><Acute><Address><Affect><Astrocytes><Astrocytus><Astroglia><Attenuated><Brain><Brain Injuries><Brain Ischemia><Brain Nervous System><Bruise><CNS Nervous System><Cell Communication and Signaling><Cell Death><Cell Signaling><Central Nervous System><Charge><Chronic><Clinical><Coenzyme II><Compensation><Complex><Contusions><Coupling><Cytoplasm><DNA Therapy><Data><Development><Dysfunction><Electrons><Encephalon><Failure><Functional disorder><Future><Gene Transfer Clinical><Generations><Genetic><Genetic Intervention><Glia><Glial Cells><Goals><H+ element><Hortega cell><Hydrogen Ions><Hyperesthesia><Hyperesthetic Sensations><IFN><Immune system><Impairment><In Vitro><Inflammation><Inflammatory><Injury><Interferons><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Ion Channel><Ionic Channels><Ischemic Encephalopathy><KO mice><Knock-out Mice><Knockout Mice><Kolliker's reticulum><Mediating><Membrane Channels><Mice><Mice Mammals><Microglia><Modeling><Molecular><Murine><Mus><NAD phosphate><NAD(H) phosphate><NADH phosphate><NADP><NADPH><NADPH Oxidase><Negative Beta Particle><Negatrons><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neuroglia><Neuroglial Cells><Neurologic><Neurologic Dysfunctions><Neurologic outcome><Neurological><Neurological outcome><Neurons><Nicotinamide-Adenine Dinucleotide Phosphate><Non-neuronal cell><Nonneuronal cell><Null Mouse><Oxidative Burst><Oxyesthesia><Oxyesthesias><Oxygen Radicals><Pathologic><Pathway interactions><Phagocytes><Phagocytic Cell><Phenotype><Physiopathology><Pro-Oxidants><Process><Production><Protons><Reactive Oxygen Species><Recovery><Recovery of Function><Reporting><Research><Respiratory Burst><Rest><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Spinal Cord Contusions><Spinal Cord Trauma><Spinal Trauma><Spinal cord injured><Spinal cord injury><Testing><Therapeutic Intervention><Transgenic Mice><Traumatic Myelopathy><Triphosphopyridine Nucleotide><Up-Regulation><Upregulation><amebocyte><astrocytic glia><attenuate><attenuates><biological signal transduction><brain damage><brain-injured><developmental><effective therapy><effective treatment><functional improvement><functional outcomes><functional recovery><gene repair therapy><gene therapy><gene-based therapy><genetic approach><genetic strategy><genetic therapy><genomic therapy><gitter cell><glial activation><glial cell activation><improve function><improved><improved functional outcomes><in vivo><inhibitor><injuries><innovative technologies><insight><intervention therapy><interventional strategy><leukocyte oxidative burst><mesoglia><microglial cell><microgliocyte><mouse model><murine model><necrocytosis><nerve cell death><nerve cell loss><nerve cement><neural inflammation><neuroinflammation><neuroinflammatory><neurological dysfunction><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><neuropathic pain><neuroprotection><neuroprotective><neurotoxic><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><painful neuropathy><pathophysiology><pathway><perivascular glial cell><pharmacologic><social role><voltage>