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Principal Investigator: Nicholas Varvel
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $331,013
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary/Abstract
Status epilepticus (SE) is a frequent neurological emergency that can reduce the quality of life of those
affected, produce cognitive deficits, and result in the development of epilepsy. Brain inflammation is an
invariable feature of seizure activity and is believed to contribute to neuronal demise and exacerbate the
deleterious behavioral consequences of unabated seizures. However, the involvement of blood-borne immune
cells in the brain's inflammatory reaction after seizures remains unresolved. We have recently identified a
subclass of circulating monocytes that invades brain tissue after seizures. Our findings indicate that blocking
monocyte infiltration, via Ccr2 knockout, reduces the deleterious consequences of SE. These results prompt us
to ask whether brain-invading monocytes are a novel therapeutic target to attenuate the adverse effects of
seizures, alleviate cognitive dysfunction, and inhibit the development of epilepsy after SE.
My hypothesis is that microglia-driven recruitment of brain-invading monocytes is a strong driver of SE-induced
neurobehavioral deficits and epileptogenesis in the weeks following SE because pro-inflammatory monocytes
migrate across the BBB promoting albumin extravasation into the brain. The lessons gleaned from completion
of the proposed studies will lead to insights into myeloid cell biology in epilepsy as well as brain disease in
general. The proposed studies will determine how the peripheral immune system can impact central immune
reactions and contribute to co-morbidities, leading to decreased quality of life in individuals afflicted with
epilepsy. Utilizing multiple techniques, my specific aims are designed to investigate and validate important
components of this hypothesis.
Aim 1. To test the hypothesis that brain-infiltrating monocytes engraft in the brain and maintain their
own pro-inflammatory profile, exacerbating a pro-inflammatory response in microglia.
Aim 2. To test the hypothesis that albumin extravasation is reliant on monocyte migration across the
BBB.
Aim 3. To determine if blocking monocyte brain entry exerts antiepileptogenic or disease modifying
effects after SE.
If our aims are achieved, then this would support continued efforts for targeting peripheral monocytes with
therapies, which could have a significant impact on reducing the burden of neurological disease, a major
mission of NINDS.
Terms: <5-Isothiocyanatofluorescein><Address><Adverse effects><Affect><Albumins><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Anti-epileptogenic><Antiepileptogenic><Anxiety><Astrocytosis><Attenuated><Behavior><Behavioral><Blood - brain barrier anatomy><Blood monocyte><Blood-Brain Barrier><Brain><Brain Diseases><Brain Disorders><Brain Inflammation><Brain Nervous System><CRE Recombinase><Candidate Disease Gene><Candidate Gene><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Clinical Trials><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Deterioration><Development><Dimensions><Disease><Disorder><Disturbance in cognition><EEG><Electroencephalogram><Electroencephalography><Encephalitis><Encephalon><Encephalon Diseases><Endothelium><Engraftment><Enterobacteria phage P1 Cre recombinase><Epilepsy><Epileptic Seizures><Epileptics><Epileptogenesis><Event><Extravasation><FITC><Fluorescein-5-isothiocyanate><Frequencies><Future><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Generalized Status Epilepticus><Glean><Hemato-Encephalic Barrier><Hortega cell><Immune><Immune reaction><Immune system><Immunes><Impaired cognition><In Vitro><Incidence><Individual><Infiltration><Inflammation><Inflammation Mediators><Inflammatory><Inflammatory Response><Interdisciplinary Research><Interdisciplinary Study><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Invaded><Knock-out><Knockout><Label><Leakage><Learning><Life><Marrow monocyte><Mediating><Medical emergency><Memory><Mice><Mice Mammals><Microglia><Mission><Modeling><Molecular><Multidisciplinary Collaboration><Multidisciplinary Research><Murine><Mus><Myeloid Cells><NINDS><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocyte><Neurologic Disorders><Neurological Disorders><Neurological emergencies><Neuron Degeneration><Neuronal Injury><Neurons><Outcome><Outcome Measure><Pathway interactions><Peripheral><Phenotype><Pilocarpine><Process><QOL><Quality of life><Reaction><Residual><Residual state><Rodent><Rodentia><Rodents Mammals><Role><Seizure Disorder><Seizures><Serum Albumin><Spillage><Status Epilepticus><Subcellular Process><Techniques><Testing><Transcript Expression Analyses><Transcript Expression Analysis><Weight><Work><amygdaloid nuclear complex><analyze gene expression><antagonism><antagonist><attenuate><attenuates><attenuation><bacteriophage P1 recombinase Cre><bloodbrain barrier><brain tissue><candidate identification><cell biology><co-morbid><co-morbidity><cognitive defects><cognitive dysfunction><cognitive loss><comorbidity><conditional knock-out><conditional knockout><design><designing><developmental><epilepsia><epileptogenic><gene expression analysis><gene expression assay><gitter cell><glial activation><glial cell activation><immunoreaction><in vivo><inflammatory mediator><insight><kainate><man><measurable outcome><mesoglia><microglial cell><microgliocyte><migration><monocyte><nano-string><nanostring><nerve cell death><nerve cell loss><neural degeneration><neural inflammation><neurobehavioral><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neurological disease><neuron cell death><neuron cell loss><neuron death><neuron injury><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal degeneration><neuronal loss><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><object recognition><outcome measurement><pathway><perivascular glial cell><pharmacologic><prevent><preventing><primary outcome><recruit><social role><success><therapeutic target><transcriptional profiling><weights>