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Principal Investigator: Matthew D Cain
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $464,714
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY/ABSTRACT
Viral infections are now recognized as risk factors for diseases of progressive pathological forgetting,
supporting a new paradigm in neuroimmunology whereby innate immune molecules that function as
modulators of a variety of normal CNS functions induce neurodegenerative diseases during host-pathogen
responses. Studying virus-mediated cognitive dysfunction through the multidisciplinary prism of immunology,
neuroscience, and virology is critical for the identification of novel mechanisms of disease, discovery of
neuroimaging tools and therapeutic treatments for a wide range of diseases of memory disorder. In my
laboratory we made unanticipated, paradigm-shifting discoveries of the roles of CNS infiltrating mononuclear
cells in microglial-mediated synapse elimination, disrupted adult neurogenesis, and generation of neurotoxic
astrocytes using novel models of recovery from encephalitogenic flaviviruses, West Nile (WNV) and Zika
(ZIKV) viruses. We identified classical complement proteins and cytokine receptor signaling as novel molecular
mediators that regulate synapse elimination, neural stem cell (NSC) fates, neuron-microglia and microglia-
astrocyte crosstalk within cortical structures that regulate memory formation and maintenance. We have also
begun leveraging novel neuroimaging modalities to develop biomarkers that may be used to predict and
monitor patients at risk for memory disorders. Our aim is to understand the mechanisms that induce alterations
in synaptic connections and methods of repair that contribute to disruption of neuronal networks after recovery
from viral infections. Our research program focuses on three broad areas related to the roles and regulation of
innate immune molecules involved in spatial learning using novel murine models of post-infectious cognitive
dysfunction. First, using genetic, pharmacologic and PET-MRI, we will identify and define molecular
interactions between T cells and microglia or neurons that drive the generation and maintenance of resident
memory T cells that promote cognitive dysfunction. We will use scRNAseq under BSL3 conditions to screen for
genes and pathways to be targeted via cell-specific deletion of cytokine or chemokine receptors, or
administration of agents that inhibit or enhance pathways. We will also develop diagnostic tools that employ
ABSL3 PET-MRI. Second, we will define how microglia-astrocyte-NSC interactions in the context of recovery
from CNS viral infections limit repair and recovery. We will use global and conditional gene targeting in mice to
delineate the in vivo roles of cytokines in neural cell types that regulate astrocyte inflammasome activation and
its relationship to neuronal and synapse recovery. We will also define innate immune mechanisms that direct
and maintain astrogenosis during acute viral infection and recovery using PET-MRI detection of P2X7R, a
marker of reactive astrocytes. Finally, will utilize reporter mice/fate mapping, bone marrow chimeras and
scRNAseq to delineate the cytokine-mediated roles of myeloid cells in the generation of neurotoxic astrocytes
during WNND recovery. Third, we will examine innate immune mechanisms triggered after viral infections that
negatively impact cortical connectivity and determine whether neuroimaging can be used to predict and follow
this process. Specifically, we will combine genetic approaches with functional optical intrinsic signal imaging of
hemoglobin and calcium dynamics to define mechanisms that negatively impact cortical connectivity. Our
research program will define new concepts in the molecular neuroimmunological regulation of synapses, T cell
and glial interactions, inform studies of related processes throughout the nervous systems, and will likely
enhance our understanding of neurodegenerative and other disorders of memory.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AD dementia><Acute><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Amentia><Area><Astrocytes><Astrocytus><Astroglia><Award><Binding><Biological Markers><Bone Marrow><Bone Marrow Reticuloendothelial System><COVID-19 virus><COVID19 virus><Calcium><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Cells><Central Nervous System Viral Diseases><Central Nervous System Viral Infections><Chemokine Receptor Gene><Chimera><Chimera organism><Clinical Trials><CoV-2><CoV2><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive Retention Disorders><Cognitive decline><Cognitive function abnormal><Complement><Complement Proteins><Cytokine Receptors><Degenerative Neurologic 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Degenerative Diseases><Neural Stem Cell><Neural degenerative Disorders><Neurocognitive Deficit><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neuroimmune><Neurologic Body System><Neurologic Degenerative Conditions><Neurologic Organ System><Neuron Degeneration><Neurons><Neurosciences><Nuclear Magnetic Resonance Imaging><Optics><Orthoflavivirus><PET><PET Scan><PET imaging><PETSCAN><PETT><Pathologic><Pathway interactions><Patient Monitoring><Patients><Persons><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Primary Senile Degenerative Dementia><Process><Progressive Disease><RNA Viruses><Rad.-PET><Receptor Signaling><Recovery><Regulation><Reporter><Research><Risk><Risk Factors><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Survivors><Synapses><Synaptic><Syndrome><T-Cells><T-Lymphocyte><Therapeutic><Transmission><Viral CNS Infections><Viral Diseases><Virus><Virus Diseases><WNV><West Nile virus><Wuhan coronavirus><ZIKV><Zeugmatography><Zika Virus><adult neurogenesis><astrocytic glia><bio-markers><biologic marker><biological signal transduction><biomarker><cell type><chemokine receptor><chimeras><cognitive dysfunction><cognitive loss><complementation><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytokine><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><diagnostic tool><forgetting><genetic approach><genetic strategy><gitter cell><hCoV19><imaging><immunoneurology><in vivo><innate immune mechanisms><intelligence quotient deficit><mesoglia><microglial cell><microgliocyte><mouse model><multidisciplinary><murine model><nCoV2><nerve stem cell><neural degeneration><neural imaging><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neuro-imaging><neurocognitive decline><neurocognitive impairment><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroimaging><neuroimmunology><neurological degeneration><neurological imaging><neuron progenitors><neuronal><neuronal degeneration><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuroprogenitor><neurotoxic><neurotropic><novel><optical><pathogen><pathway><perivascular glial cell><pharmacologic><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><primary degenerative dementia><progenitor cell fate><progenitor fate><programs><repair><repaired><resident memory T cell><response><scRNA-seq><senile dementia of the Alzheimer type><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem and progenitor cell fate><stem cell fate><synapse><thymus derived lymphocyte><tissue resident memory T cell><tool><transmission process><vector-borne infection><vectorborne infection><viral infection><virology><virus infection><virus-induced disease><zikav>