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Principal Investigator: ANDREW P LANE
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $653,305
Funding agency: National Institute on Deafness and Other Communication Disorders
Project summary:
The olfactory epithelium is situated in the nasal passages at the interface with the environment
– a location that makes it vulnerable to damage by both infectious and non-microbial threats.
While the innate immune defenses of the respiratory epithelium are increasingly well
understood, the immune mechanisms protecting the delicate olfactory neuroepithelium have not
been fully elucidated. Inflammation of the olfactory epithelium can result in the loss of the sense
of smell, which is a debilitating health problem in the United States significantly impacting the
quality of life of affected individuals. The current COVID-19 pandemic has highlighted how viral
infection and the local immune response of the olfactory epithelium can impair sense of smell
function, although the mechanism is unknown. We hypothesize that the lining cells of the
olfactory epithelium, called sustentacular cells, play a critical role protecting the underlying
neurons by maintaining a strong physical barrier and providing a supporting framework. Once
damaged, olfactory tissue has a remarkable and unique neuroregenerative capacity, allowing
rapid repair by creation of new neurons. The signals that drive and regulate regeneration by
olfactory progenitor cells are unclear. Our preliminary studies in mice reveal that regulated
inflammation is important to initiating normal repair after olfactory injury. We also have found
that olfactory stem cells deep in the mucosa are capable of communicating with immune cells to
mediate inflammation. In this way, we propose that olfactory stem cells provide innate immune
protection to the epithelium. We hypothesize that injury to the surface barrier exposes olfactory
stem cells to stimuli that drive inflammation and replacement of apical cells. The overall goal of
this proposal is to explore neuroepithelial-immune interactions in the olfactory epithelium. In
aim 1, we will investigate the innate immune activity of olfactory stem cells and demonstrate
whether inflammatory cells and their chemical signals modulate basal cell function. In aim 2, we
will explore the role of stem cells in modulating the immune response and in fighting infection.
Finally, in aim 3, we will study the immune response of sustentacular cells and olfactory stem
cells to inflammatory signals related to two common causes of loss of the sense of smell: nasal
polyps and infection with SARS-CoV-2. These studies will significantly advance current
knowledge about the olfactory system and create an opportunity to develop innovative therapies
for important health conditions impacting the sense of smell.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Address><Affect><Airway mucosa><Anatomic Sites><Anatomic structures><Anatomy><Anosmia><Apical><Basal Cell><Basal Transcription Factor><Basal transcription factor genes><Bipolar Neuron><Body Tissues><Brain><Brain Nervous System><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infection><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 virus><COVID-19 virus infection><COVID-19 years><COVID19 infection><COVID19 virus><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Function><Cell Growth in Number><Cell Interaction><Cell Line><Cell Multiplication><Cell Physiology><Cell Process><Cell Proliferation><Cell Signaling><Cell-to-Cell Interaction><CellLine><Cells><Cellular Function><Cellular Immune Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Chemicals><Chemotactic Cytokines><Chronic><CoV-2><CoV2><Communication><Encephalon><Environment><Epithelium><Foundations><General Transcription Factor Gene><General Transcription Factors><Genes><Goals><Health><Homologous Chemotactic Cytokines><Human><Immune><Immune infiltrates><Immune response><Immune signaling><Immune system><Immunes><Immunological response><Immunomodulation><Impairment><In Vitro><Individual><Infection><Inflammation><Inflammatory><Inhalation><Inhaling><Injury><Innate Immune Response><Innovative Therapy><Intercrines><Intracellular Communication and Signaling><Irritants><Knowledge><Location><Maintenance><Mediating><Mesenchymal><Mice><Mice Mammals><Microbe><Modeling><Modern Man><Mucociliary Clearance><Mucociliary Transport><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Nasal><Nasal Cavity Polyp><Nasal Passages Nose><Nasal Polyps><Natural regeneration><Nerve Cells><Nerve Regeneration><Nerve Unit><Neural Cell><Neuro-regeneration><Neurocyte><Neuroepithelial><Neuroimmune><Neuroimmune Mechanisms><Neuroimmune Processes><Neuroimmunomodulation><Neurons><Neuropeptide Tyrosine><Neuroregeneration><Nose><Olfaction><Olfactory Epithelial Cell><Olfactory Epithelium><Olfactory Mucosa><Olfactory Pathways><Olfactory system><Organ><Pathway interactions><Pattern recognition receptor><Phagocytes><Phagocytic Cell><Physiologic><Physiological><Play><Process><Progenitor Cells><Pseudostratified Epithelium><QOL><Quality of life><RNA Seq><RNA sequencing><RNAseq><Receptor Signaling><Regeneration><Research><Respiratory Epithelium><Respiratory Mucosa><Respiratory System, Nose, Nasal Passages><Rest><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><Sampling><Sensory><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 CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><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 coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Shapes><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Smell><Smell Perception><Stem Cell like><Stimulus><Strains Cell Lines><Structure><Structure of respiratory epithelium><Subcellular Process><Surface><Testing><Tissues><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><United States><Viral Diseases><Virus><Virus Diseases><Work><Wuhan coronavirus><airway epithelium><amebocyte><anosphrasia><biological signal transduction><cell type><cellular differentiation><chemoattractant cytokine><chemokine><cilium motility><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><cultured cell line><cytokine><differential expression><differentially expressed><epithelial injury><experiment><experimental research><experimental study><experiments><fighting><hCoV19><host response><immune cell infiltrate><immune function><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><injuries><insight><loss of smell><mouse model><murine model><nCoV2><nervous system regeneration><neural regeneration><neuroepithelium><neuronal><neuropeptide Y><neuroregenerative><notch><notch protein><notch receptors><novel><odor perception><olfactory circuitry><olfactory circuits><olfactory loss><olfactory perception><pathogen><pathway><progenitor><reconstitute><reconstitution><regenerate><regenerated nerve><repair><repaired><respiratory tract epithelium><response><scRNA-seq><scaffold><scaffolding><self-renew><self-renewal><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem cell characteristics><stem cells><stemness><sustentacular cell><trafficking><transcription factor><transcriptional differences><transcriptome sequencing><transcriptomic sequencing><transcriptomics><viral infection><virus infection><virus-induced disease>