Document text
Principal Investigator: Carol H Yan
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $191,873
Funding agency: National Institute on Deafness and Other Communication Disorders
PROJECT SUMMARY:
Persistent post-viral olfactory dysfunction (PVOD) is associated with a large spectrum of viruses with
significant adverse impacts on quality of life. The molecular and cellular changes in the olfactory epithelium in
cases of persistent PVOD have not been well characterized. Specifically, we are interested in studying the
response of the olfactory stem cells which are responsible for peripheral olfactory neurogenesis and the
regeneration of olfactory epithelium (OE) following injury. In the olfactory system, constitutive TNF-mediated
inflammation suppresses stem cell differentiation while elevated levels of IL-6 are correlated with persistent
olfactory loss. These findings raised the possibility that prolonged anti-viral signaling will inhibit olfactory stem
cell differentiation and thus impair OE regeneration and result in olfactory dysfunction. In our preliminary data,
we show evidence of increased type I and II interferon signaling in the olfactory mucosa of patients with SARS-
CoV-2 infection and elevated expression of interferon signaling genes in the olfactory stem cells of mice infected
with H1N1 influenza A. Furthermore, Notch signaling is known to be important in maintaining horizontal basal
cells (one of the olfactory stem cell populations) in an undifferentiated state. Thus, we hypothesize that persistent
PVOD may be related to an anti-viral olfactory epithelial response driven by the host innate immune system that
translates to a chronic upregulation of inflammatory signaling genes in the olfactory stem cells and an
upregulation of Notch signaling to result in stem cell quiescence and impaired regeneration of the olfactory
epithelium.
In the proposed studies, we will investigate the chronic anti-viral and pro-inflammatory signaling pathways
in the local olfactory epithelial environment and olfactory stem cells through cytokine analysis and single cell
transcriptomic sequencing (Aim 1). We will correlate expression levels of these cytokines and interferon
stimulated genes with objective measures of olfactory function in humans with PVOD. Furthermore, we will
assess the effects of cytokines directly on cultured olfactory stem cells in vitro. In Aim 2, we will assess the
impact of viral infection on the Notch signaling pathway in olfactory stem cells using individual cell fate mapping
with quantitative immunostaining and single cell transcriptomic sequencing. In vivo testing of Notch antagonists
using a mouse model of viral infection will help determine the reversibility of the viral impact and the efficacy of
therapeutic targeting of the Notch pathway. The incorporation of both mouse and human models in this study
will allow for precise genetic manipulation and functional testing to assess olfactory epithelial cell fate as well as
permit direct translation of post-viral changes in gene expression on clinical outcomes of olfaction. Together,
these studies will help elucidate the cellular and molecular mechanisms for persistent post-viral olfactory loss
that may shed light on potential pathways for future therapeutics.
Terms: <(IFN) α><(IFN)-α><(IFN)α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Address><Alferon><Anosmia><Anti-viral Response><Area><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Basal Cell><Behavior><Body System><Body Tissues><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 virus><COVID-19 virus infection><COVID-19 years><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Signaling><Cells><Chronic><Clinical><CoV-2><CoV2><Coronavirus Infectious Disease 2019><Data><Development><Dysfunction><Environment><Functional disorder><Future><Gene Expression><Genes><Grippe><H1N1><H1N1 Virus><HPGF><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><IFN><IFN Alpha><IFN α><IFN-Gamma><IFN-beta 2><IFN-g><IFN-α><IFN-γ><IFNB2><IFNG><IFNa><IFNα><IFNγ><IL-6><IL6 Protein><Immune Interferon><Immune response><Immunological response><Impairment><In Vitro><In vivo analysis><Individual><Infection><Inflammation><Inflammatory><Influenza><Influenza A><Influenza A Virus, H1N1 Subtype><Influenza A virus><Influenza Virus><Influenza Viruses Type A><Influenzavirus A><Injury><Innate Immune Response><Innate Immune System><Interferon Alfa-n3><Interferon Gamma><Interferon Type I><Interferon Type II><Interferon alpha><Interferon-α><Interferons><Interleukin-6><Intracellular Communication and Signaling><Knowledge><Leukocyte Interferon><Light><Link><Lymphoblast Interferon><Lymphoblastoid Interferon><MGI-2><Maps><Measures><Mediating><Mice><Mice Mammals><Modern Man><Molecular><Mucosa><Mucosal Tissue><Mucous Membrane><Mucous body substance><Mucus><Murine><Mus><Myeloid Differentiation-Inducing Protein><Natural regeneration><Notch Signaling Pathway><Olfaction><Olfactory Epithelial Cell><Olfactory Epithelium><Olfactory Mucosa><Olfactory Pathways><Olfactory dysfunction><Olfactory system><Organ System><Orthomyxovirus Type A><Outcome><Pathway interactions><Peripheral><Photoradiation><Physiopathology><Plasmacytoma Growth Factor><Population><Progenitor Cells><Proliferating><Proteolysis and Signaling Pathway of Notch><QOL><Quality of life><RNA Seq><RNA sequencing><RNAseq><Regeneration><Research><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 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><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><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><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Smell><Smell Perception><Testing><Therapeutic><Therapeutic Effect><Tissues><Translating><Translations><Treatment Efficacy><Type A Influenza><Undifferentiated><Up-Regulation><Upregulation><Viral><Viral Diseases><Virus><Virus Diseases><WNT Signaling Pathway><WNT signaling><Wuhan coronavirus><anosphrasia><antagonism><antagonist><biological signal transduction><cell behavior><cell regeneration><cellular behavior><cellular differentiation><cellular regeneration><compare to control><comparison control><coronavirus disease 2019><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 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytokine><developmental><epithelium regeneration><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><hCoV19><host response><human model><immune system response><immunoresponse><in vivo><in vivo evaluation><in vivo testing><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><influenzavirus><inhibitor><injuries><interest><interferon beta 2><intervention efficacy><lFN-Gamma><loss of smell><model of human><mouse model><mucous><murine model><nCoV2><neurogenesis><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><notch><notch protein><notch receptors><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><odor perception><olfactory circuitry><olfactory circuits><olfactory impairment><olfactory loss><olfactory neurogenesis><olfactory perception><olfactory sensory neurons><pathophysiology><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><progenitor cell differentiation><progenitor cell population><progenitor cell proliferation><progenitor differentiation><progenitor population><progenitor proliferation><regenerate><regenerate epithelium><response><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><social role><stem and progenitor cell population><stem and progenitor cell proliferation><stem and progenitor differentiation><stem cell differentiation><stem cell population><stem cell proliferation><stem cells><therapeutic efficacy><therapeutic target><therapy efficacy><transcriptome profiling><transcriptome sequencing><transcriptomic profiling><transcriptomic sequencing><translation><viral infection><virus infection><virus-induced disease>