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Principal Investigator: Justinn Barr
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $152,212
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
The airway epithelium serves as a barrier between the aerosol environment and the underlying
submucosa. Inhaled air often carries noxious agents and pathogens that can injure the lung. Severe lung injury
can lead to persistent inflammation, dysplastic repair, and permanent loss of gas exchange surface area. Injury
from common respiratory viral infection, such as influenza and SARS-CoV-2, can lead to chronic lung disease
or exacerbation of lung conditions. Airway cells contribute to regeneration following lung injury, although the
heterogeneity of airway cell identity following lung repair is incompletely understood.
My research centers on rare airway cell types and their function in the post-viral lung. We have
previously studied the differentiation of an unexpected airway cell type, tuft cells, during repair. Using single
nucleus expression and accessible chromatin sequencing to survey airway cells following influenza injury, we
identify a rare airway cell present in the post-viral lung, Microfold (M) cells. M cells have not been studied in the
lung but in other contexts associate with lymphoid follicles, where they function to capture and deliver luminal
antigens and secrete chemokines. The proposed research will identify pulmonary M cell progenitors and
determine mechanisms required for M cell differentiation. This proposal uncovers M cells as part of a follicle
associated epithelium (FAE) overlying induced bronchus associated lymphoid tissue (iBALT), implying M cells
function to promote mucosal immune responses. The proposed aims will define the role of M cells in lung
immune surveillance. My future research program will test the role of M cells in secondary bacterial infection,
as much of the morbidity of pulmonary influenza infections can be attributed to secondary bacterial infection.
Examining interactions between M cells and the immune compartment will contribute to our understanding of
immune regulation during post-viral chronic inflammation.
A second outcome from my focus on airway repair following severe influenza infection is an effort to
promote the resolution of basal-like scar tissue into normal alveolar epithelium. Bronchiolization of the distal
airway is a hallmark of multiple human lung diseases, and providing regenerative therapies will require detailed
understanding of the regulation of basal-like cells. I propose defining a genetic mouse model that promotes
differentiation of alveolar basal-like cells into alveolar epithelial cell fates.
My primary mentor is Dr. Xin Sun, a leader in the field of lung biology who has made fundamental
discoveries in lung development and disease. I will receive guidance from my mentorship committee, a group
with expertise in lung biology and physiology, immunology and epigenetics. The proposed experiments and
training plan will further my skills in bioinformatics and immunology. This research will be conducted at
University of California San Diego, a leading research institution with necessary resources and a collaborative
scientific community.
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disease rate><Mucosal Immune Responses><Nasal Epithelium><Natural regeneration><Nucleus><Null Mouse><Orthomyxovirus Type A><Outcome><Pathway interactions><Pb element><Peyer's Patches><Physiology><Pneumonia><Postdoc><Postdoctoral Fellow><Predisposition><Progenitor Cells><Pulmonary Body System><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Organ System><Receptor Signaling><Regeneration><Regulation><Research><Research Associate><Research Resources><Resolution><Resources><Respiratory Epithelium><Respiratory System><Respiratory Tracts><Respiratory tract structure><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><SIS cytokines><Scars><Secondary to><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><Single-Nucleus Sequencing><Sorting><Structure of respiratory epithelium><Subcellular Process><Submucosa><Surface><Survey Instrument><Surveys><Susceptibility><Testing><Tissues><Tracheal Epithelium><Training><Transcription Factor Proto-Oncogene><Transcription factor genes><Type A Influenza><Universities><Viral><Viral Diseases><Viral Respiratory Tract Infection><Virus Diseases><Wuhan coronavirus><airway epithelium><airway injury><airway repair><alveolar epithelium><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><bacteria infection><bacterial disease><bowel><cell motility><cell type><cellular differentiation><chemoattractant cytokine><chemokine><chronic pulmonary disease><conditional knock-out><conditional knockout><coronavirus disease 2019 virus><coronavirus disease-19 virus><diffuse interstitial pulmonary fibrosis><disease of the lung><disorder of the lung><enzyme linked immunoassay><epigenetically><experiment><experimental research><experimental study><experiments><flu infection><flu virus infection><hCoV19><heavy metal Pb><heavy metal lead><idiopathic pulmonary fibrosis><immune modulation><immune regulation><immunogen><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><impaired airway><in vivo><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><injured airway><injuries><injury and repair><lung development><lung disorder><lung function><lung injury><lung repair><lung tissue repair><mouse model><mucosa associated lymphoid tissue><mucosa associated lymphoid-tissue><mucosa-associated lymphoid tissue><mucosal site><murine model><nCoV2><pathogen><pathway><post-doc><post-doctoral><post-doctoral trainee><progenitor><programs><pulmonary><pulmonary damage><pulmonary function><pulmonary injury><pulmonary repair><pulmonary tissue damage><pulmonary tissue injury><regenerate><regeneration based therapy><regeneration therapy><regenerative repair><regenerative therapeutics><regenerative therapy><repair><repaired><research associates><resilience><resilient><resolutions><respiratory injury><respiratory tract epithelium><respiratory tract injury><sNuc-Seq><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><skills><snRNA sequencing><snRNA-seq><social role><stem><stem cells><transcription factor><viral infection><viral respiratory infection><virus infection><virus-induced disease>