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Principal Investigator: William John Zacharias
Organization: CINCINNATI CHILDRENS HOSP MED CTR
Fiscal Year: 2024
Award: $569,920
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
The alveolar region of the mammalian lung is a complex, precisely structured tissue required for the primary
functions of the respiratory system, gas exchange and tissue oxygenation. Damage to the alveolar epithelium
plays a central role in human lung diseases including Acute Respiratory Distress Syndrome (ARDS), a
prevalent, high impact clinical disorder that affects up to 5% of mechanically ventilated patients in the
developed world. The mortality rate of ARDS approaches 40%, and the recovery for ARDS survivors is
arduous, with a substantial burden of multi-system disability continuing 5 or more years following
hospitalization. Critically, while many ARDS survivors recover lung function, a subset of patients develops
persistently abnormal pulmonary function, imaging evidence of pulmonary scarring, and pulmonary symptoms
even years after ARDS. To date, no data exists regarding the mechanisms that guide ARDS recovery. These
challenges have been made more acute by the coronavirus pandemic, which has exposed a large proportion
of the human population to acute lung injury. An enormous population of patients is at risk of both acute and
chronic lung consequences of lung injury following coronavirus infection, emphasizing the clear and urgent
need for new regenerative therapies to promote recovery from acute lung disease.
Regeneration in many organs is driven by adult facultative progenitor cells. We recently discovered a facultative
progenitor cell in the mouse and human lung which participates in regeneration after viral injury we call alveolar
epithelial progenitors (AEPs). Progenitor cells control their chromatin carefully, as they must maintain more broad
potential than fully differentiated cells, and so a hallmark of progenitor chromatin state is regions of active
regulation between fully open and fully closed states, so called poised chromatin. Unique preliminary data from
our laboratory and review of the literature support the idea that the chromatin modifying complex PRC2 is a
critical regulator of the progenitor chromatin state of AEPs. In this application, using a combination of advanced
lung organoids and genetic mouse injury models, we will identify the temporal and functional requirements for
PRC2 function in lung progenitors, define the key binding partners and targets of the PRC2 complex in
maintenance of AEP progenitor state, and evaluate the genomic loci regulated by PRC2 complex activity
necessary for AEP-mediated alveolar regeneration. Understanding these fundamental mechanisms will provide
the framework needed to understand alveolar regenerative biology at a granular level and develop therapeutic
strategies to maintain and restore AT2 progenitor function to drive repair following infection and environmental
stress.
Terms: <21+ years old><ARDS><ATAC sequencing><ATAC-seq><ATACseq><Acute><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult><Adult ARDS><Adult Human><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Alveolar><Animals><Assay for Transposase-Accessible Chromatin using sequencing><Attention><Automobile Driving><Autoregulation><Binding><Biology><Body Tissues><COVID-19 infection><COVID-19 virus infection><COVID19 infection><CUT&RUN><Cell Body><Cell Differentiation><Cell Differentiation process><Cells><ChIP Sequencing><ChIP-seq><ChIPseq><Chemicals><Chromatin><Chromatin Remodeling Complex><Chromatin Remodeling Factor><Chronic><Cleavage Targets and Release Using Nuclease><Cleavage Under Targets and Release Using Nuclease><Clinical><Co-Immunoprecipitations><CoV pandemic><Complex><Computer Analysis><Coronaviridae Infections><Coronavirus Infections><Cre driver><Da Nang Lung><Data><Death Rate><Deposit><Deposition><Disease><Disorder><Drug Targeting><Drugs><Ensure><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><Fibrotic lesions in lung><Future><Gases><Gene Down-Regulation><Gene Transcription><Genetic><Genetic Transcription><Genome><Genomics><Grant><Grippe><Homeostasis><Hospital Admission><Hospitalization><Human><Image><In Vitro><Infection><Influenza><Injury><Laboratories><Literature><Lung><Lung Alveolar Epithelia><Lung Diseases><Lung Respiratory System><Lung damage><Lung scar><Lung symptom><Lung tissue regeneration><Lung tissue scar><Maintenance><Mechanical ventilation><Mediating><Medication><Mice><Mice Mammals><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Murine><Mus><Natural regeneration><Non-Polyadenylated RNA><Organ><Organoids><Patients><Pharmaceutical Preparations><Phenotype><Physiological Homeostasis><Play><Pneumonia><Population><Process><Progenitor Cells><Proliferating><Proteomics><Publishing><Pulmonary Body System><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Organ System><Pulmonary Scar><Pulmonary Tissue fibrosis><RNA><RNA Expression><RNA Gene Products><Recovery><Regeneration><Regulation><Respiratory System><Respiratory Tracts><Respiratory physiology><Respiratory tract structure><Review Literature><Ribonucleic Acid><Risk><Role><SARS-CoV-2 infection><SARS-CoV2 infection><Scarring at the lung><Scarring in the lung><Severe acute respiratory syndrome coronavirus 2 infection><Shock Lung><Specific qualifier value><Specificity><Specified><Stable Populations><Stiff lung><Stress><Structure><Survivors><System><Testing><Therapeutic><Time><Tissues><Transcription><Transcription Repression><Transcriptional Repression><Ventilator><Viral><Work><adult progenitor><adult stem cell><adulthood><aged mice><aged mouse><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><cellular differentiation><chromatin immunoprecipitation-sequencing><chromatin modifier><combinatorial><computational analyses><computational analysis><computer analyses><conformation><conformational><conformational state><conformationally><conformations><constitutive expression><constitutive gene expression><coronavirus disease 2019 infection><coronavirus pandemic><disability><disease of the lung><disorder of the lung><driving><drug/agent><elderly mice><epigenetically><epigenomics><epithelial progenitor><epithelial progenitor cell><epithelial stem cell><epithelium regeneration><exhaustion><fibrotic lung><flu infection><flu virus infection><gene locus><gene repression><genetic locus><genomic location><genomic locus><healing><imaging><improved><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 flu><infected with flu virus><infected with influenza><infected with influenza virus><infected with severe acute respiratory syndrome coronavirus 2><influenza infection><influenza virus infection><injuries><insight><life span><lifespan><lung disorder><lung function><lung injury><lung regeneration><mechanical respiratory assist><mechanically ventilated><mortality rate><mortality ratio><novel><old mice><patient population><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><premature><prematurity><prevent><preventing><progenitor><progenitor cell function><progenitor cell population><progenitor cell proliferation><progenitor cell regeneration><progenitor cell self renewal><progenitor function><progenitor population><progenitor proliferation><progenitor regeneration><progenitor self renewal><pulmonary><pulmonary damage><pulmonary function><pulmonary injury><pulmonary regeneration><pulmonary symptom><pulmonary tissue damage><pulmonary tissue injury><regenerate><regenerate epithelium><regeneration based therapy><regeneration biology><regeneration potential><regeneration therapy><regenerative><regenerative biology><regenerative potential><regenerative therapeutics><regenerative therapy><repair><repaired><respiratory function><self-renew><self-renewal><social role><somatic progenitor><somatic stem cell><stem and progenitor cell function><stem and progenitor cell population><stem and progenitor cell proliferation><stem and progenitor cell regeneration><stem and progenitor cell self renewal><stem and progenitor function><stem cell function><stem cell population><stem cell proliferation><stem cell regeneration><stem cell self renewal><stem cells><therapeutic agent development><therapeutic development><tissue oxygen saturation><tissue oxygenation><wet lung>