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Principal Investigator: ANNE LYNCH
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $48,974
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
Lower respiratory infections were the fourth leading cause of death worldwide for nearly twenty years, and in
2019 with the onset of the COVID-19 pandemic, respiratory infections quickly rose to the leading cause of
death in many countries killing over 5 million people worldwide thus far. Our lungs are equipped with stem cells
to help us recover from lung related injury caused by inhaling toxins and pathogens. However, like in many
COVID-19 cases, the stem cells cannot always handle the injury burden. Alveolar type II (AT2) cells are
facultative stem cells of the lung that secrete surfactant and aid with gas exchange. During injury, AT2 cells
withdraw from homeostatic quiescence to repair damage through proliferation and differentiation into alveolar
type I (AT1) cells, then revert to quiescence when the epithelium is restored. The mechanism behind AT2 cell
reversible activation is unclear. To better understand this mechanism, we modeled respiratory injury in mice
through a murine parainfluenza virus known as Sendai virus. Lineage tracing of AT2 cells and proliferation
revealed that AT2 cells not only activate to perform in situ wound repair, but also cluster and proliferate at
regions away from damage, specific to the edges of airways and vessels, as well as the most distal border of
the tissue, representing de novo growth. ATAC-sequencing was performed on AT2 cells from infected mice at
the peak of AT2 cell proliferation and in the recovery phase after returning to quiescence. AT2 cells gained
accessibility of AP-1 motifs during injury repair and subsequently lost accessibility for AP-1 motifs at recovery.
The hypothesis of this proposal is that AP-1 transcriptionally regulates AT2 cell activation to induce
both in situ and de novo repair during lung injury response. We will first identify the spatiotemporal
activation of AT2 cells during infection through lineage tracing AT2 cell proliferation and differentiation for
detection with light sheet microscopy to generate 3D images for deciphering if the proposed in situ and de
novo regions of activation are truly distinct. We will also perturb an airway stem cell population known to
contribute to in situ wound repair to study region specific changes in AT2 cell activation when airway
assistance is disrupted (Aim1). Second, we will investigate the regulatory mechanism in AT2 cell activation by
looking at the kinetics of epigenetic change over time through injury response with bulk ATAC and single-cell
mutiome-sequencing. We will also examine the role of AP-1 through AT2 cell specific conditional knockout of
FOSB to examine its impact on AT2 cell activation and repair (Aim2). This study will help characterize the
novel concept of in situ and de novo AT2 cell activation as well as the undiscovered epigenetic and
transcriptional regulation of lung regeneration.
Terms: <3-D><3-D Images><3-D image><3-Dimensional><3D><3D image><3D images><AP-1><AP-1 Enhancer-Binding Protein><AP1><AP1 protein><ATAC><ATAC sequencing><ATAC-seq><ATACseq><Activator Protein-1><Acute Lung Injury><Acute Pulmonary Injury><Address><Airway infections><Alveolar><Alveolar Cell Type I><Area><Assay for Transposase-Accessible Chromatin using sequencing><Benchmarking><Best Practice Analysis><Body Tissues><COVID crisis><COVID epidemic><COVID pandemic><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 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><CUT&RUN><CV-19><Cause of Death><Cell Body><Cell Death><Cell Differentiation><Cell Differentiation process><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cells><Cellular Proliferation><ChIP Sequencing><ChIP-seq><ChIPseq><Chemical Injury><Chromatin><Cleavage Targets and Release Using Nuclease><Cleavage Under Targets and Release Using Nuclease><Complement><Complement Activation><Complement Proteins><Coronavirus Infectious Disease 2019><Country><Data><Detection><Distal><Enhancer-Binding Protein AP1><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelium><FOSB><FOSB gene><GOS3><GOSB><Gases><Gene Transcription><Generalized Growth><Genetic Transcription><Genomic approach><Goals><Growth><Hemagglutinating Virus of Japan><Heterogeneity><In Situ><Infection><Inhalation><Inhaling><Injury><Intervention><Intervention Strategies><Kinetics><LPTN><Label><Light><Lobe><Lower Respiratory Tract Infection><Lower respiratory infection><Lung><Lung Adenocarcinoma><Lung Alveolar Epithelia><Lung Diseases><Lung Respiratory System><Lung damage><Lung tissue regeneration><Malignant Tumor of the Lung><Malignant neoplasm of lung><Maps><Mediating><Mice><Mice Mammals><Microscopy><Modeling><Molecular><Murine><Mus><Natural regeneration><Nature><Nuclear><Oncogene FOSB><Persons><Phase><Photoradiation><Pneumonectomy><Poison><Progenitor Cells><Proliferating><Pulmonary Cancer><Pulmonary Diseases><Pulmonary Disorder><Pulmonary malignant Neoplasm><RNA Expression><Recovery><Regeneration><Respiratory Infections><Respiratory Tract Infections><Risk><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SCM-1><SCM-1a><SCM1><SCYC1><STEM class><STEM course><STEM discipline><STEM field><STEM major><Sendai virus><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Testing><Three-Dimensional Image><Time><Tissue Growth><Tissues><Toxic Chemical><Toxic Substance><Toxin><Transcription><Transcription Factor AP-1><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Type I Pneumocyte><Type II Pneumocyte><V-FOS FBJ Murine Osteosarcoma Viral Oncogene Homolog B><Viral><Viral Diseases><Virus Diseases><Wound Repair><XCL1><XCL1 gene><airway injury><alveolar epithelium><alveolar type II cell><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><benchmark><cellular differentiation><chemical trauma><chromatin immunoprecipitation-sequencing><combat><complement pathway regulation><complementation><conditional knock-out><conditional knockout><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 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus infectious disease-19><disease of the lung><disorder of the lung><epigenetic regulation><epigenetically><epigenomics><epithelial injury><genetic approach><genetic strategy><genomic effort><genomic strategy><imaging approach><imaging based approach><impaired airway><injured airway><injuries><injury and repair><injury burden><injury response><interventional strategy><lobes><lung cancer><lung disorder><lung injury><lung regeneration><member><mouse model><multiomics><multiple omics><murine model><necrocytosis><novel><ontogeny><panomics><parainfluenza virus><pathogen><progenitor biology><progenitor cell biology><progenitor cell function><progenitor cell population><progenitor function><progenitor population><pulmonary><pulmonary damage><pulmonary injury><pulmonary regeneration><pulmonary tissue damage><pulmonary tissue injury><regenerate><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><repair><repaired><respiratory injury><respiratory tract injury><response to injury><scATAC sequencing><scATAC-seq><science, technology, engineering and math class><science, technology, engineering and math course><science, technology, engineering and math discipline><science, technology, engineering and math field><science, technology, engineering and math major><science, technology, engineering and mathematics class><science, technology, engineering and mathematics course><science, technology, engineering and mathematics discipline><science, technology, engineering and mathematics field><science, technology, engineering and mathematics major><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><single cell ATAC-seq><single cell ATAC-sequencing><single cell Assay for Transposase Accessible Chromatin sequencing><single cell analysis><single cell sequencing assay for transposase accessible chromatin><single-cell Assay for Transposase-Accessible Chromatin with sequencing><single-cell assay for transposase-accessible chromatin using sequencing><single-cell assay for transposase-accessible chromatin-seq><social role><spatiotemporal><stem and progenitor biology><stem and progenitor cell function><stem and progenitor cell population><stem and progenitor function><stem cell biology><stem cell function><stem cell population><stem cells><surfactant><three dimensional><tissue regeneration><tissue regrowth><tissue renewal><tissue repair><tissue specific regeneration><toxic compound><training opportunity><viral infection><virus infection><virus-induced disease><wound healing><wound recovery><wound resolution>