Document text
Principal Investigator: Stijn Piet Johan De Langhe
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2022
Award: $954,000
Funding agency: National Heart Lung and Blood Institute
Idiopathic pulmonary fibrosis (IPF) is a common form of interstitial lung disease (ILD), resulting in alveolar
remodeling and progressive loss of pulmonary function, respiratory failure, and death often within 5 years of
diagnosis. Genetic and experimental evidence support the concept that chronic alveolar epithelial injury and
failure to properly repair the respiratory epithelium are intrinsic to IPF disease pathogenesis. Histologically,
respiratory epithelial cells in the lung parenchyma are replaced by cells which are normally restricted to
conducting airways. Fibrotic lesions and honeycomb structures replace alveoli, the latter normally lined by
alveolar type 1 (AT1) and AT2 cells. Acute exacerbations by respiratory viral infections are the most devastating
complication of IPF, having an in-hospital mortality rate of greater than 50%. Data from previous coronavirus
pandemics such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS),
as well as emerging data from the COVID-19 pandemic, suggest there could be substantial fibrotic
consequences following SARS-CoV-2 infection, the causative agent of COVID-19. Interestingly, the major risk
factors for severe COVID-19 are shared with idiopathic pulmonary fibrosis (IPF), namely increasing age, male
sex, and comorbidities such as hypertension and diabetes. Although many patients who develop acute
respiratory distress syndrome (ARDS) survive the acute phase of the illness, a substantial proportion die as a
result of progressive pulmonary fibrosis. It remains unclear why certain individuals are able to recover from
ARDS, whereas in others there is a shift to unchecked cellular proliferation with the accumulation of BC-pods,
fibroblasts and myofibroblasts. In these patients, there is also excessive deposition of collagen alongside other
components of the extracellular matrix resulting in progressive pulmonary fibrosis. Distinct epithelial
stem/progenitor cell pools and/or their mesenchymal niches repopulate injured tissue depending on the extent
and type of injury, and the outcomes of regeneration or fibrosis in response to severe alveolar epithelial injury is
dependent in part on the dynamics of cell competition between these cell populations. In tissues harboring a
mosaic imbalance in cMyc or Yap protein levels, cells with higher cMyc or nuclear Yap levels become super-
competitors and expand at the expense of cells with lower levels, by eliminating them. Alternatively, if certain
stem cell populations are selectively wiped out due to the type of injury, other stem cell populations that escape
the injury and which may not be so adept at replacing the destroyed tissue will now have a competitive
advantage. For example, SARS-CoV-2 enters respiratory epithelial cells via its receptor, angiotensin-converting
enzyme 2 (ACE2), causing severe airway and alveolar epithelial injury. Based on Ace2 expression, distinct
stem/progenitor cell pools appear to be differentially susceptible to SARS-CoV-2 infection. This grant proposal
seeks to manipulate the underlying mechanisms of cell competition to help prevent and treat IPF and ARDS.
Cell competition might also be exploited to maximize the potential of healthy tissue replacement.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><AGTR2><AGTR2 gene><ARDS><AT2><Acute><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Age><Alveolar><Alveolus><Applications Grants><Body Tissues><Bronchial Alveolus><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infection><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 virus><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 public health crisis><COVID19 virus><CV-19><CV19><Cell Body><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell-Extracellular Matrix><Cells><Cellular Proliferation><Cessation of life><Chronic><CoV-2><CoV2><Collagen><Complication><Da Nang Lung><Data><Death><Deposit><Deposition><Diabetes Mellitus><Diagnosis><Disease><Disorder><ECM><Epithelial><Epithelial Cells><Extracellular Matrix><Failure><Fibroblasts><Fibrosing Alveolitis><Fibrosis><Genetic><Grant Proposals><Histologic><Histologically><Hospital Mortality><Hypertension><In-house Mortalities><Individual><Inhospital Mortality><Injury><Interstitial Lung Diseases><Lesion><Lung Alveolar Epithelia><Lung Parenchyma><Lung Tissue><Lung Tissue Fibrosis><MERS><MERS coronavirus disease><MERS-CoV disease><Mesenchymal><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome coronavirus disease><Mosaicism><Myofibroblast><Natural regeneration><Nuclear><Outcome><Pathogenesis><Patients><Phase><Population><Progenitor Cells><Proteins><Pulmonary Fibrosis><Receptor Protein><Regeneration><Respiratory Epithelium><Respiratory Failure><Risk Factors><SARS><SARS corona virus 2><SARS coronavirus disease><SARS-CO-V2><SARS-COVID-2><SARS-CoV disease><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 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><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><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><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 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><Shock Lung><Stiff lung><Structure><Structure of parenchyma of lung><Structure of respiratory epithelium><Tissues><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Viral Respiratory Tract Infection><Wuhan coronavirus><ages><airway epithelium><alveolar epithelium><angiotensin converting enzyme 2><angiotensin converting enzyme II><base><c myc><c-myc Genes><cmyc><co-morbid><co-morbidity><comorbidity><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><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 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><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus of pandemic concern><coronavirus of pandemic potential><coronavirus with pandemic potential><diabetes><diffuse interstitial pulmonary fibrosis><epithelial injury><fibrosis in the lung><hCoV19><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><idiopathic pulmonary fibrosis><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><injured><injuries><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lung failure><lung fibrosis><lung function><male><mosaic disorders><nCoV2><pandemic coronavirus><pandemic threat coronavirus><prevent><preventing><pulmonary failure><pulmonary function><receptor><regenerate><repair><repaired><replacement tissue><response><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><sex><stem><stem cell population><stem cells><v-myc Avian Myelocytomatosis Viral Oncogene Cellular Homolog><viral respiratory infection><wet lung>