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Principal Investigator: Andrew Vaughan
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $543,560
Funding agency: National Heart Lung and Blood Institute
Influenza alone kills as many as 500,000 people annually, and at least 4.5 million have died
from SARS-CoV-2 during this ongoing pandemic, with mortality from both respiratory viruses
largely due to viral pneumonia progressing to acute respiratory distress syndrome (ARDS).
Significant focus has been placed on regeneration of the epithelium after influenza, but relatively
little is known as to how the endothelium is repaired, a critical question since vascular
endothelial integrity is necessary to prevent ARDS-associated pulmonary edema, hypoxemia,
and mortality. We recently demonstrated that at least 20% of the lung's vascular endothelium is
regenerated by 1 month after infection, indicating a robust capacity for endothelial repair. We
therefore investigated signaling pathways which might modulate this regenerative functionality.
Somewhat unexpectedly given its role in promoting fibrosis, we observed that endothelial-
specific blockade of TGF-β signaling prevents effective repair of the lung endothelium and
results in inefficient physiologic recovery. Moreover, in order to achieve coordinated, functional
tissue repair, we reasoned that lung endothelial cells might influence repair of the adjacent
epithelium by release of angiocrine factors. In keeping with this notion, we identified a
matricellular protein, SPARCL1, which is secreted by injury-activated endothelial cells and
serves to enhance alveolar epithelial regeneration, at least in part by modulating TGF-β. Based
on our cumulative findings, we hypothesize that injury-activated endothelial cells engage
a TGF-β / SPARCL1 axis to coordinately regulate lung endothelial and epithelial repair.
The major objectives to address this hypothesis are 1) mechanistically define how TGF-β
promotes lung vascular repair and 2) determine whether and how SPARCL1 acts as an
angiocrine factor to promote alveolar epithelial regeneration. Successful completion of these
studies will inform approaches designed to enhance endothelial cell regenerative potential and
promote effective lung repair / prevent mortality in ARDS and viral pneumonia.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ARDS><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Alveolar><Animals><Assay><Autocrine Systems><Automobile Driving><Binding><Bioassay><Biological Assay><Blood Vessels><Blood capillaries><Bone-Derived Transforming Growth Factor><CD105 Antigen><COVID-19><COVID-19 virus><COVID19 virus><CV-19><Capillary Endothelial Cell><Cell Body><Cell Communication and Signaling><Cell Death><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cells><Cellular Proliferation><ChIP Sequencing><ChIP-seq><ChIPseq><CoV-2><CoV2><Coronavirus Infectious Disease 2019><Da Nang Lung><Data><Elderly><Endoglin><Endothelial Cells><Endothelium><Epithelial Cell Proliferation><Epithelial Cells><Epithelium><Exposure to><Fibrosis><Gases><Genes><Glycoproteins><Grippe><H1N1><H1N1 Virus><Hypoxemia><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><In Vitro><Individual><Infection><Influenza><Influenza A Virus, H1N1 Subtype><Injury><Intracellular Communication and Signaling><JV18><JV18-1><Lung><Lung Alveolar Epithelia><Lung Respiratory System><Lung damage><MADH2><MADH2 gene><MADR2><Mediating><Mice><Mice Mammals><Milk Growth Factor><Modeling><Molecular><Molecular Interaction><Murine><Mus><Natural regeneration><Organoids><Pathogenicity><Pathologic><Pathway interactions><Patients><Persons><Physiologic><Physiological><Platelet Transforming Growth Factor><Proliferating><Proteins><Public Health><Pulmonary Edema><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Recovery><Regeneration><Regenerative response><Reporting><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><SMAD2><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><Shock Lung><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stiff lung><TGF B><TGF-Beta Type II Receptor><TGF-beta><TGF-beta Receptors><TGF-β><TGF-β Receptors><TGFBR2><TGFBR2 gene><TGFbeta><TGFβ><Testing><Therapeutic><Toxin><Transforming Growth Factor P Receptor III><Transforming Growth Factor beta><Transforming Growth Factor beta Receptors><Transforming Growth Factor β Receptors><Transforming Growth Factor-Beta Family Gene><Up-Regulation><Upregulation><Vascular Endothelium><Vascular regeneration><Viral Pneumonia><Work><Wuhan coronavirus><advanced age><alveolar epithelium><angiogenesis><antagonism><antagonist><autocrine><biological signal transduction><capillary><capillary bed><chromatin immunoprecipitation-sequencing><coronavirus disease 2019><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><design><designing><driving><endothelial regeneration><endothelial repair><epithelial repair><epithelium regeneration><flu serotype><flu strain><flu subtype><flu viral strain><flu virus strain><geriatric><hCoV19><hypoxemic><immunosuppressed patient><improved><in vivo><induced Cre><inducible Cre><influenza serotype><influenza strain><influenza subtype><influenza viral strain><influenza virus strain><injuries><lung edema><lung function><lung injury><lung repair><lung tissue repair><mortality><nCoV2><necrocytosis><novel><overexpress><overexpression><pandemic><pandemic disease><pathogen><pathway><prevent><preventing><progenitor><protection pathway><protective pathway><pulmonary><pulmonary damage><pulmonary function><pulmonary injury><pulmonary repair><pulmonary tissue damage><pulmonary tissue injury><receptor><regenerate><regenerate epithelium><regeneration function><regeneration potential><regeneration response><regenerative function><regenerative functionality><regenerative potential><repair><repair function><repaired><reparative function><respiratory virus><scRNA-seq><seasonal flu><seasonal influenza><senior citizen><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tissue repair><transcriptome sequencing><transcriptomic sequencing><transcriptomics><transforming growth factor-beta type II receptor><transforming growth factor-β type II receptor><vascular><wet lung>