Document text
Principal Investigator: MATTHEW TIRRELL
Organization: UNIVERSITY OF CHICAGO
Fiscal Year: 2023
Award: $797,003
Funding agency: National Heart Lung and Blood Institute
Project Summary
This R01 proposal outlines a research plan which uses targeted nanomedicine to enhance disease-
modifying molecular mechanisms both in the acute injurious phase and in the subsequent chronic fibrotic
phase of viral-induced pneumonitis. The overall goal of this proposal is to use nanomedicine to modify specific
cellular subtypes during the lung disease process. Acute and chronic lung diseases are major causes of
mortality and morbidity in the US. Acute respiratory distress syndrome (ARDS), caused by widespread
endothelial barrier disruption and uncontrolled cytokine storm, is the major cause of death in critically ill
influenza and COVID-19 patients. Furthermore, pulmonary fibrosis, progressive scarring in injured lung, is a
major sequelae of viral pneumonia. Early analyses showed that discharged COVID-19 patients are at high risk
for developing pulmonary fibrosis. Currently, there are few pharmacological treatments that directly targets
ARDS, and available therapeutic options for pulmonary fibrosis remain suboptimal, underscoring unmet
medical needs in a heightened state due to COVID-19 pandemic. Strongly supported by our published and
unpublished in vivo results, we believe that targeted nanomedicine approaches have tremendous potential to
treat ARDS and pulmonary fibrosis, which will be comprehensively tested in vivo in this application. Aim 1 will
test the therapeutic effectiveness of specifically reducing endothelial dysfunction in acute lung injury (influenza
or SARS-CoV-2) in mice and perfused human lungs using a VCAM1-targeting, KLF2 mRNA-encapsulated
nanoparticles. We anticipate that specific endothelial KLF2 overexpression will reduce acute lung injury. Aim 2
will test the therapeutic effectiveness of specifically targeting lung fibroblasts in chronic pulmonary fibrosis
(bleomycin) in mice and human lung slices using PDGFRB-targeting nanoparticles to deliver shRNAs against
TXNDC5. We anticipate that specific fibroblast inhibition of TXNDC5 will reduce lung fibrosis.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ARDS><Acute><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Alveolar><Alveolus><Animal Experiments><Autopsy><Basal Transcription Factor><Basal transcription factor genes><Bleo><Bleomycin><Blood Vessels><Bronchial Alveolus><CD106><CD106 Antigens><CD140b Antigens><COVID associated ARDS><COVID associated acute respiratory distress syndrome><COVID crisis><COVID epidemic><COVID induced ARDS><COVID induced acute respiratory distress syndrome><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID related ARDS><COVID related acute respiratory distress syndrome><COVID-19><COVID-19 associated ARDS><COVID-19 associated acute respiratory distress syndrome><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 induced ARDS><COVID-19 induced acute respiratory distress syndrome><COVID-19 infected patient><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 related ARDS><COVID-19 related acute respiratory distress syndrome><COVID-19 virus><COVID-19/ARDS><COVID-19/acute respiratory distress syndrome><COVID/ARDS><COVID/acute respiratory distress syndrome><COVID19><COVID19 associated ARDS><COVID19 associated acute respiratory distress syndrome><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 induced ARDS><COVID19 induced acute respiratory distress syndrome><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 related ARDS><COVID19 related acute respiratory distress syndrome><COVID19 virus><COVID19/ARDS><COVID19/acute respiratory distress syndrome><CV-19><CV19><Cause of Death><Cell Body><Cells><Chicago><Chronic><Chronic lung disease><Cicatrix><CoV-2><CoV2><Community Medicine><Complication><Critical Illness><Critically Ill><Da Nang Lung><Data><Disease><Disorder><Disulfide Interchange Enzyme><Disulfide Isomerase><ERp59 PDI><Encapsulated><Endothelium><Engineering><Erp59><Fear><Fibroblasts><Fibrotic lesions in lung><Fright><GSBP><General Transcription Factor Gene><General Transcription Factors><Genetic><Glycosylation Site-Binding Protein><Goals><Grippe><Health><Human><Hydrogen Oxide><INCAM-110><Impairment><Inducible Cell Adhesion Molecule 110><Infection><Inflammatory><Influenza><Knowledge><Lung><Lung Inflammation><Lung Respiratory System><Lung Tissue Fibrosis><Lung damage><Lung diseases><Lung scar><Lung tissue scar><Medical><Messenger RNA><Mice><Mice Mammals><Modern Man><Modification><Molecular><Molecular Fingerprinting><Molecular Profiling><Molecular Target><Morbidity><Morbidity - disease rate><Murine><Mus><PDGF Receptor β><PDGF beta Receptor><PDGF β Receptor><PDGFR beta><PDGFR-β><Patients><Peptides><Perfusion><Pharmacological Treatment><Phase><Plasmids><Platelet-Derived Growth Factor Receptor Beta Polypeptide><Platelet-Derived Growth Factor Receptor β><Platelet-Derived Growth Factor beta Receptor><Pneumonitis><Population><Process><Protein Disulfide Isomerase><Proteins><Public Health><Publishing><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Fibrosis><Pulmonary Inflammation><Pulmonary Scar><Pulmonary Tissue fibrosis><RNA vaccine><RNA-based vaccine><Research><Reticulum><Risk><S-S rearrangase><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated ARDS><SARS-CoV-2 associated acute respiratory distress syndrome><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 induced ARDS><SARS-CoV-2 induced acute respiratory distress syndrome><SARS-CoV-2 infected patient><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related ARDS><SARS-CoV-2 related acute respiratory distress syndrome><SARS-CoV-2/ARDS><SARS-CoV-2/acute respiratory distress syndrome><SARS-CoV2><SARS-CoV2 epidemic><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><Scarring at the lung><Scarring in the lung><Scars><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 CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><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 coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Slice><Stiff lung><Stimulus><Sulfhydryl-Disulfide Interchange Enzyme><TRX gene><TRX protein><TRX1><TXN gene><Testing><Therapeutic><Therapeutic Effect><Thiol-Disulfide Transhydrogenase><Thioredoxin><Tidal Volume><Transcription Factor Proto-Oncogene><Transcription factor genes><Trypanothione-Glutathione Thioltransferase><Universities><Urd><Uridine><VCAM><VCAM-1><Vascular Cell Adhesion Molecule><Vascular Cell Adhesion Molecule-1><Vascular Endothelial Cell><Viral><Viral Activity><Viral Function><Viral Physiology><Viral Pneumonia><Virus><Water><Work><Wuhan coronavirus><animal experiment><cell type><chronic pulmonary disease><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 associated ARDS><coronavirus disease 2019 associated acute respiratory distress syndrome><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 induced ARDS><coronavirus disease 2019 induced acute respiratory distress syndrome><coronavirus disease 2019 infected patient><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 related ARDS><coronavirus disease 2019 related acute respiratory distress syndrome><coronavirus disease 2019 virus><coronavirus disease 2019/ARDS><coronavirus disease 2019/acute respiratory distress syndrome><coronavirus disease associated ARDS><coronavirus disease associated acute respiratory distress syndrome><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease induced ARDS><coronavirus disease induced acute respiratory distress syndrome><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease related ARDS><coronavirus disease related acute respiratory distress syndrome><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus disease/ARDS><coronavirus disease/acute respiratory distress syndrome><coronavirus infectious disease-19><coronavirus patient><cytokine release syndrome><cytokine storm><disease of the lung><disorder of the lung><dsbA Gene Product><dsbA Protein><dsbC Gene Product><dsbD Gene Product><endoplasm><endothelial dysfunction><experimental animal><experimental animals><fibrosis in the lung><fibrotic lung><flu virus pandemic><gene delivery system><hCoV19><high risk><immunogenicity><in vivo><in vivo evaluation><in vivo testing><inflammatory lung disease><influenza virus pandemic><lung disorder><lung fibrosis><lung function><lung injury><mRNA><mRNA vaccine><mRNA-based vaccine><molecular profile><molecular signature><mortality><nCoV2><nano medicinal><nano medicine><nano particle><nano-sized particle><nanomedicinal><nanomedicine><nanoparticle><nanosized particle><necropsy><overexpress><overexpression><pandemic flu><pandemic influenza><pandemic strain of influenza><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><postmortem><protein expression><pulmonary><pulmonary damage><pulmonary function><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><respiratory airway volume><severe acute respiratory syndrome coronavirus 2 associated ARDS><severe acute respiratory syndrome coronavirus 2 associated acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 induced ARDS><severe acute respiratory syndrome coronavirus 2 induced acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related ARDS><severe acute respiratory syndrome coronavirus 2 related acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2/ARDS><severe acute respiratory syndrome coronavirus 2/acute respiratory distress syndrome><shRNA><short hairpin RNA><small hairpin RNA><therapeutic effectiveness><therapeutic evaluation><therapeutic testing><transcription factor><vascular><vascular endothelial dysfunction><ventilation><wet lung><xprA Gene Product>