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Principal Investigator: REINHARD LAUBENBACHER
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $731,876
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
A key feature of the COVID-19 infection is the vast inter-individual heterogeneity in the
severity of the infection. The complex biological mechanisms that underlie this variability remain
mostly obscure. We propose to provide a mechanistic understanding of this susceptibility by
leveraging 3 key innovations: First, we have developed a 3-dimensional lung culture system
that allows for detailed interrogation of the early events in SARS-CoV-2 infection. Second, we
have established an animal model of COVID-19 in mice transgenic for the human ACE2
receptor in our facility. Third, we have built a multi-scale mathematical model of lung infection in
COVID-19, that we now seek to expand and personalize to individual hosts. We have two Aims
in this project: In Aim 1, we will validate, expand, and personalize our existing multi-scale
model, using an unbiased approach to identify and test hypotheses relating to susceptibility to
severe COVID-19, and in Aim 2 we will test a specific hypothesis regarding the mechanism of
the observed inter-individual heterogeneity in COVID-19 severity, namely that it is, in part,
mediated by divergent activation of the mTOR pathway in type I alveolar epithelial cells. If
successful, this project will identify the biological basis of the immune pathways that result in
heterogeneous outcome of COVID-19, paving the way for personalized, host-specific
interventions to improve the outcome of the infection.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><3-D><3-Dimensional><3D><3D cell culture><3D culture><ACE2><Affect><Animal Model><Animal Models and Related Studies><Biological><Body Tissues><COVID associated pneumonia><COVID disease severity><COVID induced pneumonia><COVID pneumonia><COVID related pneumonia><COVID severity><COVID-19><COVID-19 associated pneumonia><COVID-19 disease severity><COVID-19 induced pneumonia><COVID-19 infection><COVID-19 pneumonia><COVID-19 related pneumonia><COVID-19 severity><COVID-19 viral pneumonia><COVID-19 virus><COVID-19 virus infection><COVID19 disease severity><COVID19 infection><COVID19 severity><COVID19 virus><CV-19><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cells><Cessation of life><CoV-2><CoV2><Complex><Computer Models><Computerized Models><Confocal Microscopy><Coronavirus Infectious Disease 2019><Cryofixation><Cryopreservation><Data><Death><Engineering><Epidemiologic Determinants><Epidemiologic Factors><Epidemiological Factors><Epithelial Cells><Event><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Gene Transcription><Genetic Transcription><Goals><Grant><Heterogeneity><Human><Immune><Immune response><Immunes><Immunity><Immunological response><Immunology><Individual><Infection><Innate Immune Response><Interferon Type I><Intervention><Intervention Strategies><Intracellular Communication and Signaling><K-18><K-18 conjugate><K18><K18 combination><Literature><Lung><Lung Alveolar Epithelia><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung infections><Math Models><Measurement><Mechanistic Target of Rapamycin><Mediating><Mice><Mice Mammals><Minor><Modeling><Modern Man><Molecular><Murine><Mus><Outcome><Pathway interactions><Persons><Phosphoproteins><Predictive Factor><Predisposition><Production><Protocol><Protocols documentation><Public Health><Publishing><RAFT1><RNA Expression><Receptor Protein><Reproducibility><Risk><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated pneumonia><SARS-CoV-2 disease severity><SARS-CoV-2 induced pneumonia><SARS-CoV-2 infection><SARS-CoV-2 pneumonia><SARS-CoV-2 related pneumonia><SARS-CoV-2 severity><SARS-CoV-2 viral pneumonia><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><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 coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Structure of parenchyma of lung><Surgical Models><Susceptibility><System><Testing><Time><Tissue Donors><Tissue Preservation><Tissues><Transcription><Transgenic Mice><Transgenic Organisms><Viral><Virus><Work><Wuhan coronavirus><alveolar epithelium><angiotensin converting enzyme 2><angiotensin converting enzyme II><base><bases><biobank><biologic><biological signal transduction><biorepository><cohort><cold preservation><cold storage><computational modeling><computational models><computer based models><computerized modeling><coronavirus disease 2019><coronavirus disease 2019 associated pneumonia><coronavirus disease 2019 disease severity><coronavirus disease 2019 induced pneumonia><coronavirus disease 2019 infection><coronavirus disease 2019 pneumonia><coronavirus disease 2019 related pneumonia><coronavirus disease 2019 severity><coronavirus disease 2019 virus><coronavirus disease associated pneumonia><coronavirus disease induced pneumonia><coronavirus disease pneumonia><coronavirus disease related pneumonia><coronavirus disease severity><coronavirus disease-19><coronavirus disease-19 pneumonia><coronavirus disease-19 virus><coronavirus infectious disease-19><cytokine><digital twin><disparate effect><disparate impact><disparate result><effective therapy><effective treatment><flow cytophotometry><hCoV19><host response><immune system response><immunoresponse><improved outcome><individual heterogeneity><individual variability><individual variation><inequitable effect><inequitable impact><inequitable outcome><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><innovate><innovation><innovative><interventional strategy><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><mTOR><mTOR inhibition><mammalian target of rapamycin><mathematic model><mathematical model><mathematical modeling><model of animal><mouse model><multi-scale computational modeling><multi-scale mathematical modeling><multi-scale modeling><multiscale computational modeling><multiscale mathematical modeling><multiscale modeling><murine model><nCoV2><necrocytosis><novel><outcome disparities><outcome inequality><outcome inequity><outcome prediction><pandemic><pandemic disease><pathway><pneumonia due to COVID><pneumonia due to COVID-19><pneumonia due to SARS-CoV-2><pneumonia due to coronavirus disease><pneumonia due to coronavirus disease 2019><pneumonia due to severe acute respiratory syndrome coronavirus 2><pneumonia in COVID><pneumonia in COVID-19><pneumonia in SARS-CoV-2><pneumonia in coronavirus disease><pneumonia in coronavirus disease 2019><pneumonia in severe acute respiratory syndrome coronavirus 2><population based><pulmonary><pulmonary infections><receptor><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 associated pneumonia><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 induced pneumonia><severe acute respiratory syndrome coronavirus 2 pneumonia><severe acute respiratory syndrome coronavirus 2 related pneumonia><severe acute respiratory syndrome coronavirus 2 severity><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><therapeutic target><three dimensional><three dimensional cell culture><tool><transgenic><unequal effect><unequal impact><unequal outcome><virology>