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Principal Investigator: Ekaterina Koroleva
Organization: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
Fiscal Year: 2023
Award: $278,500
Funding agency: National Institute of Allergy and Infectious Diseases
Accumulating evidence suggest that SARS-CoV-2 infection induces tissue pathology in multiple organs in
addition to the lung, including, among others, intestine, heart, liver, kidney, and brain. Furthermore, SARS-
CoV-2 infection can exacerbate many chronic inflammatory diseases. However, mouse models that allow
to study SARS-CoV-2-induced pathology in specific organs are currently lacking. Additionally, therapeutic
strategies using the commercially available K18-hACE2 transgenic mouse model are limited due to ectopic
hACE2 expression in the brain driving high lethality. To overcome these problems, we have generated mice
with conditional tissue-specific hACE2 expression. The goal of this proposal is to characterize these novel
mouse models and define the impact of SARS-CoV-2 specifically on lung immunopathology and intestinal
disease. Our central hypothesis is that mice with conditional expression of hACE2 in Rosa26 locus
represent a robust platform to study tissue-specific SARS-CoV-2-induced pathology. In Aim 1, we will test
the hypothesis that hACE2 expression in type II alveolar epithelial cells and club cells is necessary and
sufficient for SARS-CoV-2-induced lung immunopathology. We will analyze SARS-CoV-2 infection
dynamics and lung immunopathology in mice with specific expression of hACE2 in type II alveolar epithelial
cells and club cells, using our recently developed dual reporter- expressing mCherry-Nluc recombinant
(r)SARS-CoV-2. In Aim 2, we will test the hypothesis that SARS-CoV-2 infection exacerbates intestinal
inflammation using mice with specific expression of hACE2 in intestinal epithelial cells. This proposal is
innovative and significant, as it will generate and characterize novel small animal models to study SARS-
CoV-2 mediated organ-specific disease and provide insights into mechanisms of SARS-CoV-2-mediated lung
and gut pathology. These mouse models will provide a robust platform to study and monitor SARS-CoV-2
infection in desired cell types and long-term complications of SARS-CoV-2 infection, and to perform
therapeutic interventions.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><3-D><3-Dimensional><3D><ACE2><ARDS><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Animal Model><Animal Models and Related Studies><Automobile Driving><Binding><Body Tissues><Brain><Brain Nervous System><COVID associated ARDS><COVID associated acute respiratory distress syndrome><COVID complications><COVID induced ARDS><COVID induced acute respiratory distress syndrome><COVID infected patient><COVID patient><COVID positive patient><COVID related ARDS><COVID related acute respiratory distress syndrome><COVID related complications><COVID-19><COVID-19 associated ARDS><COVID-19 associated acute respiratory distress syndrome><COVID-19 complications><COVID-19 induced ARDS><COVID-19 induced acute respiratory distress syndrome><COVID-19 infected patient><COVID-19 infection><COVID-19 monitoring><COVID-19 patient><COVID-19 positive patient><COVID-19 related ARDS><COVID-19 related acute respiratory distress syndrome><COVID-19 related complications><COVID-19 virus><COVID-19 virus infection><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 induced ARDS><COVID19 induced acute respiratory distress syndrome><COVID19 infection><COVID19 monitoring><COVID19 patient><COVID19 positive patient><COVID19 related ARDS><COVID19 related acute respiratory distress syndrome><COVID19 virus><COVID19/ARDS><COVID19/acute respiratory distress syndrome><CV-19><CV19><Cell Body><Cells><CoV-2><CoV2><Colitis><Communities><Complex><Consensus><Da Nang Lung><Data><Development><Disease><Disorder><Encephalon><Epithelial Cells><Generations><Goals><Heart><Immune><Immune response><Immunes><Immunological response><Inflammation><Intestinal><Intestinal Diseases><Intestinal Disorder><Intestines><K-18><K-18 conjugate><K18><K18 combination><Kidney><Kidney Urinary System><Liver><Luciferase Immunologic><Luciferases><Lung><Lung Alveolar Epithelia><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><Mediating><Mice><Mice Mammals><Molecular Interaction><Morbidity><Morbidity - disease rate><Mouse Strains><Murine><Mus><Organ><Pathogenesis><Pathologic><Pathology><Patients><Public Health><Pulmonary Pathology><Receptor Protein><Recombinants><Reporter><Reporter Genes><Research><Respiratory Epithelium><Role><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 induced ARDS><SARS-CoV-2 induced acute respiratory distress syndrome><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 monitoring><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 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><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 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><Shock Lung><Stiff lung><Structure of parenchyma of lung><Structure of respiratory epithelium><Testing><Therapeutic><Therapeutic Intervention><Tissues><Transgenic Mice><Type II Pneumocyte><Validation><Viral><Virus><Visualization><Wuhan coronavirus><airway epithelium><alveolar epithelium><alveolar type II cell><angiotensin converting enzyme 2><angiotensin converting enzyme II><bowel><bowel inflammation><cell type><chronic inflammatory disease><complications due to COVID-19><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 associated ARDS><coronavirus disease 2019 associated acute respiratory distress syndrome><coronavirus disease 2019 induced ARDS><coronavirus disease 2019 induced acute respiratory distress syndrome><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 monitoring><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><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 induced ARDS><coronavirus disease induced acute respiratory distress syndrome><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease related ARDS><coronavirus disease related acute respiratory distress syndrome><coronavirus disease-19><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><developmental><driving><effective therapy><effective treatment><gut inflammation><hCoV19><hepatic body system><hepatic organ system><host response><immune system response><immunopathology><immunoresponse><in vivo><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><inflamed bowel><inflamed gut><inflamed intestine><innovate><innovation><innovative><insight><intervention therapy><intestinal epithelium><intestinal inflammation><intestine disease><intestine disorder><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 injury><lung pathology><model of animal><mortality><mouse model><murine model><nCoV2><novel><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><post-COVID><post-COVID-19><post-coronavirus disease 2019><pre-clinical><preclinical><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><receptor><renal><respiratory tract epithelium><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 ARDS><severe acute respiratory syndrome coronavirus 2 associated acute respiratory distress syndrome><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 monitoring><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><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><therapeutic evaluation><therapeutic testing><three dimensional><tool><validations><wet lung>