Document text
Principal Investigator: David W Gludish
Organization: CORNELL UNIVERSITY
Fiscal Year: 2024
Award: $153,630
Funding agency: NIH Office of the Director
This application seeks support for a research-emphasis veterinarian embarking on an independent career as a
translational veterinarian-scientist. The applicant proposes to study macrophages as drivers of SARS-CoV2-
induced lung damage in humans and mouse models, and will develop novel indicator mice to report SARS-CoV2
cellular targets in mice. This multi-disciplinary approach brings together leading experts in lung biology,
macrophage biology, virology, mouse genetics and pulmonary pathology. At Cornell University College of
Veterinary Medicine, the applicant will perform research in the laboratories of Drs. David Russell and Dr. Hector
Aguilar-Carreño (Department of Microbiology and Immunology), with histopathology analyses performed in the
laboratory of Dr. Gerald Duhamel (Department of Biomedical Sciences). For specific hands-on training in lung
epithelial repair assays, the applicant will work in the laboratory of Dr. Carla Kim (Harvard Medical
School/Children’s Hospital Boston). Dr. Russell, primary mentor, is an expert in macrophage biology and their
interaction with several lung pathogens, notably M.tuberculosis and HIV. He has a proven track record in training
post-doctoral veterinarian-scientists that have gone on to tenure-track positions with federal research funding.
Dr. Aguilar-Carreño has published extensively on the entry and egress of enveloped viruses with emphasis on
paramyxoviruses, and recently has adapted his well-described mouse challenge platform for antiviral and
vaccine discovery, toward SARS-CoV2. Dr. Duhamel is a veterinary anatomic pathologist with a research focus
in infectious disease, including lung pathogens in mice. Finally, Dr. Carla Kim is a pioneer in lung epithelial repair
and stem cell biology. Adding breadth and depth to the proposed work, the applicant has assembled a team of
enthusiastic collaborators (with two practicing MD physicians), including leaders in mouse genetics and lung
injury (Drs. Kahn and Morrisey), hyaluronan biology (Dr. Hascall), and human pulmonary pathology (Dr.
Borczuk). The research environment at Cornell is exceptional in the disciplines of infectious disease and
comparative pathology, while the combined expertise of Drs. Kim and Borczuk adds a strong translational and
integrative focus on drivers of alveolar damage. The proposal will probe how resident and recruited
macrophages are dysregulated during SARS-CoV2 in mice, whether dependent on direct viral infection of
macrophages or on environmental cues. In Aim 1, reporter mice will be generated to identify SARS-CoV2-
infected cells during infection and upon asymptomatic recovery. During Aim 2, the nature of macrophage subsets
as viral targets will be studied, and their resulting functional deficits determined using assays developed by Dr.
Russell. In Aim 3, viral challenge studies in human Ace2-expressing mice will interrogate macrophages as drivers
of alveolar damage, and test whether macrophage interventions improve clinical outcomes in mice. The
candidate will begin this research as Senior Research Associate in the Department of Microbiology and
Immunology (75% research effort), with an expected junior faculty transition in the independent award phase.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Airway failure><Alveolar><Alveolar Macrophages><Alveolus><Animal Model><Animal Models and Related Studies><Animals><Assay><Award><Behavior><Bioassay><Biological Assay><Biology><Blood monocyte><Body System><Boston><Bronchial Alveolus><COVID disease severity><COVID severity><COVID-19 disease severity><COVID-19 infection><COVID-19 predisposition><COVID-19 severity><COVID-19 susceptibility><COVID-19 virus><COVID-19 virus infection><COVID-19 vulnerability><COVID19 disease severity><COVID19 infection><COVID19 severity><COVID19 virus><CRE Recombinase><CRISPR><CRISPR/Cas system><Cell Body><Cell Death><Cells><Cessation of life><Children's Hospital><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Co-culture><CoV-2><CoV2><Cocultivation><Coculture><Coculture Techniques><Communicable Diseases><Comparative Pathology><Coronaviridae><Coronavirus><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Cues><Cultured Cells><DNA><Death><Deoxyribonucleic Acid><Discipline><Disease><Disease Progression><Disorder><Drug Targeting><Drugs><Dysfunction><EC 2.7.7.48><Engineering><Enterobacteria phage P1 Cre recombinase><Environment><Epithelium><Esteroproteases><Faculty><Focal Infection><Functional disorder><Funding><Generalized Growth><Germ Lines><Growth><HIV><HIV/Mtb><HIV/TB><HIV/mycobacterium tuberculosis><HIV/tuberculosis><High Throughput Assay><Histologic><Histologically><Histopathology><Human><Human Immunodeficiency Viruses><Hyaluronan><IFN><Immune><Immunes><Immunology><Impairment><In Vitro><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Interferons><Intervention><Intervention Strategies><Investigation><LAV-HTLV-III><Laboratories><Learning><Length><Longitudinal Studies><Lung><Lung Diseases><Lung Inflammation><Lung Respiratory System><Lung damage><Lymphadenopathy-Associated Virus><M tb><M tuberculosis><M. tb><M. tuberculosis><M. tuberculosis/HIV><Macrophage><Maps><Marrow monocyte><Measures><Medication><Mentors><Mice><Mice Mammals><Microbiology><Modern Man><Molecular><Murine><Mus><Mycobacterium tuberculosis><Mφ><Nature><Neutralization Tests><Neutralizing antibody assay><Non-Polyadenylated RNA><Organ><Organ System><Organoids><Outcome><Output><PASC><Paramyxoviridae><Paramyxovirus><Pathogenicity><Pathologist><Pathology><Pediatric Hospitals><Peptidases><Peptide Hydrolases><Pharmaceutical Preparations><Phase><Phenotype><Physicians><Physiopathology><Pneumonitis><Position><Positioning Attribute><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Postdoc><Postdoctoral Fellow><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Predisposition><Productivity><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Publishing><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Inflammation><Pulmonary Macrophages><Pulmonary Pathology><RNA><RNA Gene Products><RNA Replicase><RNA-Dependent RNA Polymerase><RNA-Directed RNA Polymerase><Recovery><Replication Unit><Replicon><Reporter><Reporting><Research><Research Associate><Respiratory Failure><Ribonucleic Acid><Route><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 disease severity><SARS-CoV-2 infection><SARS-CoV-2 pathogenesis><SARS-CoV-2 predisposition><SARS-CoV-2 severity><SARS-CoV-2 susceptibility><SARS-CoV-2 vulnerability><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><Science><Scientist><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 coronavirus 2 predisposition><Severe acute respiratory syndrome coronavirus 2 susceptibility><Severe acute respiratory syndrome coronavirus 2 vulnerability><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Societies><Stimulus><Susceptibility><System><Testing><Therapeutic><Time><Tissue Growth><Training><Universities><Variant><Variation><Vero Cells><Veterinarians><Veterinary Anatomy><Veterinary Medicine><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Pathogenesis><Viral Proteins><Viral Shedding><Virion><Virus><Virus Diseases><Virus Particle><Virus Replication><Virus Shedding><Virus-HIV><Work><Wuhan coronavirus><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><angiotensin converting enzyme 2><angiotensin converting enzyme II><antibody neutralization test><bacteriophage P1 recombinase Cre><career><cellular targeting><chronic COVID-19 sequelae><clinical relevance><clinically relevant><college><collegiate><corona virus><coronavirus disease 2019 disease severity><coronavirus disease 2019 infection><coronavirus disease 2019 severity><coronavirus disease 2019 virus><coronavirus disease severity><coronavirus disease-19 virus><discover vaccines><disease of the lung><disease severity><disorder of the lung><drug/agent><epithelial repair><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following infection by SARS-CoV-2><following severe acute respiratory distress syndrome CoV-2 infection><hCoV19><high throughput screening><human model><improved><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><infection localized><interdisciplinary approach><interest><interventional strategy><local infection><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long-term sequelae><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><long-term study><longitudinal outcome studies><longterm study><lung disorder><lung injury><lung pathogen><lung pathology><lung repair><lung tissue repair><medical college><medical schools><member><model of animal><model of human><monocyte><mouse genetics><mouse model><mtb><multidisciplinary approach><murine model><nCoV2><necrocytosis><neutralizing antibody test><novel><ontogeny><pandemic><pandemic disease><pathophysiology><pneumocyte><post COVID-19 sequelae><post SARS-CoV-2 infection><post acute sequelae following COVID-19><post-acute sequelae following SARS-CoV-2 infection><post-acute sequelae of COVID-19><post-acute sequelae of acute COVID infection><post-acute sequelae of coronavirus disease 2019><post-doc><post-doctoral><post-doctoral trainee><post-doctoral training><postdoctoral training><predisposed to Coronavirus disease 2019><prevent><preventing><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><progenitor biology><progenitor cell biology><pulmonary><pulmonary damage><pulmonary injury><pulmonary pathogen><pulmonary repair><pulmonary tissue damage><pulmonary tissue injury><recruit><repair><repaired><research associates><respiratory><school of medicine><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 pathogenesis><severe acute respiratory syndrome coronavirus 2 severity><stem and progenitor biology><stem cell biology><susceptible to COVID-19><susceptible to Coronavirus disease 2019><susceptible to SARS-CoV-2><susceptible to Severe acute respiratory syndrome coronavirus 2><tenure process><tenure track><tool><transcriptomics><vaccine discovery><viral RNA><viral infection><viral multiplication><viral replication><virology><virus RNA><virus infection><virus multiplication><virus pathogenesis><virus protein><virus-induced disease><vulnerable to COVID-19><vulnerable to Coronavirus disease 2019><vulnerable to SARS-CoV-2><vulnerable to Severe acute respiratory syndrome coronavirus 2>