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Principal Investigator: Adolfo Garcia-Sastre
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2023
Award: $360,450
Funding agency: National Institute of Allergy and Infectious Diseases
Two years into the COVID-19 pandemic, SARS-CoV-2 infections are still responsible for huge economic
losses, lockdowns and stressed health care systems worldwide. Different from the situation early during the
pandemic, when the virus started circulating in the human population in the absence of pre-existing immunity,
SARS-CoV-2-specific immunity has been increased at the community level due to vaccination or previous
infection. Nevertheless, through the acquisition of mutations, new variants of the virus emerged that were able
to escape pre-existing immunity and to transmit with higher efficiency, thereby causing a continuous threat for
severe disease, especially in people with comorbidities like obesity, advanced age and associated morbidities
like type 2 diabetes and hypertension. In Project 1, we will identify key drivers and biomarkers for severe
disease networks associated with SARS-CoV-2 infection through modeling, based on multi-OMICs data
obtained from clinical and animal studies. Under AIM 1, a first dataset will be generated from clinical
samples of COVID-19 patients in the absence or presence of pre-existing immunity. Multi-OMICs data will also
be generated using established animal models (mouse and hamster) for SARS-CoV-2 infection to recapitulate
clinical characteristics and features from the human cohort studies, thereby taking advantage of our expertise
with animal models for specific comorbidities (obesity, type 2 diabetes, advanced age) while always addressing
sex and immune status as a biological variables. Both human and animal datasets will be used by the
modeling core under AIM 2 to identify networks associated with severe and mild disease outcome, and the
host and virus genes that drive them. Under AIM 3, networks and signature genes identified under AIM 2 will
be validated in vivo using the mouse and hamster infection models for SARS-CoV-1. Hereto, we will rely on the
availability of knock out mice, viral vector-mediated genetic ablation of host genes in cells licensed for SARS-
CoV infection, when available pharmacological interventions, recombinant rSARS-CoV-1 and rSARS-CoV-2
viruses and SARS-CoV-2 variants that have acquired mutations in genes of interest by nature. The
overarching goal of our highly integrated research strategy is to uncover molecular signatures associated with
distinct disease trajectories and outcomes, identifying novel targets for therapeutic interventions.
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health crisis><COVID19 virus><Cell Body><Cells><Characteristics><Clinical><Clinical Data><CoV-2><CoV2><Cohort Studies><Collection><Communities><Concurrent Studies><Coronaviridae Infections><Coronavirus Infections><Cricetinae><Data><Data Collection><Data Set><Dimensions><Disease><Disease Outcome><Disorder><Early identification><Economics><Elderly><Experimental Animal Model><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><Hamsters><Hamsters Mammals><Health Care Systems><Healthcare Systems><Host Factor><Host Factor Protein><Human><Hypertension><Immune><Immune response><Immunes><Immunity><Immunization><Immunological response><In Vitro><Individual><Infection><Integration Host Factors><Intervention><Intervention Strategies><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out Mice><Knockout Mice><Licensing><Maturity-Onset Diabetes Mellitus><Mediating><Metadata><Mice><Mice Mammals><Modeling><Modern Man><Molecular Fingerprinting><Molecular Profiling><Morbidity><Morbidity - disease rate><Multiomic Data><Murine><Mus><Mutation><NIDDM><Nature><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Null Mouse><Obesity><Outcome><Pathology><Patients><Persons><Population><Predisposition><RNA vaccine><RNA-based vaccine><Recombinants><Research><Research Specimen><Retrospective cohort><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 immunity><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-Related Coronavirus><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><Sampling><Severe Acute Respiratory Coronavirus><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 Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 immunity><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Slow-Onset Diabetes Mellitus><Specimen><Stable Diabetes Mellitus><Stress><Study models><Susceptibility><System><Systems Biology><T2 DM><T2D><T2DM><Testing><Therapeutic Intervention><Training><Transmission><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Vaccinated><Vaccination><Validation><Variant><Variation><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Viral><Viral Vector><Virus><Wuhan coronavirus><adiposity><adult onset diabetes><advanced age><animal data><bench bed side><bench bedside><bench to bed side><bench to bedside><bench to clinic><bench to clinical practice><bio-markers><biologic><biologic marker><biomarker><biomarker identification><co-morbid><co-morbidity><cohort><comorbidity><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><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 immunity><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19 global pandemic><coronavirus 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severe acute respiratory syndrome coronavirus 2><interest><intervention therapy><interventional strategy><ketosis resistant diabetes><late life><later life><lens><lenses><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><mRNA vaccine><mRNA-based vaccine><marker identification><maturity onset diabetes><medical college><medical schools><meta data><model of animal><molecular biomarker><molecular marker><molecular profile><molecular signature><multiomics><multiple omic data><multiple omics><nCoV2><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><older adult><older person><pandemic><pandemic disease><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><pharmacologic><prospective><recruit><school of medicine><senior citizen><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 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome 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