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Principal Investigator: Mingtao Zhao
Organization: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
Fiscal Year: 2023
Award: $195,000
Funding agency: National Heart Lung and Blood Institute
Down syndrome (DS) is the most common genetic disorder occurring in about 1 in 800 live births, and is
characterized by a distinctive facial appearance, intellectual disability, and developmental delays. Gene dosage
imbalance in DS patients, primarily caused by an extra copy of chromosome 21 (trisomy 21), is thought to
contribute to a broad spectrum of coexisting medical conditions. DS is frequently associated with congenital
heart defects (CHDs); approximately 40% of DS patients have some form of CHD, with atrioventricular septal
defects (AVSD) being the most prevalent. The swift global spread of coronavirus disease 2019 (COVID-19)
caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the ongoing pandemic.
Intriguingly, DS patients are more vulnerable to SARS-CoV-2 infection: there is a 4-fold increased risk for COVID-
19-related hospitalization and a 10-fold higher risk for COVID-19-related death compared to patients without DS.
Mechanisms by which individuals with DS are more susceptible to COVID-19 are largely unknown. Genetically
engineered mice made trisomic for homologous chromosome 16 (MMU16) were developed to study genotype-
phenotype correlations in DS. However, because authentic SARS-CoV-2 is unable to infect mice due to the
inefficient interaction between the viral S-protein and the mouse orthologue of its receptor, human angiotensin
converting enzyme 2 (ACE2), it is not ideal to recapitulate SARS-CoV-2 infection in DS patients using current
DS mouse models. In this R21 proposal, we aim to bridge this knowledge gap by dissecting the mechanistic
causes of the susceptibility of DS patients to COVID-19 using patient-specific induced pluripotent stem cells
(iPSCs). Some genes encoded by chromosome 21 (e.g. transmembrane proteinase serine 2, TMPRSS2) are
dysregulated in individuals with DS and have been implicated to have a role in SARS-CoV-2 infection. Our central
hypothesis is that upregulation of TMPRSS2 in DS leads to enhanced SARS-CoV-2 infection in the lungs,
resulting in an enhanced cytokine surge that increases the severity of COVID-19. In Specific Aim 1, we will
elucidate the mechanisms underlying the enhanced cytokine surge in Down syndrome in response to SARS-
CoV-2 infection using DS iPSC-derived lung organoids. In Specific Aim 2, we will determine the gene-dosage
effect of TMPRSS2 on SARS-CoV-2 infection in DS iPSC-derived cardiac and endothelial cells. It is expected
that this project will have a major impact on the understanding of susceptibility of DS patients to SARS-CoV-2
infection using clinically relevant and patient-specific cardiac and lung cells.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><AVSD><Alveolar><Appearance><Assay><Binding><Bioassay><Biologic Assays><Biological Assay><Blood Serum><Body Tissues><COVID crisis><COVID disease severity><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID severity><COVID-19><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 crisis><COVID-19 death><COVID-19 disease severity><COVID-19 epidemic><COVID-19 fatality><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infected patient><COVID-19 infection><COVID-19 mortality><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 predisposition><COVID-19 public health crisis><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 related risk><COVID-19 risk><COVID-19 risk factor><COVID-19 severity><COVID-19 susceptibility><COVID-19 virus><COVID-19 virus infection><COVID-19 vulnerability><COVID19><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 crisis><COVID19 death><COVID19 disease severity><COVID19 epidemic><COVID19 fatality><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 severity><COVID19 virus><CV-19><CV19><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Line><Cell membrane><Cell surface><CellLine><Cells><Chromosome 16><Chromosome 21><Chronic><CoV-2><CoV2><Congenital Cardiac Defects><Congenital Heart Defects><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Cytoplasmic Membrane><Developmental Delay><Developmental Delay Disorders><Down Syndrome><Down's Syndrome><Downs Syndrome><Endothelial Cells><Face><GEM model><GEMM model><Gene Copy Number><Gene Dosage><Genes><Genetic><Genetic Diseases><Genetic Materials><Genetically Engineered Mouse><Genotype><Heart><Heart Muscle Cells><Heart Vascular><Heart myocyte><Hospital Admission><Hospitalization><Human><Immune><Immunes><Incubated><Individual><Infection><Integral Membrane Protein><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Intrinsic Membrane Protein><Knowledge><Langdon Down syndrome><Live Birth><Lung><Lung Respiratory System><Medical><Membrane><Membrane Fusion><Mice><Mice Mammals><Modern Man><Molecular Interaction><Mongolism><Murine><Mus><Organ><Organoids><Patients><Pediatric cardiology><Phenotype><Plasma Membrane><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Predisposition><Proteins><RNA Viruses><Receptor Protein><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 disease severity><SARS-CoV-2 epidemic><SARS-CoV-2 fatality><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 predisposition><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 severity><SARS-CoV-2 susceptibility><SARS-CoV-2 vulnerability><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><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><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><Serum><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 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><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><Specific Child Development Disorders><Strains Cell Lines><Susceptibility><Testing><Therapeutic><Tissues><Transgenic Mice><Transmembrane Protein><Transmembrane Protein Gene><Trisomy 21><Up-Regulation><Upregulation><Viral><Virion><Virus Particle><Wuhan coronavirus><angiotensin converting enzyme 2><angiotensin converting enzyme II><atrioventricular canal defect><atrioventricular septal defect><cardiomyocyte><chromosome 21 trisomy syndrome><circulatory system><clinical relevance><clinically relevant><congenital acromicria syndrome><congenital cardiac anomalies><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 crisis><coronavirus disease 2019 death><coronavirus disease 2019 disease severity><coronavirus disease 2019 epidemic><coronavirus disease 2019 fatality><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 risk><coronavirus disease 2019 risk factor><coronavirus disease 2019 severity><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 severity><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 mortality><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cultured cell line><cytokine><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><faces><facial><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><genetic condition><genetic disorder><genetically engineered mouse model><genetically engineered murine model><hCoV19><high risk><iPS><iPS cell derived cardiomyocytes><iPSC><iPSC derived cardiomyocytes><iPSCs><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cell derived cardiomyocytes><inducible pluripotent stem cell><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><intellectual and developmental disability><limited intellectual functioning><membrane structure><morbus Down><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><mouse model><multidisciplinary><murine model><nCoV2><novel><pandemic><pandemic disease><pathogen><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><plasmalemma><predisposed to Coronavirus disease 2019><pseudohypertrophic progressive muscular dystrophy><pulmonary><receptor><response><risk associated with COVID-19><risk factor associated with COVID-19><risk factor related to COVID-19><risk related to COVID-19><scRNA-seq><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe acute respiratory syndrome coronavirus 2 severity><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><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><trisomy 21 syndrome><virology>