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Principal Investigator: Alexander Minchev Tsankov
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2023
Award: $126,750
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
COVID-19 disease, caused by the novel coronavirus SARS-CoV-2, is a global health threat due to its rapid
spread, morbidity, and mortality. It is estimated that at least 25% of severe COVID-19 disease survivors
experience persistent respiratory complications. This underscores the need to better understand how the cell
types, regenerative lineages, and cell-cell communication are altered following SARS-CoV-2 infection and what
regulatory mechanisms and interactions in affected tissue may underlie Long-COVID, the long-term medical
complications in COVID-19 long-haulers. Recent advances in high-throughput single cell RNA-sequencing
(scRNA-seq) have enabled comprehensive characterization of the cellular census of the lung, which has led to
a remarkable number of novel findings in new cell types and cell states at homeostasis and in disease.
However, our understanding of the cell type relationships and their higher order tissue organization is still
lacking in the context of COVID-19. Analyses by our lab and the Human Cell Atlas (HCA) lung network using a
compendium of tissues from healthy individuals revealed that a distinct subset of epithelial cells in the nasal
passages, airways, alveoli, and gut co-express ACE2 and TMPRSS2, consistent with organ-specific disease
presentations of COVID-19. More recently, over one million cells of scRNA-seq data from greater than one
hundred COVID-19 patients became publicly available, which provides an unprecedented resolution and
statistical power to study the variation in the lung cellular microenviroment between individuals with different
presentation of COVID-19. Such an endeavor presents several computational challenges due to the high-
dimensionality of the data and because analysis tools of cellular communication in scRNA-seq data and
integration with coordinated multicellular gene expression programs are still needed. We propose to integrate
high-dimensional scRNA-seq data and correct for batch effects between laboratories in order to build a
uniformly annotated single-cell atlas of more than one hundred COVID-19 patients. Such an atlas would
enable us to characterize the similarities and differences in cellular composition and cell-cell interactions and
assess the effects of clinical correlates--such as gender, age, medications, and smoking history--on tissue
organization. Comparisons between the lung microenvironment across our large, integrated cohort of control
and COVID-19 patients will uncover commonly dysregulated cell types and cell-cell interactions that can inform
on shared pathways to target therapeutically. Moreover, comparison of the dysregulated cell types,
regenerative lineages, and cell-cell interactions to those observed in other lung diseases will provide important
insight on how to repurpose existing drugs and recommended treatments for COVID-19 long haulers with
respiratory complications.
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Resources><Resolution><Resources><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Respiratory System, Nose, Nasal Passages><Ribonucleic Acid><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infected patient><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 survivors><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><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 related corona virus 2><Severity of illness><Smoking History><Smoking Status><Splicing><Survivors><Symptoms><TMPRSS2><TMPRSS2 gene><Tissues><Upper Respiratory System><Variant><Variation><Visualization><Work><Wuhan coronavirus><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><ages><analysis pipeline><angiotensin converting enzyme 2><angiotensin converting enzyme II><cell type><chronic COVID><chronic COVID-19><chronic novel coronavirus disease 2019><clinical effect><co-morbid><co-morbidity><cohort><comorbidity><comparative><computational analyses><computational analysis><computational framework><computer analyses><computer framework><corona virus disease 2019><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 infected patient><coronavirus disease 2019 long hauler><coronavirus 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dimensionality><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><insight><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><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long hauler><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><lung disorder><lung fibrosis><mRNA><medical complication><mortality><multidimensional data><multidimensional datasets><nCoV><nCoV2><new CoV><new corona virus><new coronavirus><new 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treatment><taste loss><tissue processing><tool><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><treatment strategy><unique treatment>