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Principal Investigator: Ming-Ming Zhou
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2020
Award: $342,914
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
This administrative supplement application is submitted for the parent award (5R01AI124465) in
response to NIAID’s Notice of Special Interest (NOT-AI-20-031) “Severe Acute Respiratory Syndrome
Coronavirus (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19)”, as well as “Administrative
Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp - Clinical Trial
Optional)” (PA-18-591). The outbreak of the new coronavirus (SARS-CoV-2) infection is spreading to
every continent around the world at an astonishing speed. As of April 15, 2020, coronavirus disease
2019 (COVID-19) has been confirmed in 2,035,764 people worldwide, causing a mortality of 6.42%,
exceeding far beyond a mortality rate of <1% from influenza. Effective treatment is urgently needed to
stop the rapid spread of SARS-CoV-2 infection in this devastating pandemic. While current focus is on
developing novel therapeutics including antivirals and vaccines, mounting evidence show that many
severe COVID-19 patients suffer from respiratory failure by acute respiratory distress syndrome
(ARDS), the leading cause of COVID-19 mortality. In this study, we aim to address this major
unmet medical need. Clinically, host cells elicit two-phased responses to SARS-CoV-2 infection. In
an early incubation and non-severe stage, immune cells such as macrophages detect the virus and
produce cytokines to eliminate the virus. But, when a protective immune response is impaired, the
virus propagates, and the disease is transitioned to a severe stage where innate inflammation is
induced by virus-caused massive tissue damage with uncontrolled cytokine release (aka Cytokine
Storm) from inflammatory macrophages and granulocytes, resulting in ARDS in the lungs. Ascended
pro-inflammatory cytokines such as IL-6, IL-10, IL-17, GM-CSF, MCP-1, IFN-γ, and TNF-α are
reported in severe COVID-19 patients. Lung hyper-inflammation is the main cause of life-threatening
respiratory disorders at the severe stage. Notably, our study shows that transcriptional activation of
these inflammatory cytokines is directed by major transcription factors NF-kB and STAT3 in concert
with chromatin regulators BRD2 and BRD4, and that their activities can be effectively blocked by
chemical inhibitors. Motivated by our findings, in this study, we propose to identify and repurpose
FDA-approved drugs to suppress SARS-CoV-2-induced cytokine storm through simultaneously
blocking NF-kB and STAT3 signaling pathways. We will achieve this goal by addressing the two
specific aims: (1) identify FDA-approved drugs to block uncontrolled cytokine release induced by
SARS2-CoV-2; (2) validate chemical inhibition of hyperinflammation in human immune cell lines
including human peripheral blood mononuclear cells from COVID-19 patients.
Terms: <(TNF)-α><2019 novel coronavirus><2019-nCoV><ARDS><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Acute respiratory failure><Address><Administrative Supplement><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Antiviral Agents><Antiviral Drugs><Antivirals><Autoimmune Diseases><Award><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BRD2><BRD2 gene><BSF-2><BSF2><Basal Transcription Factor><Basal transcription factor genes><Binding><Biology><Blood granulocytic cell><Body Tissues><Bromodomain><CCL2><CCL2 gene><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><COVID-19><COVID19><CSIF><CSIF-10><CTLA-8><CTLA8><Cachectin><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Line><CellLine><Cells><Characteristics><Chemicals><Chemokine, CC Motif, Ligand 2><Chromatin><Clinical><Clinical Trials><CoV emergence><Colitis><Complex><Cooperative Agreements><Cytokine Synthesis Inhibitory Factor><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><D6S113E><DNA-Dependent RNA Polymerase II><Da Nang Lung><Development><Disease><Disease Outbreaks><Disorder><Drugs><Enhancer Elements><Enhancers><Ensure><Expression Signature><FDA approved><FSRG1><Female Sterile Homeotic-Related Gene 1><Funding><G(s), alpha Subunit><G(s), α Subunit><G(s)alpha><G(s)α><GM-CSF><GTP-Binding Protein alpha Subunits, Gs><GTP-Binding Protein α Subunits, Gs><Gamma interferon><Gene Expression Profile><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Enhancer Element><Genetic Transcription><Genomics><Goals><Grant><Granular Leukocytes><Granulocyte-Macrophage Colony-Stimulating Factor><Granulocytic cell><Grippe><Gs alpha Family G-Protein><Gsα><Gαs><HPGF><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hepatocyte-Stimulating Factor><Histamine-Producing Cell-Stimulating Factor><Histones><Human><Hybridoma Growth Factor><IFN-Gamma><IFN-beta 2><IFN-g><IFN-γ><IFNB2><IFNG><IFNγ><IL-10><IL-17><IL-17A><IL-6><IL10><IL10A><IL17 Protein><IL17A><IL6 Protein><Immune><Immune Interferon><Immune response><Immunes><Immunoglobulin Enhancer-Binding Protein><Immunological response><Impairment><In Vitro><Individual><Inducer Cells><Inducer T-Lymphocytes><Infection><Inflammation><Inflammatory><Influenza><Interferon Gamma><Interferon Type II><Interferon-gamma><Interleukin 10 Precursor><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 Precursor><Interleukin-10><Interleukin-17><Interleukin-6><Investigation><KIAA9001><Knowledge><L-Lysine><Life><Ligands><Lung><Lung Respiratory System><Lysine><MCAF><MCP-1><MCP1><MGI-2><Macrophage-Derived TNF><Medical><Medication><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Molgramostin><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Monocyte-Derived TNF><Murine><Mus><Myeloid Differentiation-Inducing Protein><NF-kB><NF-kappa B><NF-kappaB><NFKB><NIAID><NIH><National Institute of Allergy and Infectious Disease><National Institutes of Health><Non-Polyadenylated RNA><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Outbreaks><P-TEFb><PBMC><Parents><Patients><Peptide Domain><Peripheral Blood Mononuclear Cell><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Phosphorylation><Plasmacytoma Growth Factor><Play><Positive Transcription Elongation Factor B><Positive Transcriptional Elongation Factor B><Protein Domains><Protein Family><Protein Phosphorylation><Proteins><R-Series Research Projects><R01 Mechanism><R01 Program><RING3><RNA><RNA Expression><RNA Gene Products><RNA Polymerase B><RNA Polymerase II><RNF3><Regulation><Regulatory Ns Protein><Reporting><Research Grants><Research Project Grants><Research Projects><Respiration Disorders><Respiratory Disorder><Ribonucleic Acid><Role><SARS Virus><SARS corona virus><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><SCYA2><STAT3><STAT3 gene><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe acute respiratory syndrome coronavirus 2><Shock Lung><Site><Small Inducible Cytokine A2><Speed><Stat3 Signaling Pathway><Stiff lung><Stimulatory Gs G-Protein><Strains Cell Lines><Structure><T4 Cells><T4 Lymphocytes><TC-GM-CSF><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Tertiary Protein Structure><Testicles><Testis><Tissues><Transcription><Transcription Activation><Transcription Elongation><Transcription Factor NF-kB><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Activation><Transcriptional Control><Transcriptional Regulation><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor-Cell Human GM Colony-Stimulating Factor><U-Series Cooperative Agreements><United States National Institutes of Health><Vaccines><Virus><Work><Wuhan coronavirus><adaptive immunity><alpha Subunit Stimulatory GTP-Binding Protein><alpha-Gs><anti-viral agents><anti-viral drugs><anti-virals><autoimmune disorder><biological systems><breathing disorder><cohesin><corona virus disease 2019><coronavirus disease 2019><coronavirus emergence><cultured cell line><cytokine><cytokine release syndrome><cytokine storm><design><designing><developmental><drug/agent><effective therapy><effective treatment><emergent CoV><emergent coronavirus><emerging CoV><emerging coronavirus><enhancer sequence><epigenetic drug><epigenetic modifying drugs><epigenomics><flu infection><gene expression pattern><gene expression signature><gene interaction><genetic enhancer sequence><granulocyte><granulocyte macrophage colony stimulating factor><host response><immunoresponse><in vivo><influenza infection><inhibitor><inhibitor/antagonist><insight><interest><interferon beta 2><kappa B Enhancer Binding Protein><lFN-Gamma><macrophage><mortality><nCoV><new CoV><new coronavirus><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation><next generation therapeutics><novel><novel CoV><novel coronavirus><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><nuclear factor kappa beta><pandemic><pandemic disease><programs><promoter><promotor><pulmonary><recruit><respiratory dysfunction><response><severe acute respiratory syndrome-CoV><small molecule><social role><tat-Associated Kinase><transcription factor><transcriptional signature><wet lung><α-Gs>