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Principal Investigator: Andrea Tara Obi
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $607,566
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY / ABSTRACT
Excessive endothelial inflammation, ‘endotheliitis,’ is a hallmark pathologic feature of severe SARs-CoV2
infection. The sequalae of endotheliitis, such as microthrombosis and tissue hyperpermeability, culminate in a
maladaptive host response characterized by interstitial edema, tissue damage, and end organ dysfunction.
Despite advances in vaccines and antiviral treatments, the most severely ill patients suffering from SARs-CoV2
related endotheliitis have an elevated risk of mortality. There are currently neither specific medications
available to treat nor to prevent endotheliitis. Current therapies for severe SARs-CoV-2 infection are limited to
non-specific steroids, immunomodulators and anticoagulants: all are limited in clinical use due to significant
risk profile from off-target effects. Thus, a critical need exists for understanding specific regulators of the
dysfunctional endothelial response for development of targeted therapies. Utilizing human SARs-CoV2
specimens and multiple murine coronavirus models, we identify a novel role for histone methyltransferase
MLL1 in regulating gene expression central to the endotheliitis response: cellular adhesion molecules (CAMs)
and pro-coagulant mediators (PCMs). Through a series of experiments, we have identified specific signal
transducer and activators of transcription (STATs) as important drivers of viral-induced MLL1 expression and
IL-1 receptor-associated kinases (IRAKs) as key regulators of MLL1 degradation. Hence, we identified that the
imbalance of STAT-mediated expression and IRAK-mediated degradation of MLL1 augments viral
endotheliitis. These results have led to our hypothesis that endotheliitis gene expression in response to
coronavirus is mechanistically driven by the STAT-MLL1-IRAK pathway and promotes overt endothelial
activation, microthrombosis, and end-organ damage. We further postulate that endothelial homeostasis may
be restored via nanoparticle encapsulated MLL1 inhibitor targeted to the endothelial cells, resulting in
attenuation of viral-induced endotheliitis. This hypothesis will be investigated via the following specific aims:
Aim 1: To determine the mechanism(s) by which MLL1 targets endothelial CAMs and PCMs promotor
regions. Aim 2: To determine the role of STAT-1/3 in endothelial MLL1 induction and IRAK4 in MLL1
degradation. Aim 3: To determine functional impact of endothelial specific MLL1 inhibition on EC
adhesive characteristics and thrombotic propensity in vivo. Completion of these aims will increase our
mechanistic understanding of endothelial MLL1 as master regulator of endotheliitis-related genes in an
infectious context. The results from this proposal will define for the first time the ability of an endothelial-
targeted therapy to inhibit the pathologic features of severe SARs-COV2 infection.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ALL1><ALL1 gene><Acute Lymphoblastic Leukemia Protein 1><Address><Adhesion Molecule><Adhesives><Anticoagulant Agents><Anticoagulant Drugs><Anticoagulants><Assay><Autoregulation><Bioassay><Biological Assay><Blood Vessels><Blood leukocyte><Body Tissues><COVID-19 infection><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><CXXC7><Cell Adhesion><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Adhesion><Cellular Function><Cellular Physiology><Cellular Process><Characteristics><Chromatin><Clinical><CoV-2><CoV2><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Data><Development><Disease><Disorder><Dropsy><Drosophila Homolog of Trithorax><Drugs><Dysfunction><Edema><Encapsulated><Endothelial Cells><Endothelium><Enzyme Gene><Enzymes><Functional disorder><Gatekeeping><Gene Expression><Gene Transcription><Genes><Genetic Transcription><Genetics-Mutagenesis><Goals><HRX><Health><Histone-Lysine Methyltransferase><Histone-Lysine N-Methyltransferase><Homeostasis><Human><Hydrops><IL-1 receptor-associated kinase><IRAK protein><IRAK4><IRAK4 gene><Immune response><Immunoglobulin Enhancer-Binding Protein><Immunological response><Immunomodulators><In Vitro><Inflammation><Innovative Therapy><Interleukin-1 Receptor-Associated Kinase 4><Intracellular Communication and Signaling><KMT2A><Laboratories><Leukocytes><Leukocytes Reticuloendothelial System><Lung><Lung Respiratory System><Lysine-Specific Methyltransferase 2A><MLL gene><MLL leukemia><MLL1><Marrow leukocyte><Mediating><Mediation><Mediator><Medication><Methylation><Mice><Mice Mammals><Mixed Lineage Leukemia Gene><Mixed-Lineage Leukemia><Mixed-Lineage Leukemia Protein><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Multiple lineage leukemia 1><Murine><Mus><Mutagenesis><Mutagenesis Molecular Biology><Myeloid-Lymphoid Leukemia Gene><Myeloid-Lymphoid Leukemia Protein><Myeloid/Lymphoid Leukemia Gene><Myeloid/Lymphoid Or Mixed Lineage Leukemia Protein><Myeloid/Lymphoid or Mixed Lineage Leukemia Gene><NF-kB><NF-kappa B><NF-kappaB><NFKB><NY-REN-64><Negotiating><Negotiation><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Organ><Pathologic><Pathway interactions><Patient Care><Patient Care Delivery><Patients><Pharmaceutical Preparations><Physiological Homeostasis><Physiopathology><Pneumonia><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Prevention><Promoter Regions><Promotor Regions><Property><Protein Lysine Methyltransferase><Protein Methylase III><Protein Methyltransferase III><Proto Oncogene Proteins MLL><REN64><RNA Expression><RNA Interference><RNA Silencing><RNAi><Regulation><Research Specimen><Risk><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><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><STAT protein><STAT1 protein><Sequence-Specific Posttranscriptional Gene Silencing><Series><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 related corona virus 2><Severity of illness><Signal Pathway><Signal Transducer and Activator of Transcription><Signal Transduction><Signal Transduction Systems><Signaling><Specimen><Stat-1 protein><Stat-91 protein><Stat91 protein><Steroid Compound><Steroids><Subcellular Process><Surface><System><Techniques><Testing><Thrombosis><Time><Tissues><Transcription><Transcription Factor NF-kB><Vaccines><Viral><Viral Diseases><Virus Diseases><White Blood Cells><White Cell><Wuhan coronavirus><Zinc Finger Protein HRX><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><attenuation><biological signal transduction><blood thinner><care for patients><care of patients><caring for patients><cell adhesion protein><corona virus><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19 virus><death risk><developmental><disease severity><drug/agent><epigenetic regulation><experiment><experimental research><experimental study><experiments><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><gatekeeper><genetic promoter element><genetic promoter sequence><hCoV19><histone H3 methyltransferase><histone methylase><histone methyltransferase><histone modification><host response><immune modulators><immune system response><immunoresponse><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><inhibitor><injury to the vasculature><injury to tissue><innovate><innovation><innovative><insight><interleukin-1 receptor-associated kinase><interstitial><kappa B Enhancer Binding Protein><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><migration><mortality><mortality risk><nCoV2><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><novel><nuclear factor kappa beta><pathogen><pathophysiology><pathway><pharmacologic><post SARS-CoV-2 infection><pre-clinical><preclinical><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><promoter sequence><pulmonary><recruit><research facility><response><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 coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><signal transducer and activator of transcription 1><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thromboembolic complications><thrombopoiesis inhibitor><thrombosis complications><thrombotic><thrombotic complications><thrombotic disease><thrombotic disorder><tissue injury><transcription factor Stat91><vascular><vascular endothelial dysfunction><vascular injury><viral infection><virus infection><virus-induced disease><white blood cell><white blood corpuscle>