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Principal Investigator: Yutong Zhao
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $523,559
Funding agency: National Heart Lung and Blood Institute
Abstract
Excessive lung microvascular endothelial inflammation is a pathological hallmark of acute
respiratory distress syndrome (ARDS). Upon inflammatory stimuli, lung endothelial cells (ECs)
increase chemokine and adhesion molecule expression, such as IL-6, and intercellular adhesion
molecule 1, ultimately causing neutrophil accumulation at the site of inflammation, endothelial
barrier dysfunction, and lung tissue damage in acute lung injury and sepsis. Nuclear
transcriptional factor κB (NF-κB) plays a pivotal role in EC inflammation. Inflammatory stimuli
trigger phosphorylation of NF-κB component p65, leading to increase p65 transcriptional activity.
We revealed that NF-κBp65 can be ISGylated. The ISGylated p65 is inactive in the resting ECs.
We also discovered that SCFFBXL19 E3 ligase catalyzes ISGylation of p65, impedes p65
phosphorylation, and mitigates lung EC inflammation. These observations led us to hypothesize
that p65 ISGylation by SCFFBXL19 dampens its phosphorylation, transcriptional activation, and lung
EC inflammation; and increases in FBXL19 stability mitigates lung EC inflammation through
reducing NF-kB activation. To better understand the new modification of p65, in this proposal, we
will determine molecular mechanisms by which SCFFBXL19 catalyzes p65 ISGylation and its role in
human lung microvascular EC inflammation. And then, we will determine the molecular
mechanisms by which p65 ISGylation impedes its phosphorylation and activation in human lung
microvascular ECs. Lastly, we will determine if stabilization of FBXL19 alleviates lung EC
inflammation in murine models of acute lung injury and sepsis. This application will be the first to
characterize SCFFBXL19-mediated ISGylation of NF-κBp65 and determine its role in the regulation
of p65 phosphorylation, transcriptional activation, and lung EC inflammation in acute lung injury
and sepsis.
Terms: <3-10C><AMCF-I><ARDS><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adhesion Molecule><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Basal Transcription Factor><Basal transcription factor genes><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><CD54 Antigens><CXCL8><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Function><Cell Physiology><Cell Process><Cellular Function><Cellular Physiology><Cellular Process><Chemotactic Cytokines><Da Nang Lung><Data><Development><Disease><Disorder><Dysfunction><E3 Ligase><E3 Ubiquitin Ligase><Endothelial Cells><Endothelium><Exhibits><F-Box Domain Protein><F-Box Protein Family><F-Box Proteins><Family member><Foundations><Functional disorder><GCP1><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><HPGF><Hepatocyte-Stimulating Factor><Homologous Chemotactic Cytokines><Human><Hybridoma Growth Factor><ICAM-1><IFN><IFN-beta 2><IFNB2><IL-6><IL-8><IL6 Protein><IL8><IL8 gene><Immune response><Immunoglobulin Enhancer-Binding Protein><Immunological response><Inflammation><Inflammatory><Intercellular adhesion molecule 1><Intercrines><Interferons><Interleukin-6><K60><L-Serine><Ligase><Ligase Gene><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><MGI-2><Marrow Neutrophil><Mediating><Modern Man><Modification><Molecular><Myeloid Differentiation-Inducing Protein><NF-kB><NF-kappa B><NF-kappaB><NFKB><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nuclear><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Pathogenesis><Pathologic><Pathway interactions><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Phosphorylation><Physiopathology><Plasmacytoma Growth Factor><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Process><Property><Protein Modification><Protein Phosphorylation><Proteins><RNA Expression><Regulation><Reporting><Rest><Role><SCYB8><SIS cytokines><Scheme><Sepsis><Sepsis and ARDS><Serine><Severities><Shock Lung><Site><Stiff lung><Stimulus><Structure of parenchyma of lung><Subcellular Process><Synthetases><TSG-1><Transcription><Transcription Activation><Transcription Factor NF-kB><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Activation><Transgenic Mice><Ubiquitin Like Proteins><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Up-Regulation><Upregulation><Vascular Endothelium><acute respiratory distress syndrome caused by sepsis><attenuation><b-ENAP><blood infection><bloodstream infection><cell adhesion protein><chemoattractant cytokine><chemokine><developmental><host response><immune system response><immunoresponse><interferon beta 2><isopeptidase><kappa B Enhancer Binding Protein><lung injury><lung microvascular endothelial cells><lung vascular endothelial cells><mouse model><murine model><neutrophil><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nuclear factor kappa beta><overexpress><overexpression><p65><pathophysiology><pathway><pulmonary><pulmonary damage><pulmonary injury><pulmonary microvascular endothelial cells><pulmonary tissue damage><pulmonary tissue injury><pulmonary vascular endothelial cells><response><sepsis ARDS><sepsis acute respiratory distress syndrome><sepsis and acute respiratory distress syndrome><sepsis associated acute respiratory distress syndrome><sepsis induced ARDS><sepsis induced acute respiratory distress syndrome><sepsis related acute respiratory distress syndrome><side effect><small molecular inhibitor><small molecule><small molecule inhibitor><social role><transcription factor><ubiquitin-protein ligase><vascular endothelial dysfunction><wet lung>