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Role of intravascular ERO1@ in acute lung injury

血管内ERO1@在急性肺损伤中的作用

基本信息

批准号：
10469645
负责人：
Jaehyung Cho
金额：
$ 37.99万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-21 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469645
关键词：
Acute Acute Lung Injury Acute Respiratory Distress Syndrome Address Adhesions Adhesives Admission activity Affect Alveolar Antibodies Attenuated Binding Biochemical Biological Biological Markers Blood Blood Cells Blood Platelets Blood Vessels Cell Aggregation Cell Communication Cells Complex Complication Data Disease Disease Progression Endoplasmic Reticulum Endothelial Cells Extracellular Protein Genetic Glycoproteins Goals Hematological Disease Hypoxia Imaging Techniques Impairment Inflammation Inflammatory Integrins Intensive Care Units Leukocytes Life Ligand Binding Ligands Light Lung Macrophage-1 Antigen Mediating Molecular Mus Natural Immunity Neutrophil Infiltration Organ failure Oxidases Pathogenesis Pathologic Pathology Patients Peptides Plasma Pneumonia Process Protein Disulfide Isomerase Pulmonary Edema Pulmonary Inflammation Pulmonary Valve Insufficiency Role Sepsis Severities Severity of illness Signal Transduction Site Sulfhydryl Compounds Supporting Cell Surface Testing Tissues Trauma adhesion receptor base design disulfide bond extracellular imaging approach improved inhibitor insight intravital imaging lung imaging mouse model neutrophil novel novel therapeutic intervention novel therapeutics receptor recruit septic small molecule therapeutically effective thromboinflammation vascular inflammation

项目摘要

Project Summary Acute lung injury (ALI) is a life-threatening condition, which affects > 200,000 patients annually in the U.S. It is associated with pneumonia, sepsis, and trauma, leading to pulmonary insufficiency and eventually multisystem organ failure. Since excessive recruitment of activated neutrophils to lung microvessels is a primary cause of ALI, a better understanding of the mechanism mediating neutrophil-endothelial cell interactions will provide insight into developing an effective therapeutic for treating ALI. We previously demonstrated that intravascular protein disulfide isomerase (PDI) enhances the ligand-binding activity of neutrophil and platelet surface receptors and leads to intravascular cell-cell interactions during vascular inflammation. To elucidate how extracellular PDI activity is regulated and whether the regulatory mechanism contributes to the pathology of ALI, we have found that endoplasmic reticulum oxidoreductin 1α (ERO1α, a key oxidase of PDI in the ER) promotes neutrophil recruitment during vascular inflammation. In this proposal, we will test the hypothesis that intravascular ERO1α enhances the ligand-binding function of neutrophil adhesion receptors by modifying disulfide bonds, inducing neutrophil recruitment to sites of acute lung inflammation. In Aim 1, we will determine the mechanism by which ERO1α regulates neutrophil-endothelial cell interactions. In Aim 2, we will utilize lung live imaging techniques to investigate the pathological role of intravascular ERO1α in ALI. In Aim 3, using the blood of patients with acute respiratory distress syndrome (ARDS), we will determine the contribution of ERO1α to the disease progression and severity in patients with ARDS. These studies will employ biochemical, cell biological, genetic, and confocal intravital imaging approaches. Since little is known about extracellular thiol-modifying machinery, the proposed studies will identify an essential, yet unexplored, mechanism that promotes the pathogenesis of ALI/ARDS.

项目总结