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：
10686908
负责人：
Jaehyung Cho
金额：
$ 41.33万
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/10686908
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 Hypoxia Imaging Techniques Impairment Inflammation Inflammatory Integrins Intensive Care Units Leukocytes Life Ligand Binding Ligands 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 Thrombus Tissues Trauma adhesion receptor body system 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.

项目摘要急性肺损伤（ALI）是一种威胁生命的疾病，每年在美国影响> 20万名患者与肺炎，败血症和创伤相关，导致肺部功能不全，最终导致多系统器官故障。由于过度募集活化的嗜中性粒细胞到肺微血管是 Ali，更好地理解介导中性粒细胞 - 内皮细胞相互作用的机制将提供深入了解有效治疗ALI的疗法。我们以前证明了血管内蛋白质二硫异构酶（PDI）增强了中性粒细胞和血小板表面受体的配体结合活性并导致血管内细胞相互作用在血管炎症过程中。阐明细胞外PDI 活动受到调节，调节机制是否有助于ALI的病理，我们发现那个内质网氧化还原素1α（ERO1α，ER中PDI的关键氧化酶）促进中性粒细胞血管炎症期间的募集。在此提案中，我们将测试血管内ERO1α的假设通过修饰二硫键，增强中性粒细胞粘附受体的配体结合功能，诱导中性粒细胞募集到急性肺部感染部位。在AIM 1中，我们将确定该机制 ERO1α调节中性粒细胞 - 内皮细胞相互作用。在AIM 2中，我们将利用肺实时成像技术研究血管内ERO1α在ALI中的病理作用。在AIM 3中，使用急性患者的血液呼吸窘迫综合征（ARDS），我们将确定ERO1α对疾病进展的贡献 ARDS患者的严重程度。这些研究将采用生化，细胞生物学，遗传和共焦点插入成像方法。由于对细胞外硫醇修饰机械知之甚少，因此提出的研究将确定一种必不可少但出乎意料的机制，可促进ALI/ARDS的发病机理。