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：
10027023
负责人：
Jaehyung Cho
金额：
$ 39.38万
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/10027023
关键词：
Acute Acute Lung Injury Address Adhesions Adhesives Admission activity Adult Respiratory Distress Syndrome 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 Estrogen receptor positive Extracellular Protein Genetic Glycoproteins Goals Hematological Disease Hypoxia Imaging Techniques Impairment Inflammation Inflammatory Integrins Intensive Care Units Leukocytes Life Ligand Binding Ligands Light Lung Lung Inflammation 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 Valve Insufficiency Role Sepsis Severities Severity of illness Signal Transduction Site Sulfhydryl Compounds Supporting Cell Surface Testing Tissues Trauma Treatment Efficacy adhesion receptor base design disulfide bond extracellular imaging approach improved inhibitor/antagonist insight intravital imaging lung imaging mouse model neutrophil novel novel therapeutics receptor recruit septic small molecule 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.

项目概要急性肺损伤 (ALI) 是一种危及生命的疾病，在美国每年影响超过 200,000 名患者。与肺炎、败血症和创伤有关，导致肺功能不全并最终导致多系统由于肺微血管过度募集活化的中性粒细胞是器官衰竭的主要原因。 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我们之前已经证明，血管内治疗已成为治疗 ALI 的有效疗法。蛋白质二硫键异构酶 (PDI) 增强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炎症期间血管内细胞间相互作用，以阐明细胞外 PDI 的作用。我们发现活动受到调节以及调节机制是否有助于 ALI 的病理学内质网氧化还原素 1α（ERO1α，ER 中 PDI 的关键氧化酶）促进中性粒细胞在本提案中，我们将检验血管内 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，诱导在目标 1 中，我们将确定中性粒细胞募集到急性肺部炎症部位的机制。 ERO1α 调节中性粒细胞与内皮细胞的相互作用。在目标 2 中，我们将利用肺部实时成像技术来实现。在目标 3 中，使用急性患者的血液研究血管内 ERO1α 在 ALI 中的病理作用。呼吸窘迫综合征 (ARDS)，我们将确定 ERO1α 对疾病进展的贡献这些研究将采用生化、细胞生物学、遗传学和共聚焦技术。由于对细胞外硫醇修饰机制知之甚少，因此提出了活体成像方法。研究将确定促进 ALI/ARDS 发病机制的重要但尚未探索的机制。