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Thiol isomerases in neutrophil recruitment and thromboinflammatory disease

中性粒细胞募集和血栓炎性疾病中的硫醇异构酶

基本信息

批准号：
10649685
负责人：
Jaehyung Cho
金额：
$ 41.55万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649685
关键词：
Acute Adhesions Adhesives Affect Binding Binding Proteins Biochemical Biological Blocking Antibodies Blood Platelets Blood Vessels Cell Communication Cell Surface Receptors Cell physiology Cells Complex Data Disease ERp57 Endoplasmic Reticulum Endothelial Cells Extracellular Protein Family member Glycoproteins Goals Imaging Techniques Immune response Inflammation Inflammatory Innate Immune Response Integrins Ischemic Stroke Isomerase Knockout Mice Knowledge Leukocytes Ligand Binding Ligands Macrophage-1 Antigen Mediating Modeling Modification Molecular NADPH Oxidase Natural Immunity Neutrophil Infiltration Oxidases Oxidation-Reduction Oxidative Stress Pathologic Peptides Peroxidases Process Protein Disulfide Isomerase Proteins Pulmonary Inflammation Reactive Oxygen Species Role Signal Pathway Signal Transduction Site Sulfhydryl Compounds Surface Testing Thrombus Tissues conditional knockout design disulfide bond extracellular in vivo inflammatory milieu insight lung ischemia mouse model neutrophil novel novel therapeutic intervention receptor recruit role model targeted treatment thromboinflammation vascular inflammation

项目摘要

Project Summary Neutrophil recruitment to sites of inflammation is a multi-step process mediated by the interactions between several receptors and ligands. Although the major receptors and ligands mediating neutrophil-endothelial cell interactions have been identified, it remains poorly understood how receptor-ligand interactions are regulated under inflammatory conditions. This project will provide novel fundamental knowledge of how neutrophil surface- localized ERO1α-thiol isomerase complexes target allosteric disulfide bonds in different surface receptors and promote the ligand-binding function under inflammatory conditions. Our preliminary data demonstrated that neutrophil surface-bound ERp57 and PDI cooperatively and distinctly regulate the process of neutrophil recruitment and extracellular ERO1α coordinates this regulatory mechanism. Using biochemical, cellular, and in vivo studies with novel blocking antibodies, peptides and mouse models, we will test the hypothesis that two structurally-similar thiol isomerases, ERp57 and PDI and their oxidase ERO1α facilitate modification of allosteric disulfide bonds in different surface molecules and enhance neutrophil adhesive function, contributing to tissue damage under thromboinflammatory conditions. In Aim 1, we will determine how PDI and ERp57 distinctly regulate the adhesive function of different neutrophil receptors. Also, we will test whether extracellular ERO1α controls the activity of those thiol isomerases. In Aim 2, we will test how inflammatory environments influence the function of extracellular PDI, ERp57 and ERO1α. In Aim 3, using in vivo live imaging techniques, we will study the pathological roles of extracellular PDI, ERp57 and ERO1α in intravascular cell-cell interactions and tissue damage in thromboinflammation. Our studies will provide insights into novel molecular and cellular mechanisms of neutrophil-endothelial cell interactions, which can be used to design new strategies for the treatment of thromboinflammatory disease.

项目摘要炎症部位的神经元募集是一个多步骤的过程，几种受体和配体。虽然主要的受体和配体介导嗜酸性粒细胞-内皮细胞尽管已经鉴定了受体-配体相互作用，但对受体-配体相互作用如何调节仍知之甚少在炎症条件下。该项目将提供新的基础知识如何中性粒细胞表面- 局部ERO 1 α-巯基异构酶复合物靶向不同表面受体中的变构二硫键，促进炎症条件下的配体结合功能。我们的初步数据表明，中性粒细胞表面结合的ERp 57和PDI协同且明显地调节中性粒细胞的过程，募集和细胞外ERO 1 α协调这种调节机制。利用生物化学，细胞，和在使用新型阻断抗体、肽和小鼠模型的体内研究中，我们将检验以下假设：结构相似的巯基异构酶ERp 57和PDI及其氧化酶ERO 1 α促进变构的修饰，二硫键在不同的表面分子，增强中性粒细胞粘附功能，有助于组织血栓炎性条件下的损伤。在目标1中，我们将确定PDI和ERp 57如何区别于调节不同中性粒细胞受体的粘附功能。此外，我们还将检测细胞外ERO 1 α 控制着那些巯基异构酶的活性。在目标2中，我们将测试炎症环境如何影响细胞外PDI、ERp 57和ERO 1 α的功能。在目标3中，使用体内实时成像技术，我们将研究细胞外PDI、ERp 57和ERO 1 α在血管内细胞-细胞相互作用中的病理作用，血栓炎症中的组织损伤。我们的研究将提供新的分子和细胞的见解嗜酸性粒细胞-内皮细胞相互作用的机制，可用于设计新的策略，血栓炎性疾病的治疗。