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Roles of N-glycans on neutrophil beta2 integrins in progression of acute lung injury

N-聚糖对中性粒细胞β2整合素在急性肺损伤进展中的作用

基本信息

批准号：
10509625
负责人：
BOJING SHAO
金额：
$ 26.22万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2023-05-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10509625
关键词：
Acute Acute Lung Injury Acute Respiratory Distress Syndrome Address Adhesions Adopted Affinity Animal Model Binding Biological Process CD18 Antigens COVID-19 COVID-19 patient COVID-19 treatment Cell model Cells Clinical Clinical Data Data Development Diffuse Enzymes Extracellular Domain Impairment Incidence Individual Infection Inflammation Inflammation Mediators Inflammatory Response Integrins Intensive Care Invaded Lead Ligand Binding Ligands Link Lung Lung diseases Measures Mediating Medical Medicine Membrane Proteins Microbe Modeling Molecular Conformation Mus Mutation Neuraminidase Neutrophil Infiltration Neutrophilic Infiltrate Oxidants Pathogenesis Patients Peptide Hydrolases Persons Pilot Projects Play Polysaccharides Post-Translational Protein Processing Publishing Pulmonary Inflammation Regulation Respiratory Failure Role Sialic Acids Signal Transduction Site Testing Time Tissues Tumor-infiltrating immune cells Viral Respiratory Tract Infection alveolar epithelium cell type cytokine data modeling effective therapy experience glycosylation injured innovation insight lung injury mortality mouse model neutrophil novel novel strategies novel therapeutics pandemic disease pathogen prevent receptor for advanced glycation endproducts response tool

项目摘要

PROJECT SUMMARY Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are the common cause of respiratory failure. Despite all medical innovations, treatment of ARDS remains an unsolved problem. Neutrophils are the first immune cells infiltrated into lungs during ALI, where neutrophils release proteinases, cytokines, and oxidants to kill invading microbes, as well as to injure lungs. Clinical data and animal models have proved that neutrophil recruitment and function influences the progression of ALI. Thus, insights into the fine-tuned neutrophil recruitment and function may provide a novel approach for the treatment of ALI. Integrin b2 plays an important role in the regulation of neutrophil recruitment and neutrophil functions. At inflamed sites, the intracellular signaling upregulates the integrin ligand-binding affinity, which allows ligands to bind. Ligand binding to integrin b2 in the high-affinity state arrests neutrophils, a prerequisite step for neutrophil recruitment, as well as causes integrin cluster formation (i.e. integrin valency) to enhance neutrophil arrest. Currently, the intracellular signaling is the only approach to regulate the integrin ligand-binding capability. The extracellular domain of integrin b2 is decorated with N-linked glycans. Yet, whether and how N- glycans regulate the integrin b2-ligand binding has not been studied. In addition, the receptor for advanced glycation end-products (RAGE) on alveolar epithelial cell type I (AT1) is a major mediator for inflammatory responses in lungs. Integrin aMb2 on neutrophils is a ligand for RAGE, however, the role of the interaction of integrin aMb2 with RAGE in the progression of inflammation in ALI is unknown. Our preliminary studies found that removing N-glycans increased integrin aLb2-mediated neutrophil adhesion and ligand binding-induced neutrophil cellular responses. Furthermore, removing sialic acids increased aMb2 binding to RAGE. Thus, we hypothesize that 1) N-glycans on the extracellular domain prevent integrin aLb2 to adopt the high-affinity state and/or limit the integrin cluster formation; and 2) reduced glycosylation of integrin aMb2 facilitates its binding to RAGE that may increase inflammatory responses in lungs. Thus, we propose two Aims to test the hypotheses: Aim 1: Determine if N-glycans on integrin aLb2 negatively regulate its ligand-binding affinity and valency; and Aim 2: Determine if glycans on aMb2 negatively regulate RAGE-mediated inflammatory responses in AT1 cells. Integrin b2 containing mutations on N-glycan bearing sites, a novel tool to measuring integrin affinity states, AT1 cells, and mouse models of ALI will be used to test our hypotheses. Our proposed study will decipher the role of N-glycans on neutrophil b2 integrins in the pathogenesis of ALI, which may lead to the development of a new therapy for ALI.

项目概要急性肺损伤 (ALI) 及其严重形式急性呼吸窘迫综合征 (ARDS) 是呼吸衰竭的常见原因。尽管有各种医学创新，ARDS 的治疗仍然是一个悬而未决的问题问题。中性粒细胞是 ALI 期间最先渗入肺部的免疫细胞，其中中性粒细胞释放蛋白酶、细胞因子和氧化剂杀死入侵的微生物，并损伤肺部。临床数据和动物模型已证明中性粒细胞的募集和功能影响 ALI 的进展。因此，对微调中性粒细胞募集和功能的深入了解可能会提供一种新的治疗方法阿里的。整合素 b2 在中性粒细胞募集和中性粒细胞功能的调节中发挥着重要作用。在发炎部位，细胞内信号传导上调整合素配体结合亲和力，从而使配体绑定。在高亲和力状态下与整合素 b2 结合的配体可抑制中性粒细胞，这是中性粒细胞募集，并导致整合素簇形成（即整合素价）以增强中性粒细胞逮捕。目前，细胞内信号传导是调节整合素配体结合的唯一方法能力。整合素 b2 的胞外结构域用 N 连接聚糖装饰。然而，是否以及如何 N- 聚糖调节整合素 b2-配体结合尚未得到研究。此外，高级受体 I 型肺泡上皮细胞 (AT1) 上的糖基化终产物 (RAGE) 是炎症的主要介质肺部的反应。中性粒细胞上的整合素 aMb2 是 RAGE 的配体，然而，整合素 aMb2 与 RAGE 在 ALI 炎症进展中的作用尚不清楚。我们的初步研究发现，去除 N-聚糖会增加整合素 aLb2 介导的中性粒细胞粘附和配体结合诱导中性粒细胞反应。此外，去除唾液酸增加 aMb2 与 RAGE 的结合。因此，我们假设 1) 胞外域上的 N-聚糖可防止整合素aLb2采用高亲和力状态和/或限制整合素簇形成； 2) 减少整合素 aMb2 的糖基化促进其与 RAGE 的结合，从而可能增加炎症反应肺。因此，我们提出两个目标来检验假设：目标 1：确定整合素 aLb2 上是否存在 N-聚糖负向调节其配体结合亲和力和价态；目标 2：确定 aMb2 上的聚糖是否产生负面影响调节 AT1 细胞中 RAGE 介导的炎症反应。整合素 b2 含有 N-聚糖突变轴承位点、测量整合素亲和力状态、AT1 细胞和 ALI 小鼠模型的新工具将用于检验我们的假设。我们提出的研究将破译 N-聚糖对中性粒细胞 b2 整合素的作用 ALI 的发病机制，这可能会导致 ALI 的新疗法的开发。