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:
  • 金额:
    $ 26.22万
  • 依托单位:
  • 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

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.
项目摘要 急性肺损伤(ALI)及其严重形式,急性呼吸窘迫综合征(ARDS), 呼吸衰竭的常见原因尽管有各种医学创新,ARDS的治疗仍然是一个未解决的问题。 问题.中性粒细胞是ALI期间最先浸润到肺中的免疫细胞, 蛋白酶、细胞因子和氧化剂来杀死入侵的微生物以及损伤肺。临床数据和 动物模型已经证明中性粒细胞的募集和功能影响ALI的进展。因此,在本发明中, 对中性粒细胞募集和功能的深入了解可能为治疗提供一种新的方法。 的阿里。 整合素b2在调节中性粒细胞募集和中性粒细胞功能中起重要作用。 在发炎部位,细胞内信号传导上调整合素配体结合亲和力,这使得配体 绑定。在高亲和力状态下,配体与整合素b2的结合阻止了中性粒细胞,这是 中性粒细胞募集,以及引起整联蛋白簇形成(即整联蛋白价),以增强中性粒细胞 逮捕了目前,胞内信号转导是调控整合素配体结合的唯一途径 能力。整联蛋白b2的细胞外结构域用N-连接的聚糖修饰。然而,是否以及如何N- 聚糖调节整联蛋白B2-配体结合尚未被研究。此外,晚期乳腺癌的受体 I型肺泡上皮细胞(AT 1)上的糖基化终产物(AGEs)是炎症反应的主要介质, 肺部的反应。中性粒细胞上的整合素aMb 2是一种β-内酰胺酶的配体,然而, 整合素aMb 2与ALI炎症进展的关系尚不清楚。 我们的初步研究发现,去除N-聚糖增加了整合素aLb 2介导的中性粒细胞 粘附和配体结合诱导的嗜中性粒细胞反应。此外,去除唾液酸 增加aMb 2与p53的结合。因此,我们假设1)细胞外结构域上的N-聚糖阻止了 整合素aLb 2以采用高亲和力状态和/或限制整合素簇形成;和2)减少整合素aLb 2的亲和力, 整联蛋白aMb 2的糖基化促进其与可增加炎症反应的炎症因子的结合。 肺因此,我们提出两个目的来检验假设:目的1:确定整合素aLb 2上的N-聚糖 目的2:确定aMb 2上的聚糖是否负调节其配体结合亲和力和价态;以及 调节AT 1细胞中RAGE介导的炎症反应。在N-聚糖上含有突变的整合素b2 作为一种新的检测整合素亲和状态的工具,AT 1细胞和ALI小鼠模型, 用来验证我们的假设我们提出的研究将解释N-聚糖对中性粒细胞b2整合素的作用, 在ALI发病机制中的作用,可能为ALI的治疗提供新的思路。

项目成果

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BOJING SHAO其他文献

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{{ truncateString('BOJING SHAO', 18)}}的其他基金

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
  • 批准号:
    10837431
  • 财政年份:
    2023
  • 资助金额:
    $ 26.22万
  • 项目类别:

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