Regulation of airway epithelial cell-mediated inflammation by CRAC channels

CRAC 通道对气道上皮细胞介导的炎症的调节

• 批准号: 10198037
• 负责人: Murali Prakriya
• 金额: $ 46.44万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198037
• 关键词: ATP Receptors; Address; Airway Disease; Allergens; Allergic; Antioxidants; Asthma; Automobile Driving; Biological Assay; Bronchoalveolar Lavage; Cell physiology; Cell surface; Cells; Clinical Trials; Development; Disease; Effector Cell; Enzyme Activation; Enzymes; Epithelial Cells; Event; Exocytosis; G-Protein-Coupled Receptors; Gene Expression; Generations; Genetic Transcription; Goals; Homeostasis; Human; Immunologic Deficiency Syndromes; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Infusion procedures; Intranasal Administration; Link; Liquid substance; Lung; Lung diseases; Measurement; Mediating; Mediator of activation protein; Mitochondria; Molecular; Nucleotides; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Pattern; Peptide Hydrolases; Physiological; Production; Proteinase-Activated Receptors; Pulmonary Inflammation; Pyroglyphidae; Reactive Oxygen Species; Regulation; Role; STIM1 gene; Signal Pathway; Signal Transduction; System; Testing; airway epithelium; airway inflammation; allergic airway disease; asthma model; asthmatic patient; autocrine; bronchial epithelium; channel blockers; chemokine; cytokine; extracellular; in vivo; inhibitor/antagonist; injured airway; lung injury; mouse model; novel; novel therapeutics; paracrine; response; transcription factor; vesicular release

Abstract Ca2+ is a ubiquitous signaling messenger mediating many essential functions such as excitability, exocytosis and transcription. In the airway epithelial cells (AECs) lining the conducting airways of the lung, Ca2+ signals are implicated in numerous cellular functions through effects on enzymatic cascades and transcriptional factors. Ca2+ homeostasis is also closely integrated with other signaling systems including that of reactive oxygen species (ROS), which has many cellular functions of its own and is implicated in allergic lung diseases and injury. We have recently shown that store-operated Ca2+ release-activated Ca2+ (CRAC) channels serve as the main pathway for Ca2+ entry in bronchial epithelial cells and their activation leads to increases in levels of numerous proinflammatory cytokines. However, the broader significance of CRAC channels in AECs for mediating airway inflammation and potential crosstalk with ROS and other signaling pathways mediating inflammation remains unknown. We hypothesize that CRAC channels are a major mechanism for controlling the generation of inflammatory mediators from AECs in response to stimulation of cell surface G-protein coupled receptors such as protease-activated and ATP receptors, and are an essential mediator of pulmonary inflammation in diseases such as asthma. We will address this hypothesis through three specific goals: 1) examine the physiological contributions of CRAC channels for allergen- mediated release of ATP and determine how this release stimulates inflammatory cytokines from AECs, 2) investigate the functional interactions between CRAC channels and mitochondrial ROS signaling and assess the impact of this crosstalk for inflammatory cytokine generation, and 3) evaluate the contribution of CRAC channels for mediating airway inflammation in vivo in a mouse model of house dust mite-induced asthma. Together, these studies will advance our understanding of how CRAC channels regulate cellular Ca2+-dependent signaling pathways to modulate allergen-stimulated inflammatory mediators in the airways, and advance the quest for developing novel treatments for allergic airway diseases.

抽象的 CA2+是一种无处不在的信号传导Messenger，介导了许多基本功能，例如 兴奋性，胞吐和转录。在气道上皮细胞（AEC）中 进行肺气道，Ca2+信号与许多细胞功能有关 通过对酶级联反应和转录因子的影响。 CA2+稳态也是 与其他信号系统紧密整合，包括活性氧（ROS）， 它具有许多细胞功能，并且与过敏性肺部疾病有关 受伤。我们最近表明，商店经营的Ca2+释放激活的Ca2+（CRAC） 通道是支气管上皮细胞中Ca2+进入的主要途径 激活导致众多促炎细胞因子的水平升高。但是， CRAC通道在AEC中的更广泛的意义，用于介导气道炎症和潜力 与ROS和其他介导炎症的信号通路的串扰尚不清楚。我们 假设CRAC通道是控制生成的主要机制 响应于刺激细胞表面G蛋白耦合的炎症介质 蛋白酶激活和ATP受体等受体，是 疾病（例如哮喘）中的肺部炎症。我们将通过 三个具体目标：1）检查过敏原CRAC通道的生理贡献 - 介导的ATP释放并确定该释放如何刺激炎症细胞因子 来自AEC，2）研究CRAC通道和 线粒体ROS信号传导并评估该串扰对炎症细胞因子的影响 生成和3）评估CRAC通道介导气道的贡献 房屋尘螨诱导的哮喘的小鼠模型中的体内炎症。在一起，这些 研究将促进我们对CRAC通道如何调节细胞Ca2+依赖性的理解 信号传导途径调节过敏原刺激的炎症介质，并 促进寻求为过敏气道疾病开发新型治疗方法。