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.

摘要 Ca 2+是一种普遍存在的信号信使，介导许多基本功能， 兴奋性、胞吐和转录。在气道上皮细胞（AECs）中， 作为肺的传导气道，Ca 2+信号涉及许多细胞功能 通过影响酶级联和转录因子。Ca 2+稳态也是 与包括活性氧（ROS）在内的其它信号系统紧密结合， 其自身具有许多细胞功能，并与变应性肺病有关， 损伤我们最近的研究表明，钙库操纵的钙释放激活的钙（CRAC） 通道是支气管上皮细胞内Ca 2+进入的主要途径， 激活导致多种促炎细胞因子水平的增加。但 AEC中CRAC通道介导气道炎症和潜在的 与ROS和其它介导炎症的信号传导途径的串扰仍然未知。我们 假设CRAC通道是控制 AECs对细胞表面G蛋白偶联刺激反应的炎症介质 受体，如蛋白酶激活和ATP受体，是一种重要的介质， 哮喘等疾病中的肺部炎症。我们将通过以下方式来解决这一假设： 三个具体目标：1）检查CRAC通道对过敏原的生理贡献- 介导的ATP释放，并确定这种释放如何刺激炎症细胞因子 2）研究CRAC通道之间的功能相互作用， 线粒体ROS信号传导，并评估这种串扰对炎症细胞因子的影响 3）评估CRAC通道对介导气道炎症的贡献， 室内尘螨诱导哮喘小鼠模型体内炎症。所有这些 研究将促进我们对CRAC通道如何调节细胞Ca 2+依赖性的理解。 调节气道中过敏原刺激的炎症介质的信号传导途径，以及 推进对开发过敏性气道疾病的新疗法的探索。