The role of airway epithelial CRAC channels in allergic lung inflammation

气道上皮CRAC通道在过敏性肺部炎症中的作用

基本信息

批准号：
10396679
负责人：
Timothy Kountz
金额：
$ 0.39万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396679
关键词：
ATP Receptors Air Airway Disease Allergens Allergic Allergic inflammation Asthma Automobile Driving Binding Biological Assay Biological Phenomena Biological Process Bronchoalveolar Lavage Fluid Bronchodilation Calcium Calcium Channel Cause of Death Cell physiology Cells Chronic Chronic Obstructive Pulmonary Disease Cytosol Data Dinoprostone Disease Disease model Enzyme-Linked Immunosorbent Assay Enzymes Epithelial Cells Exocytosis Extracellular Space Genetic Transcription Goblet Cells Histology Image Immune Immune response In Vitro Inflammation Inflammatory Ion Channel Knock-out Knockout Mice Lead Ligands Link Lipids Liquid substance Luciferases Lung Lung diseases Maintenance Measures Mediating Mentorship Modeling Molecular Molecular Biology Mucins Mucous body substance Mus Nucleotides PTGS2 gene Pathway interactions Pattern Pattern recognition receptor Phospholipase A2 Phosphorylation Plug-in Process Production Prostaglandins Proteins Pulmonary Inflammation Pyroglyphidae Receptor Signaling Regulation Research Role Route STIM1 gene Second Messenger Systems Severe Combined Immunodeficiency Signal Transduction T-Lymphocyte Testing Therapeutic Tissues Total Internal Reflection Fluorescent Vasodilation Vesicle Western Blotting airway epithelium airway hyperresponsiveness airway inflammation asthma model asthmatic asthmatic patient cyclooxygenase 1 cytokine enzyme activity extracellular histological stains immunoregulation in vivo live cell imaging loss of function mutation mouse model mucin hypersecretion new therapeutic target novel prevent pulmonary function receptor recruit response transcription factor

项目摘要

Abstract: For many years, the primary responsibility of airway epithelial cells was considered to be the maintenance of barrier function. Recently, airway epithelial cells (AECs) have emerged as key orchestrators of immune responses. For instance, AECs can respond to allergen presence in the airway lumen and thereby direct immune cells, promoting allergic sensitization. The allergens can activate pattern recognition receptors on AECs leading to the production of immunostimulatory lipids and proteins. Many of these receptors transduce signals through the ubiquitous signaling ion Ca2+. Another class of molecules that can activate receptors on AECs is damage-associated molecular patterns (DAMPs). One DAMP that has been linked to Ca2+ signaling and asthma is ATP. Extracellular ATP is known to contribute both to allergic sensitization and chronic inflammation. These effects are likely linked to ATP-mediated production of cytokines, prostaglandins and mucin proteins from AECs. We recently discovered Calcium Release-Activated Calcium (CRAC) channels are a major mechanism for Ca2+ signaling in AECs ultimately driving cytokine production. Preliminary data suggests that ATP receptors can activate CRAC channels in AECs. However, how CRAC channels interface with ATP signaling to drive inflammatory processes is unclear. Therefore, in this proposal, we will further interrogate the significance of AEC CRAC channels in airway inflammation and disease models of asthma. We will do this through the following aims. Aim 1: Determine the mechanism for how AEC CRAC channel activation induces prostaglandin E2 synthesis. Aim 2: Investigate the role of AEC CRAC channels in receptor-stimulated exocytosis. Aim 3: Define the role of AEC CRAC channels in allergic lung inflammation in vivo. We will approach these studies through the use of an integrated analysis using calcium imaging, molecular biology, ELISAs, live cell imaging, tissue-specific knockout mice, histology and assessment of lung function. This research will occur under the direct mentorship of Dr. Murali Prakriya. Collectively, this research has the potential to unveil new targets to inhibit the chronic inflammation driving asthma.

抽象的：多年来，气道上皮细胞的主要责任被认为是维持屏障功能。最近，气道上皮细胞（AEC）已成为关键免疫反应的协调者。例如，AEC 可以对环境中存在的过敏原做出反应气道管腔，从而引导免疫细胞，促进过敏致敏。过敏原可以激活 AEC 上的模式识别受体，导致免疫刺激脂质的产生和蛋白质。许多这些受体通过普遍存在的信号离子 Ca2+ 转导信号。另一类可以激活 AEC 上受体的分子是损伤相关分子模式（DAMP）。 ATP 是一种与 Ca2+ 信号传导和哮喘相关的 DAMP。已知细胞外 ATP 会导致过敏性致敏和慢性炎症。这些效应可能与 ATP 介导的细胞因子、前列腺素和粘蛋白的产生有关来自 AEC。我们最近发现钙释放激活钙 (CRAC) 通道是一种 AEC 中 Ca2+ 信号传导最终驱动细胞因子产生的主要机制。初步数据表明 ATP 受体可以激活 AEC 中的 CRAC 通道。然而，CRAC 如何渠道与 ATP 信号传导驱动炎症过程的界面尚不清楚。因此，在本提案中，我们将进一步探讨 AEC CRAC 通道在气道炎症中的重要性哮喘疾病模型。我们将通过以下目标来实现这一目标。目标 1：确定 AEC CRAC 通道激活如何诱导前列腺素 E2 合成的机制。目标 2：研究 AEC CRAC 通道在受体刺激的胞吐作用中的作用。目标 3：定义角色 AEC CRAC 通道在体内过敏性肺部炎症中的作用。我们将通过以下方式进行这些研究使用钙成像、分子生物学、ELISA、活细胞成像的综合分析，组织特异性基因敲除小鼠、组织学和肺功能评估。这项研究将发生在 Murali Prakriya 博士的直接指导下。总的来说，这项研究有潜力揭示了抑制导致哮喘的慢性炎症的新目标。