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：多年以来，气道上皮细胞的主要责任被认为是维护屏障功能。最近，气道上皮细胞（AEC）已成为钥匙免疫反应的编排者。例如，AEC可以对过敏原反应气道管腔及其直接免疫细胞，促进过敏反应。过敏原可以激活AEC上的模式识别受体，导致产生免疫刺激性脂质和蛋白质。这些受体中的许多通过无处不在的信号传导离子Ca2+传递信号。可以在AEC上激活受体的另一类分子是损伤相关的分子图案（潮湿）。与Ca2+信号传导和哮喘相关的一个潮湿是ATP。众所周知，细胞外ATP既有助于过敏敏化和慢性炎症。这些作用可能与ATP介导的细胞因子，前列腺素和粘蛋白蛋白的产生有关来自AEC。我们最近发现钙释放激活钙（CRAC）通道是一个 AEC中Ca2+信号传导的主要机制最终驱动细胞因子产生。初步数据表明ATP受体可以激活AEC中的CRAC通道。但是，crac频道如何与ATP信号传导以驱动炎症过程的接口尚不清楚。因此，在此提案中我们将进一步询问AEC CRAC通道在气道炎症和哮喘的疾病模型。我们将通过以下目标来做到这一点。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：定义角色过敏性肺部炎症中的AEC CRAC通道的体内。我们将通过使用钙成像，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，这项研究有可能揭示新的靶标，以抑制慢性炎症驱动哮喘。