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Integration of Leukotriene and Prostaglandin Receptor Signaling in Mast Cell Activation and Pulmonary Inflammation during Asthma

白三烯和前列腺素受体信号在哮喘期间肥大细胞激活和肺部炎症中的整合

基本信息

批准号：
10080708
负责人：
Sailaja Paruchuri
金额：
$ 1.23万
依托单位：
UNIVERSITY OF AKRON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-20 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080708
关键词：
Accounting Adenosine Diphosphate Affect Agonist Allergens Allergic Disease Allergic inflammation Anti-Inflammatory Agents Asthma Binding Blood Vessels Bronchoconstrictor Agents CCL4 gene Cell physiology Cells Chemosensitization Collaborations Combined Modality Therapy Complex Cyclic GMP Cytoplasmic Granules Development Dimerization Dinoprostone Disease Dose Effector Cell Eicosanoids Emergency department visit Extravasation FOS gene Fluorescence Future G-Protein-Coupled Receptors GPR17 gene GTP-Binding Protein alpha Subunits, Gs Generations Goblet Cells Human Immune Immune response Immunologics Individual Infectious Agent Inflammation Inflammation Mediators Inflammatory Inflammatory Response Intranasal Administration Laboratories Leukotriene C4 Leukotriene D4 Leukotriene E4 Leukotriene Receptor Ligands Lipids Macrophage Inflammatory Proteins Mediating Mediator of activation protein Metaplastic Cell Mucositis Mus Outcome PPAR gamma PTGS2 gene Pathogenesis Pathogenicity Pathologic Pathway interactions Peripheral Peroxisome Proliferators Pharmaceutical Preparations Physiologic pulse Physiological Physiology Play Positioning Attribute Production Prostaglandin D2 Prostaglandin Receptor Prostaglandins Pulmonary Inflammation Receptor Signaling Role Sampling Signal Transduction Site Source Spectrum Analysis Steroids Testing Therapeutic Transcript Translations United States Up-Regulation Urine airway hyperresponsiveness asthma model asthmatic patient base biophysical techniques chemokine clinical efficacy clopidogrel combat cysteinyl leukotriene receptor cysteinyl-leukotriene in vivo mast cell novel preference pyroglyphid receptor recruit release of sequestered calcium ion into cytoplasm response synergism transcription factor treatment strategy

项目摘要

Project Summary Mast cells (MCs) are effector cells in asthma and their activation causes secretion of cysteinyl leukotrienes (cys-LTs) and prostaglandins (PGs). MCs not only secrete these mediators, but they also possess receptors for them, to perceive their signals. Cys-LTs are potent bronchoconstrictors, powerful inducers of vascular leakage, potentiators of airway hyper-responsiveness and play an important role in asthma and other inflammatory disorders. Cys-LTs mainly act through two G-protein-coupled receptors (GPCR), CysLT1R and CysLT2R. Another GPCR, GPR17 is activated by LTD4. Both CysLT2R and GPR17 negatively regulate CysLT1R function. LTE4, the most abundant and stable of the cys-LTs, is a weak, partial agonist for the CysLT1R and CysLT2R. However, LTE4 induces unique responses in vivo that cannot be recapitulated by LTC4 or LTD4. In MC, LTE4 is more potent than LTD4 and relays signals through peroxisome proliferator activating receptor (PPAR)-γ and P2Y12R. Recently, GPR99 was identified as another CysLTR with a preference for LTE4. Understanding how all these cys-LT receptors (CysLTR) interact with each other in response to multiple ligands is critical, especially considering their role in airway physiology. Further, cys-LTs together with PGE2 synergistically potentiate calcium flux, c- Fos, COX-2, PGD2 and Macrophage Inflammatory Protein-1β (MIP-1β; CCL4)) generation in MCs. Interestingly, LTD4-PGE2 synergism is blocked only by combined treatment of CysLT1R antagonist (MK571/ singulair) and EP3 antagonist (L-798), suggesting the need for a combination of CysLT1R antagonists and EP3R antagonists to treat inflammation in asthma. LTD4+PGE2 synergism also potentiates pulmonary inflammation in der f sensitized mice (recruitment of immune cells, goblet cell metaplasia, up-regulation of inflammatory transcripts). Similar to LTD4, LTE4 synergizes with PGE2 but it differs from LTD4 via signals involving PPARγ. Based on these observations, we hypothesize that cys- LTs induce complex interactions between cys-LT-responsive receptors to profoundly influence the downstream signaling by switching anti-inflammatory PGE2 signaling to pro-inflammatory, upregulating COX-2 and PGD2 production in MC impacting Th2 inflammation and asthma. We will test this hypothesis in the following specific aims: 1) To determine the interplay between the known (CysLT1R and CysLT2R) and putative (GPR99, P2Y12R and PPARɣ) CysLTRs in response to cys-LTs, influencing MC function, 2) To uncover the mechanism by which cys-LT-PGE2 synergism induces PGD2 production and MC activation and 3) To determine the physiological significance of cys-LT+PGE2 interactions and MC in pulmonary inflammation in vivo. We will analyze pathologic, physiologic, and immunologic signatures of the immune response and evaluate the contribution of MCs. These studies will carry substantial pathogenic and therapeutic implications for asthma and allergic diseases as well as provide the basis for development and translation of future therapeutic molecules that regulate inflammation.

项目总结