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LPA and Edg Receptors in the Pulmonary Immune Respose

LPA 和 Edg 受体在肺免疫反应中的作用

基本信息

批准号：
8471746
负责人：
Steve N Georas
金额：
$ 36.4万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8471746
关键词：
Affect Allergens Allergic American Anti-Inflammatory Agents Anti-inflammatory Asthma Binding Biological Assay Bone Marrow Bronchoalveolar Lavage Fluid CD4 Positive T Lymphocytes Cells Chimera organism Chronic Disease Coculture Techniques Data Dendritic Cells Dendritic cell activation Development Disease Drug or chemical Tissue Distribution Enzymes Family Future G-Protein-Coupled Receptors Generations Goals Homing Hydrolysis Immigration Immune Immune response Inflammatory Lead Learning Life Location Lung Lung Inflammation Lung diseases Lysophosphatidic Acid Receptors Lysophosphatidylcholines Lysophospholipids Mass Spectrum Analysis Mediator of activation protein Modeling Mus Myelogenous Pathogenesis Pathway interactions Physiological Play Production Reagent Regulation Reporting Research Role Schools Sphingosine-1-Phosphate Receptor Symptoms T-Lymphocyte Testing Therapeutic Agents Time Work Wound Healing airway hyperresponsiveness airway inflammation allergic airway inflammation asthmatic patient base cell motility defined contribution effective therapy enzyme activity extracellular gain of function human subject in vivo lipid mediator loss of function lysophosphatidic acid member migration mouse model novel novel therapeutics programs public health relevance receptor vzg-1 Receptor

项目摘要

DESCRIPTION (provided by applicant): The role of lysophosphatidic acid (LPA) in immune regulation is rapidly being elucidated. This pleiotropic lipid mediator is now known to regulate many aspects of immune responses, with recent studies indicating a role in regulating cell homing. Growing evidence indicates that LPA contributes to the pathogenesis of asthma. We recently reported that lysophosphatidic acid is constitutively present in bronchoalveolar lavage (BAL) fluids but significantly increased after segmental allergen challenge of allergic human subjects. Extracellular LPA is thought to be generated by hydrolysis of lysophosphatidylcholine by the enzyme autotaxin (ATX), but very little is known about ATX expression or LPA generation in the lung. LPA can bind and activate different G-protein coupled receptors, including the classical receptors LPA1, LPA2 and LPA3. Our proposal is based on two fundamentally new observations, namely that: (i) LPA plays a previously unsuspected role in the initiation of immune responses, and (ii) LPA2 appears to be a previously underappreciated negative regulatory receptor in mouse models of allergic lung inflammation. Here we will build on these findings and characterize ATX expression and LPA generation in the lung using novel assays of enzyme activity and quantitative mass spectrometry (Aim 1a), use loss-of-function and gain-of-function approaches to manipulate ATX expression in vivo (Aim 1b), explore the role of other LPA receptors in mouse models of allergic airway inflammation using new receptor antagonists (Aim 2), and determine the precise mechanisms by LPA2 inhibits allergic immune responses using complementary approaches to dissect the contributions of lung structural cells, dendritic cells, and CD4+ T lymphocytes (Aim 3). Taken together, these studies will allow us to construct new and definitive models of LPA generation and action in the lung, and should lay the groundwork for novel future therapies in asthma.

描述（由申请人提供）：溶血磷脂酸（LPA）在免疫调节中的作用正在迅速阐明。现在已知这种多效性脂质介质调节免疫应答的许多方面，最近的研究表明其在调节细胞归巢中的作用。越来越多的证据表明LPA参与了哮喘的发病机制。我们最近报道，溶血磷脂酸是组成性存在于支气管肺泡灌洗液（BAL）的液体，但显着增加后，过敏性人类受试者的节段性过敏原的挑战。细胞外LPA被认为是通过酶自分泌运动因子（ATX）水解溶血磷脂酰胆碱而产生的，但对肺中ATX表达或LPA产生知之甚少。LPA可以结合并激活不同的G蛋白偶联受体，包括经典受体LPA1、LPA2和LPA3。我们的建议是基于两个根本性的新观察，即：（i）LPA在免疫应答的启动中起着以前未被怀疑的作用，以及（ii）LPA 2似乎是过敏性肺炎小鼠模型中以前未被重视的负调节受体。在此，我们将以这些发现为基础，并使用酶活性和定量质谱的新测定来表征肺中ATX表达和LPA产生（Aim 1a），使用功能丧失和功能获得方法来操纵ATX体内表达（Aim 1b），使用新的受体拮抗剂来探索其他LPA受体在小鼠过敏性气道炎症模型中的作用（Aim 2），并使用互补方法来剖析肺结构细胞、树突状细胞和CD4+ T淋巴细胞的贡献，确定LPA2抑制过敏性免疫应答的精确机制（Aim 3）。总之，这些研究将使我们能够构建新的和明确的LPA在肺中的产生和作用的模型，并为未来哮喘的新疗法奠定基础。