LPA and Edg Receptors in the Pulmonary Immune Respose

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被阐明。这种多效性脂质介质现在被认为可以调节免疫反应的许多方面，最近的研究表明它在调节细胞归巢中起作用。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）中，但在过敏性人类受试者的节段性过敏原攻击后显著增加。细胞外LPA被认为是由酶autotaxin （ATX）水解溶血磷脂酰胆碱产生的，但对肺中ATX的表达或LPA的产生知之甚少。LPA可以结合和激活不同的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基本的新观察，即：(i) LPA在免疫应答的启动中起着以前未被怀疑的作用，（ii） LPA2似乎是以前未被重视的过敏性肺炎症小鼠模型中的负调节受体。在这里，我们将以这些发现为基础，使用新的酶活性和定量质谱分析（Aim 1a）来表征肺中ATX的表达和LPA的产生，使用功能丧失和功能获得的方法来控制体内ATX的表达（Aim 1b），使用新的受体拮抗剂探索其他LPA受体在小鼠变应性气道炎症模型中的作用（Aim 2）。并利用互补方法分析肺结构细胞、树突状细胞和CD4+ T淋巴细胞的作用，确定LPA2抑制过敏性免疫反应的确切机制（Aim 3）。综上所述，这些研究将使我们能够构建LPA在肺部产生和作用的新的和明确的模型，并为未来哮喘的新疗法奠定基础。

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. PUBLIC HEALTH RELEVANCE: Asthma is a chronic disease that affects millions of Americans, and is a common cause of lost days from school and work. Despite the availability of effective therapies, asthma is not a curable disease and asthmatic patients must learn to live with and manage their symptoms. Asthma is now known to be caused by airway inflammation. The goal of our research program is to define the role of new molecules that cause lung inflammation in asthma with the hope that this will lead to the use of new therapeutic agents in this disease.