LPA and Edg Receptors in the Pulmonary Immune Respose

描述(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。这种多效性脂质介体现在已知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发挥作用。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存在于支气管肺泡灌洗(BAL)液中，但在过敏性受试者的节段性变应原攻击后显著增加。细胞外LPA被认为是通过自体趋化酶(ATX)对溶血磷脂酰胆碱的降解而产生的，但对ATX在肺中的表达或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，包括经典的受体LPA1、LPA2和LPA3。我们的建议基于两个全新的观察结果，即：(I)LPA在启动免疫反应中发挥了先前未被怀疑的作用，(Ii)LPA2似乎是先前在过敏性肺炎小鼠模型中被低估的负调节受体。在这里，我们将在这些发现的基础上，使用酶活性和定量质谱学的新分析方法来表征ATX在肺中的表达和LPA的产生(目标1a)，使用功能丧失和功能获得的方法来操纵体内ATX的表达(目标1b)，使用新的受体拮抗剂(目标2)探索其他LPA受体在过敏性气道炎症小鼠模型中的作用(目标2)，并通过补充方法来解剖肺结构细胞、树突状细胞和CD4T淋巴细胞的贡献来确定LPA2抑制过敏免疫反应的精确机制(目标3)。综上所述，这些研究将使我们能够构建新的、明确的LPA在肺中的生成和作用模型，并为未来治疗哮喘的新疗法奠定基础。 与公共卫生相关：哮喘是一种慢性疾病，影响着数百万美国人，也是导致缺课和工作时间减少的常见原因。尽管有有效的治疗方法，但哮喘不是一种可以治愈的疾病，哮喘患者必须学会忍受和管理他们的症状。现在已知哮喘是由呼吸道炎症引起的。我们研究计划的目标是确定导致哮喘肺部炎症的新分子的作用，希望这将导致新的治疗药物在这种疾病中的使用。

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.