Mediators and Mechanisms of Innate Immunity in the Lung

C5L2是一种神秘的蛇纹石受体，与C5a受体在许多细胞类型上共表达 包括中性粒细胞。没有C5L2到G蛋白的偶联，以及我们的初步数据， 提示这种受体并不像经典的C5a受体那样传递信号，而是可能 调节C5a的生物活性。体内研究支持C5L2充当诱饵的概念 受体。或者，它可能通过形成分子间复合体(如 异二聚体)与C5aR。C5L2也可能存在不同的信号机制。 携带C5L2靶向缺失的小鼠表现出增强的C5a/C5adesArg生物活性-因此， C5L2的生物学功能似乎是限制对使用过敏毒素的促炎反应 一种或多种上述机制。因此，C5L2的上调可能对 由C5a驱动的炎症状态，可能与脓毒症、哮喘、囊性纤维化和慢性阻塞性肺有关 疾病。C5L2的其他潜在作用已被提出，包括上调抗- 炎性神经内分泌轴、甘油三酯合成的调节以及干细胞向骨的归巢 骨髓。我们在鼠标中创建的工具将允许证明或拒绝这些响应，如下所示 由C5L2介导。 在当前的更新应用中，我们建议表征C5L2与ITS的功能相互作用 配体C5a和C5adeSArg及其与经典C5a受体的关系 目的：1)研究免疫模型中C5L2-/-小鼠的免疫表型 复合损伤、感染性休克、Th1/Th2炎症。我们将进一步研究C5L2的作用 在肾上腺皮质轴的甘油三酯合成和调节中。2)我们将在其中生成小鼠 C5L2在肺中过度表达，在其中人C5aR表达的小鼠代替小鼠 CSAR，允许用受体拮抗剂药理阻断C5aR。这些动物会 C5L2在免疫复合体损伤和脓毒症中的抗炎作用 令人震惊。3)我们将确定C5L2作为C5a结合蛋白的结构。最后，我们会 研究C5a/C5adeSArg与C5L2结合所介导的潜在的替代信号机制。 成功完成这项研究计划将增加我们对急性和慢性疾病的相关知识 肺损伤。这些疾病的潜在治疗方案可能会通过转化研究而产生 通过这项提议。

C5L2 is a enigmatic serpentine receptor that is co-expressed with the C5a receptor on many cell types including PMN neutrophils. The absence of coupling of C5L2 to G proteins, as well as our preliminary data, suggest that this receptor does not transduce signals like the classical C5a receptor, but may instead modulate the biological activity of C5a. In vivo studies support the concept that C5L2 acts as a decoy receptor. Alternatively, it may affect function through formation of intermolecular complexes (eg heterodimers) with the C5aR. A distinct signaling mechanism may also exist for C5L2. Mice bearing a targeted deletion of C5L2 exhibit enhanced biological activity of C5a/C5adesArg- Thus, the biological function of C5L2 appears to be to limit the proinflammatory response to the anaphylatoxin utilizing one or more of the mechanisms described above. Accordingly, up-regulation of C5L2 may be of benefit in inflammatory states driven by C5a, potentially in sepsis, asthma, cystic fibrosis and chronic obstructive lung disease. Other potential actions of C5L2 that have been proposed include up-regulation of the anti- inflammatory neuroendocrine axis, regulation of triglyceride synthesis, and homing of stem cells to bone marrow. The tools we have created in the mouse will allow for proof or rejection of these responses as mediated by C5L2. In the current renewal application, we propose to characterize the functional interactions of C5L2 with its ligands, C5a and C5adeSArg, and its relationship with the classical C5a receptor through the following Specific Aims: 1)we will characterize the phenotype of C5L2-/- mice in the na'i've state, in models of immune complex injury, septic shock, and Th1/Th2 inflammation. Wewill further investigate the role of C5L2 in triglyceride synthesis and regulation of the adrenocortical axis. 2) We will generate mice in which C5L2 is over-expressed in the lung, and mice in which human C5aR is expressed in place of murine CSaR, allowing pharmacological blockade of the C5aR with receptor antagonists. These animals will be used to evaluate the anti-inflammatory actions of C5L2 in immune complex injury and septic shock. 3) We will determine the structure of C5L2 as a C5a binding protein. Finally, 4) we will examine potential alternative signaling mechanisms mediated by binding of C5a/C5adeSArg to C5L2. Successful completion of this research program will increase our knowledge relevant to acute and chronic lung injury. Potential treatment options for these diseases could arise through translational research inspired by this proposal.