Mediators and Mechanisms of Innate Immunity in the Lung

肺部先天免疫的介质和机制

• 批准号: 7379928
• 负责人: CRAIG GERARD
• 金额: $ 41.02万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7379928
• 关键词: Acute; Address; Adipocytes; Affect; Anaphylatoxin; Anaphylatoxins; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Antibody Complex; Arginine; Asthma; Binding; Binding Proteins; Biological; Biological Process; Bone Marrow; C5a anaphylatoxin receptor; Chronic; Chronic Obstructive Airway Disease; Complement 3a; Complement 5a; Complement component C4a; Complex; Condition; Coupling; Cystic Fibrosis; Data; Disease; Exhibits; Funding; GTP-Binding Proteins; Gene Deletion; Grant; Homing; Human; Inflammation; Inflammatory; Inflammatory Response; Injury; Knowledge; Laboratories; Leucine; Ligands; Ligation; Lung; Lung diseases; Mediating; Mediator of activation protein; Modeling; Multiple Organ Failure; Mus; Mutate; Natural Immunity; Neurosecretory Systems; Organ; Pathway interactions; Phenotype; Pituitary Gland; Pituitary-Adrenal System; Protein Tyrosine Kinase; Proteins; Puncture procedure; Regulation; Relative (related person); Reporting; Research; Research Design; Research Personnel; Role; Sepsis; Septic Shock; Signal Transduction; Signaling Molecule; Stem cells; Structure; Syndrome; Tetracycline Control; Transcriptional Activation; Transgenic Animals; Translational Research; Triglycerides; Up-Regulation; beta-arrestin; cell type; concept; in vivo; lipid metabolism; lung injury; neutrophil; programs; protective effect; protein function; receptor; response; tool

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.

C5L2 是一种神秘的蛇形受体，在许多细胞类型上与 C5a 受体共表达 包括 PMN 中性粒细胞。 C5L2 与 G 蛋白没有偶联，以及我们的初步数据， 表明该受体不像经典的 C5a 受体那样转导信号，但可能相反 调节C5a的生物活性。体内研究支持 C5L2 作为诱饵的概念 受体。或者，它可能通过形成分子间复合物（例如 异二聚体）与 C5aR。 C5L2 也可能存在独特的信号传导机制。 带有 C5L2 靶向缺失的小鼠表现出增强的 C5a/C5adesArg 生物活性。 C5L2 的生物学功能似乎是限制对利用过敏毒素的促炎反应 上述的一种或多种机制。因此，C5L2 的上调可能有益于 由 C5a 驱动的炎症状态，可能导致败血症、哮喘、囊性纤维化和慢性阻塞性肺 疾病。已提出的 C5L2 的其他潜在作用包括上调抗- 炎症神经内分泌轴、甘油三酯合成的调节以及干细胞归巢到骨 骨髓。我们在小鼠中创建的工具将允许证明或拒绝这些响应 由C5L2介导。 在当前的更新应用中，我们建议描述 C5L2 与其功能相互作用的特征 配体 C5a 和 C5adeSArg，及其与经典 C5a 受体的关系通过以下具体 目的：1）我们将在免疫模型中表征 C5L2-/- 小鼠在初始状态下的表型 复杂损伤、感染性休克和 Th1/Th2 炎症。我们将进一步研究C5L2的作用 甘油三酯的合成和肾上腺皮质轴的调节。 2）我们将生成小鼠，其中 C5L2 在肺中过度表达，而用人 C5aR 代替小鼠表达的小鼠 CSaR，允许用受体拮抗剂对 C5aR 进行药理学阻断。这些动物会 用于评估 C5L2 在免疫复合物损伤和脓毒症中的抗炎作用 震惊。 3)我们将确定C5L2作为C5a结合蛋白的结构。最后，4）我们将 检查 C5a/C5adeSArg 与 C5L2 结合介导的潜在替代信号传导机制。 成功完成该研究计划将增加我们对急性和慢性疾病的了解 肺损伤。通过转化研究启发可能会出现这些疾病的潜在治疗方案 通过这个提议。