Negative Regulation of Lung Inflammation by ABR/BCR

ABR/BCR 对肺部炎症的负调节

• 批准号: 7827982
• 负责人: JOHN H GROFFEN
• 金额: $ 31.66万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7827982
• 关键词: Actins; Acute; Adverse effects; Alveolar; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Bronchopulmonary Dysplasia; Cell Communication; Cells; Chronic lung disease; Collaborations; Cytoskeletal Modeling; Data; Development; Down-Regulation; Endothelial Cells; Endothelium; Endotoxins; Escherichia coli; Event; Exposure to; Fibrosis; GTP-Binding Proteins; GTPase-Activating Proteins; Gene Expression; Hemorrhage; Human; Hyperoxia; Ice; Infant; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Intervention; Kinetics; Lead; Lung; Lung Inflammation; Medical; Molecular; Monomeric GTP-Binding Proteins; Morphogenesis; Mus; Mutant Strains Mice; Myeloid Cell Activation; Myeloid Cells; Newborn Infant; Pathogenesis; Pathway interactions; Peptides; Phagocytes; Phagocytosis; Pneumonia; Process; Production; Proteins; Reactive Oxygen Species; Reagent; Regulation; Research Personnel; Role; Sepsis; Signal Transduction; Staging; Surface; Testing; base; cell motility; cell type; cytokine; injury and repair; insight; interstitial; intravenous injection; lung basal segment; lung injury; macrophage; man; mutant; neutrophil; novel; novel strategies; programs; receptor expression; research study

Prematurely born human infants often develop chronic lung disease (CLD), in which inflammation is a key upstream event. The ability to overcome and resolve the adverse effects of lung inflammation may in fact determine whether an infant will go on to develop CLD or not. The mechanisms that negatively regulate and terminate inflammation, both in the lung and elsewhere, are poorly understood. Upon injection with LPS, a bacterial endotoxin, mice lacking Bcr and Abr die of sepsis with lung injury because they are unable to down regulate and resolve an episode of acute inflammation. These two related proteins negatively regulate a small GTPase, Rac. Macrophages Iacking A br a nd B cr contain elevated Ievels o f active R ac. Active R ac stimulates multiple functions of inflammatory cells including phagocytosis, motility and reactive oxygen species production. Based on our preliminary data, we hypothesize that Bcr and Abr negatively regulate inflammation in the lung through their action on Rac. Our studies are aimed at deciphering the tempo-spatial events (cell types, recruitment kinetics, interactions, cytokines) that lead to increased lung injury in mice lacking Abr and Bcr, after exposure to insults that are relevant to the pathogenesis of human CLD, and to simultaneously seek therapies to down regulate this process. We propose to 1) determine LPS-evoked kinetics of myeloid cell mobilization and cytokine production in mice without Abr and Bcr 2) investigate proinflammatory cytokine-induced gene expression involving Abr and Bcr in alveolar macrophages, including TGF-131 3) examine the role of the lung endothelium in the pulmonary injury seen in mice lacking Abr and Bcr 4) investigate if unresolved inflammation and CLD will develop in newborn mice lacking Abr and Bcr after exposure to mild hyperoxia and LPS 5) explore lentiviral and peptide strategies to terminate LPS-induced inflammation based on Abr, Bcr and Rac. Studies will be performed using primary alveolar macrophages, endothelial cells and null mutant mice. The data obtained from our experiments will provide insight into mechanisms that exist to resolve inflammation, which have never been explored. Moreover, new therapies for pulmonary inflammation will be tested. Because inflammation is a major upstream factor in the development of CLD, our studies directly relate to the Program Project's main theme of seeking to understand and ultimately cure CLD.

早产儿常患慢性肺部疾病(CLD)，其中炎症 是一个关键的上游事件。克服和化解肺部不良反应的能力 事实上，炎症可能决定婴儿是否会继续发展为慢性阻塞性肺疾病。这个 负向调节和终止炎症的机制，无论是在肺部还是其他地方， 人们对此了解甚少。注射细菌内毒素后，缺乏bcr和abr的小鼠 死于脓毒症合并肺损伤，因为他们无法下调和解决一次发作 急性炎症。这两个相关蛋白负调控一个小的GTP酶，RAC。 巨噬细胞活化的A受体和B受体的活性受体水平升高。有源Rac刺激 炎性细胞的多种功能，包括吞噬、运动和活性氧 物种生产。根据我们的初步数据，我们假设BCR和ABR为负 通过它们对RAC的作用来调节肺部炎症。我们的研究目的是 破译时空事件(细胞类型、招募动力学、相互作用、细胞因子) 在暴露于相关侮辱后，导致缺乏ABR和BCR的小鼠肺损伤增加 与人类CLD的发病机制密切相关，并同时寻求下调这种疾病的治疗方法 进程。我们建议1)确定内毒素诱导的髓系细胞动员的动力学和 ABR和bcr缺失型小鼠细胞因子的产生2)研究促炎症细胞因子诱导的 肺泡巨噬细胞中涉及ABR和BCR的基因表达，包括转化生长因子-131 3)检测 肺内皮细胞在ABR和BCR4缺失小鼠肺损伤中的作用 研究缺乏ABR和BCR的新生小鼠是否会发生未消退的炎症和CLD 在暴露于轻度高氧和内毒素后，探索慢病毒和多肽策略来终止 基于ABR、BCR和RAC的脂多糖诱导的炎症反应。研究将使用初级 肺泡巨噬细胞、内皮细胞和零突变小鼠。从我们的网站获得的数据 实验将提供对现有的消炎机制的洞察，这些机制具有 从未被探索过。此外，还将测试治疗肺部炎症的新疗法。因为 炎症是慢性阻塞性肺疾病发生发展的主要上游因素，我们的研究直接与 该计划项目的主题是寻求了解并最终治愈慢性阻塞性肺病。