NEGATIVE REGULATORS OF LUNG INFLAMMATION

肺部炎症的负调节因子

• 批准号: 6684499
• 负责人: JOHN H GROFFEN
• 金额: $ 37.2万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684499
• 关键词: actins; biological signal transduction; cytoskeleton; endotoxins; enzyme activity; flow cytometry; free radical oxygen; guanosinetriphosphatases; immunoprecipitation; immunoregulation; inflammation; laboratory mouse; lipopolysaccharides; lung disorder; lung injury; macrophage; monocyte; phagocytosis; posttranslational modifications; proteins; tissue /cell culture

DESCRIPTION (provided by applicant): Prematurely born infants are at increased risk of dying from chronic lung disease (CLD). Inflammation is a key initiating and contributing factor to CLD and also to acute respiratory distress syndrome (ARDS). Together, these account for a significant number of deaths each year. In addition, inhalation anthrax is emerging as a potential public health threat. Although processes that initiate and promote inflammation through the innate immune system are intensely studied, the active down regulation of the same processes in the adult and developing lung has gone virtually unexplored. Bcr and Abr are two related proteins that are closely conserved between man and mouse. In phagocytic cells, they negatively regulate the activity of the small GTPase Rac, which stimulates phagocytosis, adhesion, motility and reactive oxygen species production in these cells. Abr x bcr null mutant mice, but not single knockouts or wild types develop acute lung inflammation subsequent to a single IV injection of LPS and possess remarkably hyper-reactive phagocytic cells. Based on our preliminary data, we hypothesize that Bcr and Abr are negative regulators of inflammation through their action on Rac, and that a further definition of their activity in vivo and on a molecular level will lead to the identification of new avenues of treatment for chronic and acute pulmonary inflammation and sepsis. To investigate this, we propose to 1) define which specific proinflammatory signals are subjected to regulation through Abr and Bcr in phagocytic cells using primary null mutant macrophages 2) elucidate how lung inflammation is negatively regulated by Bcr and Abr in vivo in null mutant mouse models 3) investigate rational therapeutic intervention of pulmonary inflammation, based on the amplified response to LPS in the abr x bcr double null mutants and the signal transduction pathways that cause this excessive response. An in-depth study of Abr and Bcr function will provide not only significant insight into the normal active down regulation of inflammation in the lung, but also new possibilities of treatment for CLD, ARDS and inhalation anthrax.

描述(申请人提供)：早产儿死于慢性肺部疾病(CLD)的风险增加。炎症是慢性阻塞性肺疾病和急性呼吸窘迫综合征(ARDS)的关键启动和致病因素。这些因素加在一起，每年造成的死亡人数相当可观。此外，吸入性炭疽病正在成为一种潜在的公共卫生威胁。尽管通过先天免疫系统启动和促进炎症的过程已经得到了深入的研究，但在成人和发育中的肺中，相同过程的主动下调几乎还没有被探索过。BCR和ABR是两个在人和鼠之间高度保守的相关蛋白。在吞噬细胞中，它们负向调节小GTP酶Rac的活性，从而刺激这些细胞的吞噬、黏附、运动和活性氧的产生。ABR x bcr基因缺失突变小鼠，但不是单一基因敲除或野生型小鼠，在单次静脉注射脂多糖后出现急性肺炎症，并具有显著的高反应性吞噬细胞。根据我们的初步数据，我们假设BCR和ABR通过它们对RAC的作用是炎症的负调控因子，进一步定义它们在体内和分子水平的活性将导致发现治疗慢性和急性肺部炎症和败血症的新途径。为了研究这一点，我们建议1)确定在原代零突变巨噬细胞的吞噬细胞中哪些特定的促炎信号受到ABR和BCR的调节2)阐明在体内BCR和ABR如何在零突变小鼠模型中负调控肺部炎症3)基于abr x bcr双零突变对内毒素的放大反应和导致这种过度反应的信号转导途径，研究对肺部炎症的合理治疗干预。对ABR和BCR功能的深入研究不仅将对肺内炎症的正常主动下调提供重要的洞察，而且将为CLD、ARDS和吸入性炭疽的治疗提供新的可能性。