NEGATIVE REGULATORS OF LUNG INFLAMMATION

肺部炎症的负调节因子

• 批准号: 6909945
• 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/6909945
• 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（由申请人提供）：早产儿死于慢性肺病（CLD）的风险增加。 炎症是CLD和急性呼吸窘迫综合征（ARDS）的关键起始和促成因素。这些因素加在一起，每年造成大量死亡。此外，吸入性炭疽正在成为一种潜在的公共卫生威胁。虽然通过先天免疫系统启动和促进炎症的过程被深入研究，但在成人和发育中的肺中相同过程的主动下调几乎未被探索。Bcr和Abr是两种在人和小鼠之间高度保守的相关蛋白。在吞噬细胞中，它们负调节小GTdR ac的活性，其刺激这些细胞中的吞噬作用、粘附、运动性和活性氧物质的产生。 Abr x bcr无效突变小鼠，但不是单敲除或野生型小鼠，在单次IV注射LPS后发生急性肺部炎症，并具有显著的高反应性吞噬细胞。基于我们的初步数据，我们假设Bcr和Abr是炎症的负调节因子，通过它们对Rac的作用，并且进一步定义它们在体内和分子水平上的活性将导致识别慢性和急性肺部炎症和脓毒症的新治疗途径。为了研究这一点，我们建议1）使用原代无效突变巨噬细胞来定义哪些特定的促炎信号通过吞噬细胞中的Abr和Bcr进行调节2）阐明无效突变小鼠模型中Bcr和Abr如何在体内负向调节肺部炎症3）研究肺部炎症的合理治疗干预，基于abr × bcr双无效突变体中对LPS的扩增反应和引起这种过度反应的信号转导途径。对Abr和Bcr功能的深入研究不仅将提供对肺中炎症的正常主动下调的重要见解，而且还为CLD、ARDS和吸入性炭疽的治疗提供新的可能性。