NEGATIVE REGULATORS OF LUNG INFLAMMATION

肺部炎症的负调节因子

• 批准号: 6789885
• 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/6789885
• 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）：早产婴儿死于慢性肺病（CLD）的风险增加。 炎症是慢性肺病和急性呼吸窘迫综合征 (ARDS) 的关键引发和促成因素。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潜在的公共卫生威胁。尽管通过先天免疫系统引发和促进炎症的过程已得到深入研究，但成人和发育中的肺部中相同过程的主动下调实际上尚未被探索。 Bcr 和 Abr 是两种相关的蛋白质，在人和小鼠之间密切保守。在吞噬细胞中，它们负向调节小 GTP 酶 Rac 的活性，从而刺激这些细胞中的吞噬作用、粘附、运动和活性氧的产生。 Abr x bcr 无效突变小鼠（但不是单一敲除小鼠或野生型小鼠）在单次静脉注射 LPS 后会出现急性肺部炎症，并且具有明显高反应性的吞噬细胞。根据我们的初步数据，我们假设 Bcr 和 Abr 通过对 Rac 的作用而成为炎症的负调节因子，并且进一步定义它们在体内和分子水平上的活性将导致确定慢性治疗的新途径。以及急性肺部炎症和败血症。为了研究这一点，我们建议 1) 使用原代无效突变巨噬细胞确定吞噬细胞中哪些特定促炎信号通过 Abr 和 Bcr 受到调节 2) 阐明在无效突变小鼠模型中，Bcr 和 Abr 在体内如何负向调节肺部炎症3）基于abr x bcr双无效突变体对LPS的放大反应以及导致这种过度反应的信号转导途径，研究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为了解肺部炎症的正常主动下调提供重要见解，而且为治疗 CLD、ARDS 和吸入性炭疽提供新的可能性。