Macrophage Inflammasome Regulation

巨噬细胞炎症小体调节

• 批准号: 6875275
• 负责人: Mark Damian Wewers
• 金额: $ 37.38万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875275
• 关键词: JAK kinase; biological signal transduction; chloride channels; clinical research; cysteine endopeptidases; endotoxins; genetically modified animals; human subject; immune response; interleukin 1; laboratory mouse; leukocyte activation /transformation; macrophage; phosphorylation; protein sequence; protein structure function; protein tyrosine kinase

DESCRIPTION (provided by applicant): Lung macrophages represent a key first line defense against pathogens. Macrophages sense microbes that induce the production, processing and release of the proinflammatory cytokine IL-1beta. Regulation of IL-1beta is fundamental to many types of lung inflammatory diseases including acute lung injury and sepsis. In this context, macrophages are suppressed in their ability to process and release IL-1beta compared to monocytes. This is despite the fact that, after endotoxin challenge, macrophages contain abundant precursor IL-1beta and caspase-1. Recently, a new class of host defense molecules has been described that may shed light on this important difference. These proteins, termed CATERPILLERs, are homologues of plant disease resistance genes. They contain CARD and PYRIN domains that direct molecular groupings. One such grouping, termed the inflammasome, regulates the ability of caspase-1 to cleave the precursors of IL-1beta and IL-18 to their functional forms. This led us to hypothesize that modifications of the inflammasome dictate innate host responses in macrophages. Preliminary data presented here show that signaling through tyrosine kinase and JAK/STAT pathways can respectively activate or suppress function of the inflammasome. Therefore, to determine the specifics of this central innate host response, this application uses the monocyte macrophage difference to discover key inflammasome structure function relationships. Specifically, this proposal will 1) determine the role of CARD and PYRIN domain proteins as regulators of IL-1beta release during monocyte maturation; 2) test the hypothesis that JAK/STAT pathways induce functional changes in the inflammasome; 3) determine how certain CATERPILLER proteins inhibit function of the inflammasome; and 4) test the hypothesis that tyrosine kinase activity is required for correct inflammasome assembly. Successful completion of these aims will provide novel insights into innate host responses and create new therapeutic opportunities to prevent and treat inflammatory lung diseases.

描述（由申请人提供）：肺巨噬细胞代表针对病原体的关键第一线防御。巨噬细胞感知微生物，可诱导促炎性细胞因子IL-1Beta的产生，加工和释放。 IL-1BETA的调节是许多类型的肺炎性疾病，包括急性肺损伤和败血症的基础。在这种情况下，与单核细胞相比，巨噬细胞的处理和释放IL-1Beta的能力被抑制了。尽管事实是，在内毒素挑战之后，巨噬细胞含有丰富的前体IL-1Beta和caspase-1。最近，已经描述了一类新的宿主防御分子，可以阐明这一重要差异。这些蛋白质（称为猫）是植物性疾病基因的同源物。它们包含直接分子组的卡和吡啶结构域。一个这样的分组称为炎性体，调节caspase-1将IL-1Beta和IL-18的前体裂解的能力为其功能形式。这使我们假设炎性体的修改决定了巨噬细胞中先天的宿主反应。此处介绍的初步数据表明，通过酪氨酸激酶和JAK/STAT途径的信号传导可以分别激活或抑制炎症体的功能。因此，为了确定此中央先天宿主响应的细节，该应用使用单核细胞巨噬细胞差异来发现关键的炎性体结构函数关系。具体而言，该提案将1）确定单核细胞成熟过程中CARD和PYRIN结构域蛋白作为IL-1Beta释放的调节剂的作用； 2）检验以下假设：JAK/STAT途径诱导炎症体的功能变化； 3）确定某些caterpiller蛋白如何抑制炎症体的功能； 4）检验酪氨酸激酶活性才能正确炎症体组装所需的假设。这些目标的成功完成将提供对先天宿主反应的新见解，并为预防和治疗炎症性肺部疾病创造新的治疗机会。