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（由申请方提供）：肺巨噬细胞代表了对抗病原体的关键第一线防御。诱导促炎细胞因子IL-1 β产生、加工和释放的巨噬细胞感觉微生物。IL-1 β的调节是许多类型的肺炎性疾病的基础，包括急性肺损伤和脓毒症。在这种情况下，与单核细胞相比，巨噬细胞加工和释放IL-1 β的能力受到抑制。尽管事实上，在内毒素攻击后，巨噬细胞含有丰富的前体IL-1 β和半胱天冬酶-1。最近，一类新的宿主防御分子已经被描述，可能揭示了这一重要差异。这些蛋白质称为CATERPILLER，是植物抗病基因的同源物。它们含有指导分子分组的CARD和PYRIN结构域。其中一组被称为炎性小体，调节胱天蛋白酶-1将IL-1 β和IL-18的前体切割成其功能形式的能力。这使我们假设炎性小体的修饰决定了巨噬细胞中的先天宿主反应。本文提供的初步数据表明，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性小体的功能。因此，为了确定这种中枢先天宿主反应的具体情况，本申请使用单核细胞巨噬细胞差异来发现关键的炎性小体结构功能关系。具体而言，该提议将1）确定CARD和PYRIN结构域蛋白作为单核细胞成熟期间IL-1 β释放的调节剂的作用; 2）检验JAK/STAT途径诱导炎性小体功能变化的假设; 3）确定某些CATERPILLER蛋白如何抑制炎性小体的功能;和4）检验酪氨酸激酶活性是正确的炎性小体组装所需的假设。这些目标的成功实现将为先天宿主反应提供新的见解，并为预防和治疗炎症性肺病创造新的治疗机会。