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）：肺巨噬细胞是抵抗病原体的关键第一道防线。巨噬细胞感知诱导促炎细胞因子 IL-1β 产生、加工和释放的微生物。 IL-1β 的调节对于许多类型的肺部炎症性疾病（包括急性肺损伤和脓毒症）至关重要。在这种情况下，与单核细胞相比，巨噬细胞处理和释放 IL-1β 的能力受到抑制。尽管事实是在内毒素攻击后，巨噬细胞含有丰富的前体 IL-1β 和 caspase-1。最近，一类新的宿主防御分子被描述，可能有助于阐明这一重要差异。这些蛋白质被称为毛毛虫，是植物抗病基因的同源物。它们包含指导分子分组的 CARD 和 PYRIN 结构域。其中一种称为炎症小体的分组，可调节 caspase-1 将 IL-1beta 和 IL-18 前体裂解为其功能形式的能力。这使我们推测炎症小体的修饰决定了巨噬细胞的先天宿主反应。这里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症小体的功能。因此，为了确定这种中枢先天宿主反应的细节，本应用利用单核细胞巨噬细胞差异来发现关键的炎性体结构功能关系。具体来说，该提案将 1) 确定 CARD 和 PYRIN 结构域蛋白作为单核细胞成熟过程中 IL-1beta 释放调节剂的作用； 2）检验JAK/STAT通路诱导炎症小体功能变化的假设； 3) 确定某些 CATERPILLER 蛋白如何抑制炎性体的功能； 4) 检验酪氨酸激酶活性是正确的炎性小体组装所必需的假设。这些目标的成功完成将为宿主先天反应提供新的见解，并为预防和治疗炎症性肺部疾病创造新的治疗机会。