Macrophage Inflammasome Regulation

巨噬细胞炎症小体调节

• 批准号: 7151145
• 负责人: Mark Damian Wewers
• 金额: $ 35.44万
• 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/7151145
• 关键词: AG 126; AG 556; Acute Lung Injury; Affect; Animals; Caspase; Caspase-1; Cells; Class; Cleaved cell; Data; Disease; Endotoxins; Genes; Goals; Grouping; Homologous Gene; Host Defense; Immune response; Inflammatory; Interleukin-18; JAK3 gene; Light; Lung; Lung diseases; Microbe; Modification; Molecular; Mono-S; Mus; Pathway interactions; Phosphotransferases; Plant Diseases; Process; Production; Protein Tyrosine Kinase; Proteins; Regulation; Resistance; Role; Sepsis; Septic Shock; Signal Transduction; Structure; Structure-Activity Relationship; Tertiary Protein Structure; Testing; Trefoil Motif; Tyrosine; caspase-5; cytokine; inhibitor/antagonist; insight; kinase inhibitor; macrophage; marenostrin; monocyte; novel; novel therapeutics; pathogen; prevent; response

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(申请人提供)：肺巨噬细胞是对抗病原体的关键一线防御。巨噬细胞感知微生物，诱导产生、加工和释放促炎细胞因子IL-1β。IL-1β的调节是许多类型肺部炎症性疾病的基础，包括急性肺损伤和脓毒症。在这种情况下，与单核细胞相比，巨噬细胞处理和释放IL-1β的能力受到抑制。尽管在内毒素攻击后，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出来，可能会揭示这一重要的差异。这些蛋白质被称为毛虫，是植物抗病基因的同源物。它们含有引导分子分组的CARD和PYRIN结构域。其中一类被称为炎症体，调节caspase-1将IL-1β和IL-18的前体切割成其功能形式的能力。这导致我们假设，炎症体的修饰决定了巨噬细胞的固有宿主反应。初步数据显示，通过酪氨酸激酶和JAK/STAT信号通路可以分别激活或抑制炎症体的功能。因此，为了确定这种中央固有宿主反应的特异性，该应用程序使用单核巨噬细胞差异来发现关键的炎症体结构功能关系。具体地说，这项提议将1)确定CARD和PYRIN结构域蛋白作为单核细胞成熟过程中IL-1β释放的调节因子的作用；2)检验JAK/STAT通路导致炎症体功能变化的假设；3)确定某些卡特彼勒蛋白如何抑制炎症体的功能；以及4)测试正确的炎症体组装所必需的酪氨酸激酶活性的假设。这些目标的成功实现将为天然宿主反应提供新的见解，并为预防和治疗炎症性肺部疾病创造新的治疗机会。