Molecular Mechanisms of Inflammasome Activation During Salmonella Infections

沙门氏菌感染期间炎症小体激活的分子机制

• 批准号: 8966608
• 负责人: Denise M Monack
• 金额: $ 36.62万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8966608
• 关键词: Biochemical; Biochemical Genetics; Biological; CASP1 gene; Caspase; Cell Death; Cell Maturation; Cells; Cessation of life; Communicable Diseases; Complex; Data; Disease; Event; Genetic; Goals; Host Defense; Human; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory; Integration Host Factors; Interleukin-1; Knowledge; Lead; Link; Location; Mediating; Microbe; Mission; Molecular; Multiprotein Complexes; Natural Immunity; Pathway interactions; Peptide Hydrolases; Prevention approach; Preventive; Preventive Intervention; Production; Proteins; Public Health; Regulation; Research; Salmonella; Salmonella infections; Salmonella typhimurium; Signal Pathway; Signal Transduction; Stimulus; Therapeutic; Therapeutic Intervention; Work; base; cytokine; design; genetic approach; innovation; insight; macrophage; novel therapeutics; pathogen; response; sensor

DESCRIPTION (provided by applicant): We study Salmonella-host interactions and have shown that the mammalian inflammasome, an innate immune protective complex that mediates a pro-inflammatory host response, is important for controlling S. typhimurium infection. The long-term goal of this research application is to understand how the host recognizes intracellular S. typhimurium and how this pathogen has evolved to subvert innate immune defenses. We have demonstrated that multiple host cytosolic sensors are involved in recognizing intracellular S. typhimurium and activating the inflammasome. In addition, we have shown that multiple caspase-1 complexes are formed in response to intracellular S. typhimurium. In Aim1, we will use genetic and biochemical approaches to identify new host molecules and pathways involved in caspase- 1-dependent maturation and release of pro-inflammatory cytokines. In Aim 2, we will take biochemical and genetic approaches to identify host molecules and pathways involved in caspase-1-induced macrophage death. In Aim 3, we will characterize the spatial and temporal relationships between caspase-1 complex formation, cytokine release and host cell death. These studies are aimed at gaining a better understanding of the molecular mechanisms of intracellular recognition, which will lead to the rational design of therapeutics that will benefit public health.

描述(申请人提供)：我们研究了沙门氏菌与宿主的相互作用，并表明哺乳动物的炎症体是一种先天免疫保护复合体，介导促炎宿主反应，对于控制鼠伤寒沙门氏菌感染是重要的。这项研究的长期目标是了解宿主如何识别细胞内的鼠伤寒沙门氏菌，以及这种病原体是如何进化来颠覆天然免疫防御的。我们已经证明，多个宿主胞液传感器参与识别细胞内的鼠伤寒沙门氏菌并激活炎症体。此外，我们还证明了细胞内的鼠伤寒沙门氏菌会形成多个caspase-1复合体。在Aim1中，我们将使用遗传和生化方法来鉴定新的宿主分子和途径，这些分子和途径涉及caspase-1依赖的成熟和促炎细胞因子的释放。在目标2中，我们将采用生物化学和遗传学的方法来鉴定参与caspase-1诱导的巨噬细胞死亡的宿主分子和途径。在目标3中，我们将描述caspase-1复合体形成、细胞因子释放和宿主细胞死亡之间的时空关系。这些研究旨在更好地了解细胞内识别的分子机制，这将导致合理设计有利于公众健康的治疗方法。