The Non-Inflammasome NLRs in Immunity and Host defense

免疫和宿主防御中的非炎性体 NLR

• 批准号: 9243972
• 负责人: Thirumala-Devi Kanneganti
• 金额: $ 44.88万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243972
• 关键词: Address; Autoimmune Diseases; Autoimmune Process; Award; Bacterial Infections; Biochemical; CASP1 gene; Cells; Cellular Stress; Communicable Diseases; Complex; Data; Disease; Employee Strikes; FRAP1 gene; Family; Generations; Genes; Genetic Polymorphism; Grant; Hereditary Disease; Host Defense; Human; IRAK1 gene; Immune; Immune System Diseases; Immune response; Immune signaling; Immunity; Immunologic Receptors; Immunology; Immunosuppression; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Influenza A virus; Interleukin-1 beta; Interleukin-18; Lead; Link; MAP Kinase Gene; Malignant Neoplasms; Mediating; Missense Mutation; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; National Institute of Allergy and Infectious Disease; Natural Immunity; Outcome; Pathology; Pathway interactions; Patients; Peptidoglycan; Physiological; Play; Predisposition; Proto-Oncogene Proteins c-akt; Recruitment Activity; Regulation; Regulatory Pathway; Research; Role; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Toll-like receptors; Ubiquitin; Vaccines; Virus Diseases; Work; adaptive immune response; adaptive immunity; autoinflammatory; base; cancer cell; cytokine; design; exhaustion; experimental study; human disease; immunopathology; immunoregulation; improved; in vivo; interest; macrophage; member; mortality; multicatalytic endopeptidase complex; novel; pathogen; premature; protein complex; public health relevance; receptor; response; sensor

 DESCRIPTION (provided by applicant): NOD-like receptors (NLRs) are a family of intracellular sensor molecules involved in the regulation of inflammatory signaling in response to infection and cellular stress. Recent studies have revealed pivotal roles for NLR-mediated inflammation in a spectrum of diverse human autoimmune and inflammatory disorders. The vast majority of NLRs to date have been defined as activators of inflammatory signaling in innate immune cells. For instance, the prototypical NLR members, NOD1 and NOD2, initiate proinflammatory NF-κB and MAPK signaling in response to their direct recognition of bacterial peptidoglycan fragments. Multiple NLRs have also been described to promote the activation and secretion of the proinflammatory cytokines IL-1β and IL-18 by coordinating the assembly of the inflammasome complex. In contrast, some NLRs, such as NLRP6, NLRP12, NLRC3 and NLRX1, negatively regulate inflammatory signaling. However, the cellular and molecular mechanisms that direct the suppression of inflammation by this new class of inhibitory NLRs are not known. Missense mutations in NLRP12 are associated with inflammatory diseases in humans, but the biochemical mechanisms and pathways underlying these pathologies remain unclear. Recent work from our lab demonstrates that NLRP12 functions as a key negative regulator of NF-κB signaling. Importantly, inflammation and immunopathology are not exclusively restricted to inflammatory and autoimmune diseases. The dysregulation of innate and adaptive immunity can also result in striking differences with regard to morbidity and mortality during infectious disease. In this regard, NLRP12's role in viral infection and generation of adaptive immune responses has not been investigated. Therefore, this project is highly significant, as it will lead to the identification of key immune mechanisms involved in host defense and inflammatory control mechanisms dependent on NLRP12 that regulate inflammation. We will examine these mechanisms through the use of influenza A virus.

 描述（由申请人提供）：NOD样受体（NLR）是细胞内传感器分子家族，参与响应感染和细胞应激而调节炎症信号传导。最近的研究揭示了 NLR 介导的炎症在一系列不同的人类自身免疫和炎症性疾病中的关键作用。迄今为止，绝大多数 NLR 已被定义为先天免疫细胞中炎症信号传导的激活剂。例如，典型的 NLR 成员 NOD1 和 NOD2 响应其对细菌肽聚糖片段的直接识别，启动促炎 NF-κB 和 MAPK 信号传导。多个 NLR 也被描述为通过协调炎性体复合物的组装来促进促炎细胞因子 IL-1β 和 IL-18 的激活和分泌。相反，一些 NLR，例如 NLRP6、NLRP12、NLRC3 和 NLRX1，负向调节炎症信号传导。然而，这种新型抑制性 NLR 抑制炎症的细胞和分子机制尚不清楚。 NLRP12 的错义突变与人类炎症性疾病相关，但这些病理背后的生化机制和途径仍不清楚。我们实验室最近的工作表明，NLRP12 是 NF-κB 信号传导的关键负调节因子。重要的是，炎症和免疫病理学不仅仅局限于炎症和自身免疫性疾病。先天性和适应性免疫的失调也可能导致传染病期间发病率和死亡率的显着差异。在这方面，NLRP12 在病毒感染和适应性免疫反应产生中的作用尚未得到研究。因此，该项目非常重要，因为它将导致宿主关键免疫机制的鉴定。 防御和炎症控制机制依赖于调节炎症的 NLRP12。我们将通过使用甲型流感病毒来研究这些机制。