Role of Protein Ubiquitination in Sepsis

蛋白质泛素化在脓毒症中的作用

• 批准号: 9175444
• 负责人: JIAN ZHANG
• 金额: $ 34.01万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-24 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175444
• 关键词: Attenuated; Binding; Biological; CASP1 gene; Caring; Caspase; Cell Wall; Cessation of life; Complex; Data; Deubiquitinating Enzyme; Development; Dose; Endotoxins; Enzymes; Feedback; Genetic Polymorphism; Gram-Negative Bacteria; Healthcare Systems; Human; Immune response; Immunity; In Vitro; Infection; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Interleukin-1; Interleukin-1 beta; Lead; Leucine-Rich Repeat; Ligation; Link; Lipopolysaccharides; Mediating; Medical; Medicine; Molecular; Morbidity - disease rate; Mus; Mutation; Patients; Phosphorylation; Polyubiquitination; Production; Proteins; Puncture procedure; Role; Sepsis; Sepsis Syndrome; Septic Shock; Signal Pathway; Signal Transduction; Site; Stress; Study models; Testing; Therapeutic; Time; Tyrosine Phosphorylation; Ubiquitination; Wild Type Mouse; attenuation; caspase 12; combat; cost; cytokine; cytosolic receptor; in vivo; insight; macrophage; microbial; mortality; novel; pathogen; prevent; protein complex; receptor; research study; response; sensor; septic; src-Family Kinases; ubiquitin ligase; ubiquitin-protein ligase

Project Summary Sepsis with its complications is a major challenge in contemporary medicine. Approximately 250,000 cases of sepsis lead to fatalities in the USA annually at huge costs for the healthcare system. Depending on the standards of medical care, the worldwide mortality rates in septic humans range from 30% to 70% with an aggregate mortality rate of ~50%. NLRP3 is a key component of the macromolecular signaling complex called the inflammasome that promotes caspase 1-dependent production of IL-1β pro-inflammatory cytokine involved in the development of sepsis. Although the factors leading to NLRP3 inflammasome activation have been extensively studied, the mechanisms for negatively regulating the activation of the NLRP3 inflammasome, and thus, controlling sepsis, are not known. We found that NLRP3 is inhibited by ubiquitination by Cbl-b, an E3 ubiquitin ligase. The significance of this finding is demonstrated by the observation that that lipopolysaccharide (LPS) injection or cecal ligation and puncture (CLP) induces a significant mortality in Cblb-/- mice compared to wild-type (WT) controls, and this increased mortality in Cblb-/- mice induced by LPS is blocked by an IL-1 receptor antagonist or by introducing NLRP3 deficiency. Therefore, our central hypothesis is that during sepsis, Cbl-b is autoubiquitinated/activated and ubiquitinates NLRP3, which in turn inhibits NLRP3 and attenuates NLRP3-mediated innate responses. We propose to determine 1) how Cbl-b regulates NLRP3 inflammasome activation; 2) whether and how Cbl-b controls non-canonical NLRP3 inflammasome in vivo using CLP-induced sepsis and LPS-induced septic shock as the study models. Understanding the role of Cbl-b in regulating the NLRP3 inflammasome-mediated signaling pathway will provide novel insights and therapeutic strategies to combat sepsis.

项目概要 脓毒症及其并发症是当代医学面临的一项重大挑战。 在美国，脓毒症每年都会导致死亡，给医疗保健系统带来巨大成本。 根据医疗护理标准，全世界脓毒症患者的死亡率为 30% 至 70%，其中 总死亡率约为 50%。NLRP3 是称为大分子信号复合物的关键组成部分。 促进半胱天冬酶 1 依赖性产生 IL-1β 促炎细胞因子的炎症小体 尽管导致 NLRP3 炎症小体激活的因素已被证实。 普遍研究的负向调节 NLRP3 炎症小体激活的机制，以及 因此，控制败血症尚不清楚，我们发现 NLRP3 被 Cbl-b（一种 E3）泛素化所抑制。 脂多糖的观察证明了这一发现的重要性。 与 Cblb-/- 小鼠相比，LPS 注射或盲肠结扎穿刺 (CLP) 导致 Cblb-/- 小鼠显着死亡 野生型 (WT) 对照，LPS 诱导的 Cblb-/- 小鼠死亡率增加被 IL-1 阻断 受体拮抗剂或通过引入 NLRP3 缺陷因此，我们的中心假设是在脓毒症期间， Cbl-b 被自动泛素化/激活并泛素化 NLRP3，进而抑制 NLRP3 并减弱 我们建议确定 NLRP3 介导的先天反应：1) Cbl-b 如何调节 NLRP3 炎症小体。 2) Cbl-b 是否以及如何利用 CLP 诱导体内控制非典型 NLRP3 炎症小体 脓毒症和 LPS 诱导的感染性休克作为研究模型，了解 Cbl-b 在调节中的作用。 NLRP3炎症小体介导的信号通路将为以下疾病提供新的见解和治疗策略： 对抗败血症。