Immunometabolism in microbial sepsis

微生物脓毒症的免疫代谢

• 批准号: 9764389
• 负责人: Haitao Wen
• 金额: $ 28.6万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764389
• 关键词: Acute; Affect; Anabolism; Animal Model; Anti-Bacterial Agents; Anti-inflammatory; Antibacterial Response; Antisepsis; Bacterial Infections; CASP1 gene; Cause of Death; Cell physiology; Cells; Cessation of life; Clinical Trials; Complex; DNA Sequence Alteration; Defense Mechanisms; Development; Enzymes; Foundations; Fumarates; Future; G6PD gene; Generations; Genetic; Glucose; Glucosephosphate Dehydrogenase; Goals; Healthcare Systems; Hexosamines; Immune; Immune system; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Intensive Care Units; Knowledge; Lead; Link; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Nuclear; O-GlcNAc transferase; Pathogenesis; Pathway interactions; Pentosephosphate Pathway; Phagocytosis; Pharmacology; Play; Prevention; Production; Protein-Serine-Threonine Kinases; RIPK3 gene; Regimen; Regulation; Role; Sepsis; Signal Transduction; Sum; Syndrome; Testing; Therapeutic; Trauma; United States; base; cecal ligation puncture; combat; cullin-3; cytokine; cytokine release syndrome; enzyme pathway; glucose metabolism; immune activation; in vivo; innate immune function; insight; macrophage; microbial; mortality; new therapeutic target; novel; novel strategies; polymicrobial sepsis; receptor; septic; septic patients; therapeutic target

Project Summary/Abstract Sepsis is the most common cause of mortality in many intensive care units and is responsible for more than 250,000 deaths in the United States annually. Microbial infection and trauma are the most common causes of sepsis. Sepsis is characterized by an exaggerated innate immune response leading to a cytokine storm. Recent studies suggest that activation of the innate immune cells causes vigorous metabolic changes towards increased glucose utilization. Elevated glucose metabolism is also a common feature in the initial state of sepsis. However, the role of glucose metabolism reprogramming in the regulation of innate immune function and its relevance to sepsis is poorly understood. In this Proposal, we aim to study the role of two individual glucose metabolism pathways in microbial sepsis, the hexosamine biosynthesis pathway (HBP) and the pentose phosphate pathway (PPP). Our preliminary studies revealed essential roles of HBP-associated O- GlcNAc (O-linked β-N-acetylglucosamine) signaling and PPP in antagonizing inflammatory response and bacterial spreading, respectively. We further identified nuclear factor E2-related factor-2 (Nrf2) as a critical mediator of both HBP and PPP pathways. Therefore, promoting the activities of HBP and PPP pathways through pharmacological activation of Nrf2 may represent a promising therapeutic regimen for treating microbial sepsis. We hypothesize that 1) HBP-associated O-GlcNAc signaling inhibits the innate immune activation through O-GlcNAcylation of RIPK3 (receptor-interacting serine/threonine kinase 3); 2) PPP is required for macrophage bacterial killing and host survival in sepsis by mediating caspase-1 activation; 3) Genetic and pharmacological activation of these glucose metabolism pathways is effective in the treatment of microbial sepsis. Cecal ligation and puncture-induced polymicrobial sepsis model will be employed to examine the role and functions of glucose metabolism pathways. We will test whether dimethyl fumarate (DMF) treatment plays a protective role in sepsis-induced mortality. The goal of the proposal is to examine the function and mechanism of two glucose metabolism pathways on macrophage bacterial killing and inflammation, both of which are key determinants of host survival. Results of these studies will provide novel insights into the regulation and function of glucose metabolism signaling, which can potentially lead to the identification of new therapeutic targets in the treatment of microbial sepsis.

项目摘要/摘要 败血症是许多重症监护病房中最常见的死亡率原因，负责超过 每年在美国25万人死亡。微生物感染和创伤是最常见的原因 败血症。败血症的特征是夸张的先天免疫反应，导致细胞因子风暴。 最近的研究表明，先天免疫细胞的激活会导致剧烈的代谢变化 葡萄糖利用率增加。升高的葡萄糖代谢也是初始状态的常见特征 败血症。但是，葡萄糖代谢重编程在先天免疫功能调节中的作用 它与脓毒症的相关性知之甚少。在此提案中，我们旨在研究两个人的作用 微生物败血症，己糖胺生物合成途径（HBP）中的葡萄糖代谢途径和 戊糖磷酸途径（PPP）。我们的初步研究揭示了与HBP相关的O-的重要作用 GlcNAC（O连接的β-N-乙酰葡萄糖）信号传导和PPP在拮抗炎症反应和PPP中 细菌扩散。我们进一步将核因子E2相关因子2（NRF2）视为关键 HBP和PPP途径的介体。因此，促进HBP和PPP途径的活动 通过NRF2的药物激活可能代表一种有前途的治疗方案 微生物败血症。我们假设1）与HBP相关的O-GLCNAC信号抑制了先天免疫 通过RIPK3的O-Glcnacylation（受体相互作用的丝氨酸/苏氨酸激酶3）激活； 2）PPP是 通过介导caspase-1激活，巨噬细菌在败血症中杀死和宿主存活所必需的； 3） 这些葡萄糖代谢途径的遗传和药物激活有效地治疗 微生物败血症。将雇用盲肠结扎和穿刺诱导的多症败血症模型来检查 葡萄糖代谢途径的作用和功能。我们将测试富马酸二甲基（DMF）是否 治疗在败血症引起的死亡率中起受保护的作用。该提议的目的是检查 巨噬细菌杀死和 炎症，两者都是宿主存活的关键决定者。这些研究的结果将提供新颖 对葡萄糖代谢信号传导的调节和功能的见解，这可能会导致 鉴定新的治疗靶标在微生物败血症治疗中。