Immunometabolism in microbial sepsis

微生物脓毒症的免疫代谢

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要脓毒症是许多重症监护病房最常见的死亡原因，导致超过在美国，每年有 25 万人死亡，微生物感染和创伤是最常见的原因。脓毒症的特征是过度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升高也是初始状态的一个常见特征。然而，葡萄糖代谢重编程在调节先天免疫功能中的作用。其与脓毒症的相关性尚不清楚。在本提案中，我们旨在研究两个人的作用。微生物败血症中的葡萄糖代谢途径、己糖胺生物合成途径（HBP）和我们的初步研究揭示了 HBP 相关 O- 的重要作用。 GlcNAc（O-连接 β-N-乙酰氨基葡萄糖）信号传导和 PPP 对抗炎症反应和我们进一步确定了核因子 E2 相关因子 2 (Nrf2) 是一个关键因素。 HBP 和 PPP 途径的中介者，因此促进 HBP 和 PPP 途径的活动。通过药物激活 Nrf2 可能代表一种有前途的治疗方案我们勇敢地承认 1) HBP 相关的 O-GlcNAc 信号传导会抑制先天免疫。通过 RIPK3（受体相互作用丝氨酸/苏氨酸激酶 3）的 O-GlcNA 酰化激活；PPP 是通过介导 caspase-1 激活，杀死巨噬细胞并维持脓毒症宿主的生存；3) 这些葡萄糖代谢途径的遗传和药理学激活可有效治疗将采用盲肠结扎和穿刺诱导的多种微生物败血症模型来检查。我们将测试富马酸二甲酯 (DMF) 的作用和功能。治疗对脓毒症引起的死亡率具有保护作用。该提案的目的是检查脓毒症引起的死亡率。两种糖代谢途径对巨噬细胞杀灭细菌的作用及机制炎症，两者都是宿主生存的关键决定因素，这些研究的结果将提供新的结果。对葡萄糖代谢信号的调节和功能的深入了解，这可能会导致确定治疗微生物脓毒症的新治疗靶点。