Immunometabolism in Sepsis

脓毒症的免疫代谢

基本信息

批准号：
8937151
负责人：
TIMOTHY R BILLIAR
金额：
$ 30.42万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8937151
关键词：
3-phosphoglycerate 5&apos -AMP-activated protein kinase Ablation Affect Antibiotic Therapy Cause of Death Cells Clinical Data Disease Endothelial Cells Endotoxemia Endotoxins Enzymes Experimental Animal Model Functional disorder Future Genes Genetic Transcription Glycolysis HMGB1 Protein Histone Deacetylase Histones Human Hypoxia Inducible Factor Immune Immune response In Vitro Infection Inflammation Inflammatory Inflammatory Response Injury Intensive Care Intensive Care Units Interleukins Intervention Investigation Knock-out Knockout Mice Lead Ligation Mediating Mediator of activation protein Metabolic Metabolism Metformin Mus Myeloid Cells Non-Histone Chromosomal Proteins Organ Pathogenesis Patients Phosphoenolpyruvate Play Poly(ADP-ribose) Polymerases Production Puncture procedure Pyruvate Kinase Regulation Resveratrol Role Sepsis Sepsis Syndrome Septic Shock Testing Therapeutic Time Tumor Necrosis Factor-alpha United States aerobic glycolysis cytokine improved in vivo inhibitor/antagonist insight macrophage microbial monocyte novel novel therapeutics phosphoglycerate prevent public health relevance response sensor small hairpin RNA therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Sepsis, a clinical systemic inflammatory response syndrome occurring in patients following infection or injury, remains the leading cause of death in intensive care units worldwide, including the United States. Emerging evidence indicates that immunometabolism may play an important role in the pathogenesis of sepsis through its ability to regulate the expression and release of cytokines. In particular, we recently provided the first direct evidence that PKM2-mediated aerobic glycolysis promotes the release of HMGB1, a late mediator of lethal systemic inflammation with a wider therapeutic time window for clinical intervention. These exciting findings raise several important questions regarding the previously unknown role of PKM2 in the pathogenesis of sepsis, as well as the novel mechanisms underlying the regulation of PKM2 expression and HMGB1 release. We hypothesize that PKM2-mediated immunometabolism is an emerging hallmark of sepsis that contributes to cytokine (e.g., HMGB1) release and the subsequent systemic inflammatory response. We propose the following specific aims: Aim 1. Define the mechanism underlying the regulation of PKM2 expression and activity in both immune and non-immune cells during sepsis. We will test the hypothesis that AMPK is a negative regulator of PKM2 expression and activity, and therefore suppresses aerobic glycolysis and HMGB1 release in activated macrophages, monocytes, and endothelial cells in vitro and in vivo. Aim 2. Define the mechanism underlying the regulation of HMGB1 release by aerobic glycolysis in both immune and non-immune cells during sepsis. We will test the hypothesis that metabolites production (e.g., lactate) from PKM2-mediated aerobic glycolysis can inhibit the activity of histone deacetylases including SIRT1, which in turn enables HMGB1 hyperacetylation and subsequent release in activated macrophages, monocytes, and endothelial cells in vitro and in vivo. Aim 3. Determine the efficacy of PKM2 inhibition in protecting against sepsis in two experimental animal models. We will test the hypothesis that mice with PKM2 ablation in myeloid cells are protected from lethal endotoxemia or cecal ligation and puncture-induced polymicrobial sepsis through altering lactate accumulation, HMGB1 release, inflammatory response, and organ dysfunction. The completion of these exciting studies will further improve our understanding of the emerging role of immunometabolism in inflammation and the mechanisms of HMGB1 release and guide future development of therapeutic strategies to treat sepsis and other lethal inflammatory diseases.

描述（由申请人提供）：脓毒症是一种发生在感染或受伤后患者的临床全身炎症反应综合征，仍然是包括美国在内的全世界重症监护病房的主要死亡原因。特别是，我们最近提供了第一个直接证据表明 PKM2 介导的有氧糖酵解促进了细胞因子的释放。 HMGB1 是致命性全身炎症的晚期介质，具有更宽的临床干预治疗时间窗，这些令人兴奋的发现提出了一些关于 PKM2 在脓毒症发病机制中未知作用的重要问题，以及 PKM2 调节的新机制。我们勇敢地承认 PKM2 介导的免疫代谢是脓毒症的一个新标志，有助于细胞因子（例如 HMGB1）的释放和随后的全身炎症反应。提出以下具体目标：目的 1. 明确败血症期间免疫和非免疫细胞中 PKM2 表达和活性调节的机制我们将检验 AMPK 是 PKM2 表达和活性负调节因子的假设。在体外和体内抑制活化的巨噬细胞、单核细胞和内皮细胞的有氧糖酵解和 HMGB1 释放。目标 2. 定义通过调节 HMGB1 释放的机制。我们将测试以下假设：PKM2 介导的有氧糖酵解产生的代谢物（例如乳酸）可以抑制组蛋白脱乙酰酶（包括 SIRT1）的活性，从而使 HMGB1 过度乙酰化并随后发生。体外和体内活化的巨噬细胞、单核细胞和内皮细胞中的释放。目标 3。 PKM2 抑制在两个实验动物模型中预防败血症的功效我们将测试这样的假设：骨髓细胞中 PKM2 消融的小鼠通过改变乳酸积累、HMGB1 释放、炎症而免受致命性内毒素血症或盲肠结扎和穿刺诱导的多种微生物败血症。这些令人兴奋的研究的完成将进一步提高我们对免疫代谢在炎症中的新作用以及 HMGB1 释放机制的理解。并指导未来治疗脓毒症和其他致命炎症性疾病的治疗策略的发展。