权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.