Neutrophil A2A receptors in sepsis

脓毒症中的中性粒细胞 A2A 受体

基本信息

批准号：
10478933
负责人：
George HASKO
金额：
$ 53.63万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10478933
关键词：
ADORA2A gene ADORA3 gene Abnormal Neutrophil Address Adenosine Adoptive Transfer Agonist Apoptosis Bacteria Binding Brain Hypoxia-Ischemia Cell surface Cells Cessation of life Characteristics Chemotaxis Clinical Clinical Trials Coupled Critical Care Critical Illness Data FDA approved Functional disorder GTP-Binding Proteins Gene Expression Genetic Goals Growth Helper-Inducer T-Lymphocyte Hospitals Human Immune Immune System Diseases Immune response Immune system Immunosuppression Individual Infection Inflammation Inflammation Process Ingestion Innate Immune System Life Lipopolysaccharides Mediating Medicine Metabolic stress Metabolism Modeling Morbidity - disease rate Multiple Organ Failure Mus Organ Organ failure Patients Phagocytosis Pharmacology Phenotype Plasma Production Purinergic P1 Receptors Purines Regulation Regulatory T-Lymphocyte Respiratory Burst Role Sepsis Signal Transduction Signaling Molecule Site Surface Syndrome TNF gene Trauma activated Protein C antagonist arm base cecal ligation puncture cell type chronic infection clinically relevant cytokine exhaustion extracellular immune function immunoregulation macrophage migration monocyte mortality neutrophil organ injury pathogen receptor secondary infection septic septic patients transcriptome sequencing

项目摘要

SUMMARY Sepsis is a clinical syndrome that complicates severe infection. Sepsis remains the leading cause of morbidity and mortality in critically ill patients. There are no specific FDA-approved medicines for the treatment of sepsis. Current concepts of the pathophysiology of sepsis suggest that inappropriate regulation of neutrophil functions contribute to organ failure and mortality in sepsis. This manifests as an inability to control bacterial growth and dissemination, persistent and secondary infections, inflammation, and end organ injury. Extracellular adenosine is a biologically active signaling molecule that accumulates at sites of metabolic stress in sepsis. Extracellular adenosine has potent immunosuppressive effects by binding to and activating G protein-coupled A2A adenosine receptors (ARs) on the surface of neutrophils. A2AAR signaling reproduces many of the phenotypic changes in neutrophils that are characteristic of sepsis, including decreased chemotaxis, diminished ability to ingest and kill bacteria and delayed apoptosis. Given this similarity between septic neutrophil alterations and the ones caused by A2AAR signaling, we hypothesized that endogenous adenosine would contribute to the sepsis-induced onset of neutrophil dysfunction via stimulation of A2AARs. Our preliminary data using both targeted genetic deletion and pharmacological antagonism in mice with cecal ligation and puncture-induced sepsis have confirmed that A2AARs contribute to bacterial dissemination, organ injury, and mortality. Our data with human patients demonstrate increased plasma adenosine and neutrophil A2AAR expression indicating increased A2AAR signaling leading to neutrophil dysfunction. Based on these data, we hypothesize that endogenous adenosine contributes to sepsis-induced immune dysregulation, bacterial dissemination, organ injury and mortality through A2AAR signaling in neutrophils. To address this hypothesis, we propose 2 Specific Aims. Specific Aim 1 will delineate the role of A2AAR signaling in neutrophils in contributing to bacterial dissemination, organ injury, and mortality in CLP-induced sepsis in mice. Specific Aim 2 will study the contribution of A2AAR signaling to neutrophil dysfunction in patients with sepsis. The long-term goal of this study is to pharmacologically target A2AAR signaling as a treatment option for the management of patients with sepsis.

概括败血症是一种临床综合征，使严重的感染复杂化。败血症仍然是发病率的主要原因重症患者的死亡率和死亡率。没有特定的FDA批准药物用于治疗败血症。败血症病理生理学的当前概念表明，中性粒细胞功能的不适当调节有助于败血症的器官衰竭和死亡率。这表明无法控制细菌的生长和传播，持续性和继发感染，炎症和最终器官损伤。细胞外腺苷是一种具有生物活性的信号分子，可在败血症中积聚在代谢应激部位。细胞外腺苷通过结合并激活G蛋白偶联的A2A腺苷具有有效的免疫抑制作用中性粒细胞表面的受体（AR）。 A2AAR信号传导重现了许多表型变化败血症特征的中性粒细胞，包括趋化性降低，摄入和杀死的能力降低细菌和细胞凋亡延迟。鉴于败血性嗜中性粒细胞改变与引起的相似性通过A2AAR信号，我们假设内源性腺苷将有助于败血症诱导的发作通过刺激A2AAR的中性粒细胞功能障碍。我们的初步数据都使用两个目标遗传缺失与盲肠结扎和穿刺诱导的败血症的小鼠的药理拮抗作用已证实 A2AAR有助于细菌传播，器官损伤和死亡率。我们与人类患者的数据证明血浆腺苷和中性粒细胞A2AAR表达增加，表明A2AAR增加信号导致中性粒细胞功能障碍。基于这些数据，我们假设内源性腺苷导致败血症引起的免疫失调，细菌传播，器官损伤和通过中性粒细胞中的A2AAR信号传导。为了解决这一假设，我们提出了2个具体目标。具体目标1将描述A2AAR信号在中性粒细胞中的作用在有助于细菌传播，器官损伤和小鼠CLP诱导的败血症的死亡率。特定目标2将研究A2AAR信号对中性粒细胞的贡献败血症患者的功能障碍。这项研究的长期目标是在药理上靶向A2AAR信号传导作为治疗败血症患者的治疗选择。