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：
10267891
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/10267891
关键词：
ADORA2A gene ADORA3 gene Abnormal Neutrophil Address Adenosine Adoptive Transfer Agonist Apoptosis Bacteria Binding Biological 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 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.

概括脓毒症是一种使严重感染复杂化的临床综合征。脓毒症仍然是发病的主要原因和危重病人的死亡率。 FDA 没有批准用于治疗脓毒症的特定药物。目前脓毒症病理生理学的概念表明，中性粒细胞功能的不当调节导致脓毒症的器官衰竭和死亡。这表现为无法控制细菌生长和传播、持续性和继发性感染、炎症和终末器官损伤。细胞外腺苷是一种生物活性信号分子，在脓毒症代谢应激部位积聚。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脓毒症特征性的中性粒细胞，包括趋化性下降、摄取和杀伤能力下降细菌并延迟细胞凋亡。鉴于脓毒性中性粒细胞改变与引起的改变之间的相似性通过 A2AAR 信号传导，我们假设内源性腺苷会导致脓毒症诱发的发作通过刺激 A2AAR 来治疗中性粒细胞功能障碍。我们使用靶向基因删除的初步数据盲肠结扎和穿刺诱发败血症的小鼠中的药理拮抗作用已证实 A2AAR 会导致细菌传播、器官损伤和死亡。我们与人类患者的数据血浆腺苷和中性粒细胞 A2AAR 表达增加，表明 A2AAR 增加信号传导导致中性粒细胞功能障碍。根据这些数据，我们假设内源性腺苷通过以下方式导致脓毒症引起的免疫失调、细菌传播、器官损伤和死亡中性粒细胞中的 A2AAR 信号传导。为了解决这个假设，我们提出了 2 个具体目标。具体目标 1 将描述中性粒细胞中 A2AAR 信号传导在细菌传播、器官损伤和 CLP 诱导的小鼠脓毒症死亡率。具体目标 2 将研究 A2AAR 信号传导对中性粒细胞的贡献败血症患者的功能障碍。本研究的长期目标是通过药理学靶向 A2AAR 信号传导作为脓毒症患者管理的治疗选择。