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:
- 金额:$ 53.63万
- 依托单位:
- 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:
- 关键词:ADORA2A geneADORA3 geneAbnormal NeutrophilAddressAdenosineAdoptive TransferAgonistApoptosisBacteriaBindingBiologicalBrain Hypoxia-IschemiaCell surfaceCellsCessation of lifeCharacteristicsChemotaxisClinicalClinical TrialsCoupledCritical CareCritical IllnessDataFDA approvedFunctional disorderGTP-Binding ProteinsGene ExpressionGeneticGoalsGrowthHelper-Inducer T-LymphocyteHospitalsHumanImmuneImmune System DiseasesImmune responseImmune systemImmunosuppressionIndividualInfectionInflammationInflammation ProcessIngestionInnate Immune SystemLifeLipopolysaccharidesMediatingMedicineMetabolic stressMetabolismModelingMorbidity - disease rateMultiple Organ FailureMusOrganOrgan failurePatientsPhagocytosisPharmacologyPhenotypePlasmaProductionPurinergic P1 ReceptorsPurinesRegulationRegulatory T-LymphocyteRespiratory BurstRoleSepsisSignal TransductionSignaling MoleculeSiteSurfaceSyndromeTNF geneTraumaactivated Protein Carmbasececal ligation puncturecell typechronic infectionclinically relevantcytokineexhaustionextracellularimmune functionimmunoregulationmacrophagemigrationmonocytemortalityneutrophilorgan injurypathogenreceptorsecondary infectionsepticseptic patientstranscriptome 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.
总结
脓毒症是严重感染并发的临床综合征。脓毒症仍然是发病的主要原因
和死亡率之间的关系。目前尚无FDA批准的治疗败血症的特定药物。
目前脓毒症的病理生理学概念表明,中性粒细胞功能的不适当调节
导致败血症中的器官衰竭和死亡率。这表现为无法控制细菌生长,
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,在脓毒症的代谢应激部位积累。细胞外
腺苷通过结合并激活G蛋白偶联的A2A腺苷而具有有效的免疫抑制作用
受体(AR)在中性粒细胞表面。A2AAR信号转导在细胞内复制了许多表型变化,
脓毒症特征性中性粒细胞,包括趋化性降低、摄取和杀伤能力降低
细菌和延迟凋亡。鉴于脓毒性中性粒细胞改变与
通过A2AAR信号转导,我们假设内源性腺苷参与脓毒症诱导的发病,
通过刺激A2AAR引起的中性粒细胞功能障碍。我们的初步数据使用两种靶向基因缺失
在盲肠结扎和穿孔诱导的脓毒症小鼠中的药理学拮抗作用已经证实,
A2AAR导致细菌传播、器官损伤和死亡。我们的人类患者数据
表明血浆腺苷和中性粒细胞A2AAR表达增加,表明A2AAR增加
导致中性粒细胞功能障碍的信号传导。基于这些数据,我们假设内源性腺苷
通过以下方式导致脓毒症诱导的免疫失调、细菌传播、器官损伤和死亡
中性粒细胞中的A2AAR信号传导。为了解决这个问题,我们提出了两个具体的目标。具体目标1将
描述中性粒细胞中A2AAR信号在促进细菌传播、器官损伤和
CLP诱导的脓毒症小鼠死亡率。具体目标2将研究A2AAR信号传导对中性粒细胞的贡献。
脓毒症患者的功能障碍。本研究的长期目标是研究靶向A2AAR信号转导
作为脓毒症患者管理的治疗选择。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
George HASKO其他文献
George HASKO的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}