Adenosine in trauma and sepsis

腺苷在创伤和脓毒症中的作用

基本信息

批准号：
8733173
负责人：
George HASKO
金额：
$ 31.8万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8733173
关键词：
5&apos -Nucleotidase Address Adenosine Adenosine A1 Receptor Adoptive Cell Transfers Apoptosis Bacteria Binding Body part Cell Adhesion Molecules Cell Lineage Cell surface Cells Coupled Coupling Critical Illness Drug or chemical Tissue Distribution GTP-Binding Proteins Goals Histocompatibility Antigens Class II Human Hypoxia IRAK1 gene Immune Immune response Immune system Immunity Immunosuppression Infection Inflammation Inflammatory Injury Interferons Ischemia Knock-out Laboratories Ligation Macrophage Activation Measures Mediating Metabolic stress Metabolism Modeling Molecular Morbidity - disease rate Mus Myelogenous Natural Immunity Neutrophil Activation Organ Organ failure Patients Phagocytosis Population Process Production Puncture procedure Purine Nucleosides Purinergic P1 Receptors Receptor Signaling Regulation Respiratory Burst Role Sepsis Septic Shock Signal Transduction Signaling Molecule Small Interfering RNA Staging Sterility Surface TNF receptor-associated factor 3 TRAF6 gene Techniques Technology Testing Tissues Toll-like receptors Trauma Up-Regulation adapter protein apoptosis in lymphocytes base cell type chemokine clinically relevant cytokine ectoADPase extracellular human IRAK1 protein hypoxia inducible factor 1 in vivo macrophage microbial mortality neutrophil prevent protective effect public health relevance receptor research study response septic small hairpin RNA tripolyphosphate

项目摘要

DESCRIPTION (provided by applicant): Systemic illness triggered by microbial invasion of normally sterile parts of the body is referred to as sepsis. Sepsis remains the leading cause of morbidity and mortality in critically ill patients. Current concepts suggest that organ failure and mortality in sepsis are caused by inappropriate regulation of the immune system, which manifests as excessive inflammation in the presence of immunosuppression. Recent evidence gathered in our laboratory suggests that extracellular adenosine that accumulates during sepsis modulates the immune system by activating adenosine receptors on the surface of immune cells. The production of extracellular adenosine is the consequence of the cellular release of its precursors ATP and ADP, and their sequential cell surface phosphohydrolysis to AMP by ectonucleoside triphosphate diphosphohydrolase 1 (E-NTPDase1, CD39) and then to adenosine by ecto-5'-nucleotidase (Ecto5'Ntase, CD73). We found that both CD39 and CD73 are upregulated during sepsis and have pivotal roles in restraining inflammation and organ damage by initiating adenosine receptor signaling. Specific Aim 1 will test the precise mechanisms by which CD39 and CD73 prevent excessive inflammation and organ injury during sepsis using adoptive cell transfer techniques, the "cre-lox" techology, and ex vivo studies on innate immune cells. Specific Aim 2 will define the molecular basis of the upregulation of CD39 and CD73 on macrophages, which may serve to curb excessive macrophage activation by producing adenosine during sepsis. The overarching goal here is to delineate the role of the ectonucleotidase cascade consisting of CD39 and CD73 in protecting against sepsis and to determine whether this cascade can be therapeutically targeted to manage patients with sepsis.

描述（由申请人提供）：由微生物侵入正常无菌部位引发的全身性疾病称为败血症。脓毒症仍然是危重患者发病和死亡的主要原因。目前的概念表明，器官衰竭和脓毒症的死亡是由免疫系统调节不当引起的，表现为免疫抑制时过度炎症。我们实验室收集的最新证据表明，脓毒症期间积累的细胞外腺苷通过激活免疫细胞表面的腺苷受体来调节免疫系统。细胞外腺苷的产生是细胞释放其前体 ATP 和 ADP 以及它们在细胞表面通过外核苷三磷酸二磷酸水解酶 1 (E-NTPDase1、CD39) 磷酸水解为 AMP，然后通过外切 5'-核苷酸酶磷酸水解为腺苷的结果。（Ecto5'Ntase，CD73）。我们发现 CD39 和 CD73 在脓毒症期间均上调，并通过启动腺苷受体信号传导在抑制炎症和器官损伤方面发挥关键作用。具体目标 1 将使用过继细胞转移技术、“cre-lox”技术以及先天免疫细胞的离体研究来测试 CD39 和 CD73 在脓毒症期间预防过度炎症和器官损伤的精确机制。具体目标 2 将定义巨噬细胞上 CD39 和 CD73 上调的分子基础，这可能有助于通过在脓毒症期间产生腺苷来抑制巨噬细胞过度激活。这里的首要目标是描述由 CD39 和 CD73 组成的核酸外切酶级联在预防脓毒症中的作用，并确定该级联是否可以作为治疗目标来管理脓毒症患者。