Role of purinergic signaling in pediatric multi-organ failure

嘌呤能信号在儿童多器官衰竭中的作用

• 批准号: 10829152
• 负责人: WOLFGANG G JUNGER
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10829152
• 关键词: Role; purinergic; signaling; pediatric; multi

Infection leading to very severe or multiple organ dysfunction is called severe sepsis, a leading cause of death in children. Worsening organ dysfunction develops due to an impaired host response that can progress even after clearance of the pathogen. Most therapeutic approaches to improve outcome in septic patients have resulted in disappointment. Progress in this field requires a better understanding of the reasons why the immune response in critically ill children is impaired. Our previous work has revealed that endogenous ATP release and autocrine purinergic signaling mechanisms regulate neutrophil (PMN) functions and that exogenous ATP and adenosine disrupt normal PMN functions. Based on this work, we hypothesize that infections and tissue damage elevate plasma ATP levels, which impairs the ability of PMNs to eliminate bacteria and promotes PMN-mediated tissue damage that causes MODS in pediatric critical care patients. Aim 1: Contribution of systemic ATP to MODS in pediatric patients: First, we will assess ATP and adenosine levels in the plasma of pediatric patients with sepsis with varying degrees of MODS. Next, we will study how these levels influence PMN functions that protect patients and functions that worsening MODS. Aim 2: Does the purinergic system of pediatric PMNs contribute to MODS? Next, we will study how the PMNs of children differ from adults with regard to the purinergic signaling mechanisms that regulate protective and harmful PMN functions. Aim 3: Possible therapeutic targets for sepsis-related MODS: Finally, we will study how purinergic signaling can be targeted to improve the protective functions of PMNs and to minimize collateral damage to host organs. We expect to find that innate differences in plasma ATP levels and purinergic signaling impair PMNs of children, making them susceptible to infections. Common pathogens in children produce cytolysins that further increase systemic ATP levels and PMN dysregulation, preventing antimicrobial host defenses and promoting collateral tissue damage and MODS. Blocking ATP release or removal of systemic ATP are promising therapeutic strategies to restore PMN function and reduce the risks of severe MODS during infection.

导致非常严重或多个器官功能障碍的感染称为严重败血症，这是死亡的主要原因 在儿童中。由于宿主反应受损而导致器官功能障碍的恶化，甚至可以进步 清除病原体后。大多数改善化脓性患者预后的治疗方法 导致失望。该领域的进步需要更好地理解为什么 重症儿童的免疫反应受损。我们以前的工作表明内源性ATP 释放和自分泌嘌呤能信号传导机制调节中性粒细胞（PMN）功能， 外源ATP和腺苷破坏了正常的PMN功能。基于这项工作，我们假设 感染和组织损伤提高了血浆ATP水平，这会损害PMN消除的能力 细菌并促进PMN介导的组织损伤，从而导致小儿重症监护患者的MOD。 目标1：系统性ATP对儿科患者的MODS的贡献：首先，我们将评估ATP和 小儿脓毒症患者血浆中的腺苷水平，MOD不同程度。接下来，我们会的 研究这些水平如何影响PMN功能，以保护患者和使MOD的功能恶化。 目标2：小儿PMN的嘌呤能系统是否有助于mod？接下来，我们将研究 儿童的PMN与成年人不同，在调节保护性的嘌呤能信号传导机制方面 和有害的PMN功能。 目标3：与败血症相关的mods的可能的治疗靶标：最后，我们将研究嘌呤能 可以针对信号来提高PMN的保护功能，并最大程度地减少附带损害 主机器官。 我们希望发现血浆ATP水平的先天差异和嘌呤能信号传导损害了PMN 儿童，使他们容易感染。儿童的常见病原体产生的细胞赛蛋白进一步 增加全身性ATP水平和PMN失调，防止抗菌宿主防御并促进 抵押组织损伤和mod。阻止ATP释放或去除全身性ATP是有希望的 恢复PMN功能并降低感染过程中严重MOD的风险的治疗策略。