Cellular Signaling Mechanisms in Macrophage Activation.

巨噬细胞激活中的细胞信号传导机制。

• 批准号: 7119242
• 负责人: Joseph Cuschieri
• 金额: $ 12.93万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7119242
• 关键词: actins; adult respiratory distress syndrome; biological signal transduction; calcium flux; calmodulin dependent protein kinase; clinical research; endotoxins; enzyme linked immunosorbent assay; hemorrhage; human subject; inflammation; intracellular; ischemia; leukocyte activation /transformation; macrophage; multiple organ failure; oxidative stress; platelet activating factor; polymerization; reperfusion; second messengers; septicemia

DESCRIPTION (provided by applicant): Sepsis, following trauma/hemorrhage and ischemia/reperfusion, is a common etiology for subsequent Acute Respiratory Distress Syndrome (ARDS) and multiple organ dysfunction syndrome (MODS) and remains a leading cause of subsequent morbidity and mortality. A number of different inflammatory cells are responsible for this condition; however, it appears that the macrophage is the common central orchestrating cell underlying these conditions. It is becoming evident that this inflammatory driven signaling cascade is affected by a number of different "priming" agents, such as platelet activating factor (PAF) and oxidant stress. "Priming" does not lead to pro-inflammatory mediator production; rather it causes enhanced responsiveness by the macrophage to secondary inflammatory stimuli, such as endotoxin. The mechanism in which these "priming" agents cause this enhanced response is unknown. Therefore, the purpose of this grant is to better delineate the intracellular signaling mechanisms which are responsible for this affect. This proposal will focus on the potential role that the secondary messenger, calcium, plays during initial "priming". Although calcium flux occurs during "priming", it is unknown if and how calcium could modulate endotoxin-mediated signaling. We, therefore, hypothesis that the increase in intracellular calcium results in the activation of regulatory kinases, such as calcium/calmodulin-dependent protein kinases (CaMK), leads to enhanced endotoxin-mediated signaling. Furthermore, we hypothesis that CaMK activation leads to modulation of actin polymerization and stress fiber polymerization induced by endotoxin resulting in enhanced intracellular spatial relationships and optimal endotoxin signaling. The role of calcium and CaMK during "priming" will be investigated through the use of specific inhibitors and activators on the ability of PAF and oxidant stress to induce "priming" of endotoxin-mediated activation within the macrophage. The overall aim of this proposal is to provide further insight into potential mechanisms that serve in the activation and "priming" of the macrophage. Through an enhanced understanding of these mechanisms it is our goal that potential therapeutic targets may be discovered to regulate the inflammatory response following trauma/hemorrhage and ischemia/reperfusion.

描述（由申请人提供）： 创伤/出血和缺血/再灌注后的脓毒症是随后的急性呼吸窘迫综合征（ARDS）和多器官功能障碍综合征（MODS）的常见病因，并且仍然是随后发病和死亡的主要原因。许多不同的炎症细胞都是造成这种情况的原因。然而，巨噬细胞似乎是这些条件下常见的中央协调细胞。越来越明显的是，这种炎症驱动的信号级联受到许多不同“引发”剂的影响，例如血小板激活因子（PAF）和氧化应激。 “启动”不会导致促炎介质的产生；相反，它会导致巨噬细胞对继发性炎症刺激（例如内毒素）的反应性增强。这些“引发”剂引起这种增强反应的机制尚不清楚。因此，这项资助的目的是更好地描述造成这种影响的细胞内信号传导机制。该提案将重点关注第二信使钙在初始“启动”过程中发挥的潜在作用。尽管钙流动发生在“启动”期间，但尚不清楚钙是否以及如何调节内毒素介导的信号传导。因此，我们假设细胞内钙的增加会导致调节激酶（例如钙/钙调蛋白依赖性蛋白激酶（CaMK））的激活，从而导致内毒素介导的信号传导增强。此外，我们假设 CaMK 激活导致内毒素诱导的肌动蛋白聚合和应力纤维聚合的调节，从而增强细胞内空间关系和最佳内毒素信号传导。将通过使用特定抑制剂和激活剂对 PAF 和氧化应激诱导巨噬细胞内内毒素介导的激活“启动”的能力来研究钙和 CaMK 在“启动”过程中的作用。该提案的总体目标是进一步深入了解巨噬细胞激活和“启动”的潜在机制。通过增强对这些机制的理解，我们的目标是发现潜在的治疗靶点来调节创伤/出血和缺血/再灌注后的炎症反应。