Cellular Signaling Mechanisms in Macrophage Activation.
巨噬细胞激活中的细胞信号传导机制。
基本信息
- 批准号:6911417
- 负责人:
- 金额:$ 12.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:actinsadult respiratory distress syndromebiological signal transductioncalcium fluxcalmodulin dependent protein kinaseclinical researchendotoxinsenzyme linked immunosorbent assayhemorrhagehuman subjectinflammationintracellularischemialeukocyte activation /transformationmacrophagemultiple organ failureoxidative stressplatelet activating factorpolymerizationreperfusionsecond messengerssepticemia
项目摘要
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率和死亡率的主要原因。许多不同的炎性细胞负责这种情况;然而,似乎巨噬细胞是这些情况下的共同中央协调细胞。越来越明显的是,这种炎症驱动的信号级联反应受到许多不同的“引发”剂的影响,如血小板活化因子(PAF)和氧化应激。“致敏”不导致促炎介质产生;相反,它引起巨噬细胞对继发性炎症刺激(如内毒素)的增强的反应性。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负责这种影响的细胞内信号机制。这项建议将集中在潜在的作用,第二信使,钙,在最初的“启动”。虽然钙流发生在“启动”,它是未知的,如果钙可以调节内毒素介导的信号。因此,我们假设细胞内钙的增加导致调节激酶的激活,如钙/钙调蛋白依赖性蛋白激酶(CaMK),导致内毒素介导的信号转导增强。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。将通过使用特异性抑制剂和激活剂对PAF和氧化应激诱导巨噬细胞内内毒素介导的激活的“引发”的能力来研究钙和CaMK在“引发”期间的作用。该提案的总体目标是提供对巨噬细胞激活和“启动”的潜在机制的进一步了解。通过对这些机制的深入了解,我们的目标是发现潜在的治疗靶点,以调节创伤/出血和缺血/再灌注后的炎症反应。
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)
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Joseph Cuschieri其他文献
Joseph Cuschieri的其他文献
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{{ truncateString('Joseph Cuschieri', 18)}}的其他基金
ENDOTOXIN EXPOSURE IN THE MACROPHAGE: ANALYSIS OF LIPID RAFT PROTEOMICS
巨噬细胞中的内毒素暴露:脂筏蛋白质组学分析
- 批准号:
7721400 - 财政年份:2008
- 资助金额:
$ 12.93万 - 项目类别:
TRAUMA & SEPSIS INDUCED CHANGES IN IMMUNE CELL MEMBRANE RECEPTOR TRAFFICKING
创伤
- 批准号:
7294030 - 财政年份:2007
- 资助金额:
$ 12.93万 - 项目类别:
TRAUMA & SEPSIS INDUCED CHANGES IN IMMUNE CELL MEMBRANE RECEPTOR TRAFFICKING
创伤
- 批准号:
8096537 - 财政年份:2007
- 资助金额:
$ 12.93万 - 项目类别:
TRAUMA & SEPSIS INDUCED CHANGES IN IMMUNE CELL MEMBRANE RECEPTOR TRAFFICKING
创伤
- 批准号:
7489990 - 财政年份:2007
- 资助金额:
$ 12.93万 - 项目类别:
TRAUMA & SEPSIS INDUCED CHANGES IN IMMUNE CELL MEMBRANE RECEPTOR TRAFFICKING
创伤
- 批准号:
7657322 - 财政年份:2007
- 资助金额:
$ 12.93万 - 项目类别:
TRAUMA & SEPSIS INDUCED CHANGES IN IMMUNE CELL MEMBRANE RECEPTOR TRAFFICKING
创伤
- 批准号:
7878793 - 财政年份:2007
- 资助金额:
$ 12.93万 - 项目类别:
TRAUMA-INDUCED REPROGRAMMING: CHANGES IN LIPID RAFT PROTEIN CONTENT
创伤引起的重编程:脂筏蛋白含量的变化
- 批准号:
7602876 - 财政年份:2007
- 资助金额:
$ 12.93万 - 项目类别:
TRAUMA-INDUCED REPROGRAMMING: CHANGES IN LIPID RAFT PROTEIN CONTENT
创伤引起的重编程:脂筏蛋白含量的变化
- 批准号:
7359117 - 财政年份:2006
- 资助金额:
$ 12.93万 - 项目类别:
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 - 财政年份:2003
- 资助金额:
$ 12.93万 - 项目类别:
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:
6793748 - 财政年份:2003
- 资助金额:
$ 12.93万 - 项目类别:
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