Mechanisms Regulating Human Neutrophil Apoptosis
调节人类中性粒细胞凋亡的机制
基本信息
- 批准号:6782489
- 负责人:
- 金额:$ 31.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-08-01 至 2006-07-31
- 项目状态:已结题
- 来源:
- 关键词:DNA damageactinomycinapoptosisbiological signal transductioncrosslinkcysteine endopeptidasesenzyme activityenzyme inhibitorsextracellular matrix proteinsgenetic regulationgenetic transcriptiongenetic translationhuman tissueimmunoprecipitationintegrinsmessenger RNAmitogen activated protein kinasemonoclonal antibodyneutrophilnuclear runoff assayoxidative stressposttranslational modificationsprotein structure functionterminal nick end labelingwestern blottings
项目摘要
Apoptosis (Ao) is thought to represent a central pathophysiologic mechanism that contributes to the orderly resolution of the human inflammatory. Over the past several years, there has been an increasing recognition that the polymorphonuclear leukocyte (PMN) plays a central role in maintaining the homeostasis between a regulated and dysregulated inflammatory response. Normal PMN function (i.e. bactericidal capability) contributes to maintaining health while upregulated PMN function (i.e. excessive proteolytic enzyme release and oxidant production) contributes to various disease states including ARDS and SIRS. Increasing evidence suggests that dysregulated PMN Ao with increase PMN half-life plays a critical role in contributing to these diverse processes. With the increasing recognition that lung injury is compartmentalized in its etiology, the role of cytokines regulating PMN Ao in the intravascular space has been previously studied. Importantly, however, two critical processes that must occut for PMN-induced tissue injury to occur, i.e. diapedesis into the interstitium with subsequent integrin stimulation via binding to matrix proteins and oxidative stress in the form of hypoxemia + reoxygenation have not been probed with regard to their effect on PMN Ao. Therefore, understanding the fundamental mechanisms that regulate those processes that control PMN Ao is crucial to advance our ability to maintain an orderly resolution of the inflammatory response. Our central hypothesis is that those processes that are essential to beginning an inflammatory response at the same time are triggers that control the Ao response. Specifically, we propose that the processes of integrin engagement via matrix protein adherence and oxidative stress represent two key pathophysiologic processes that regulate PMN Ao. Further, we propose that an understanding of the mechanisms included in this process will also provide the opportunity to modulate the PMN half-life (i.e. rate of Ao over time) and thereby manipulate the human inflammatory response.
细胞凋亡(Ao)被认为是促进人类炎症有序消退的一种中枢病理生理机制。在过去的几年里,人们越来越认识到,多形核白细胞(PMN)在维持调节和失调的炎症反应之间的动态平衡方面发挥着核心作用。正常的PMN功能(即杀菌能力)有助于维持健康,而PMN功能上调(即过度的蛋白水解酶释放和氧化剂产生)有助于各种疾病状态,包括ARDS和SIRS。越来越多的证据表明,随着PMN半衰期的增加,PMN Ao的调节失调在这些不同的过程中起着关键作用。随着越来越多的人认识到肺损伤在其病因上是分区的,细胞因子在血管内间隙调节PMN-Ao的作用已经被研究。然而,重要的是,PMN诱导的组织损伤发生必须发生的两个关键过程,即通过与基质蛋白结合而进入间质并随后的整合素刺激以及以低氧+复氧形式的氧化应激对PMN aO的影响尚未被探讨。因此,了解控制PMN Ao的基本机制对于提高我们维持炎症反应的有序消退的能力至关重要。我们的中心假设是,那些对同时开始炎症反应至关重要的过程是控制AO反应的触发因素。具体地说,我们认为,通过基质蛋白黏附和氧化应激参与整合素参与的过程是调节PMN aO的两个关键病理生理过程。此外,我们认为,对这一过程中包含的机制的理解也将提供调节PMN半衰期(即随着时间的变化而变化的AO率)的机会,从而操纵人类的炎症反应。
项目成果
期刊论文数量(2)
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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EDMUND J MILLER其他文献
EDMUND J MILLER的其他文献
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{{ truncateString('EDMUND J MILLER', 18)}}的其他基金
MIF-Thyroxine Interactions in the Pathogenesis of Pulmonary Arterial Hypertension
MIF-甲状腺素相互作用在肺动脉高压发病机制中的作用
- 批准号:
8502955 - 财政年份:2013
- 资助金额:
$ 31.59万 - 项目类别:
MIF-Thyroxine Interactions in the Pathogenesis of Pulmonary Arterial Hypertension
MIF-甲状腺素相互作用在肺动脉高压发病机制中的作用
- 批准号:
9120922 - 财政年份:2013
- 资助金额:
$ 31.59万 - 项目类别:
MIF-Thyroxine Interactions in the Pathogenesis of Pulmonary Arterial Hypertension
MIF-甲状腺素相互作用在肺动脉高压发病机制中的作用
- 批准号:
8666033 - 财政年份:2013
- 资助金额:
$ 31.59万 - 项目类别:
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