Mechanisms of Free Radical Mediated Injury

自由基介导的损伤机制

• 批准号: 7006502
• 负责人: PAUL ALLEN ROSENBERG
• 金额: $ 31.38万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006502
• 关键词: brain injury; disease /disorder etiology; disease /disorder prevention /control; genetically modified animals; inflammation; laboratory mouse; microglia; mixed tissue /cell culture; molecular pathology; neuropathology; nitric oxide synthase; oligodendroglia; oxidative stress; peroxynitrites; white matter

Periventricular leukomalacia (PVL) is the predominant pathology underlying cerebral palsy in premature infants. The primary cell type that is injured in PVL is the oligodendrocyte (OL). Because the period of peak incidence for PVL is prior to the onset of myelination, PVL appears to be a lesion involving premyelinating OLs (preOLs), as opposed to mature, myelin basic protein expressing, OLs. We now know that microglia are an important constituent of the PVL lesion, and that inducible nitric oxide synthase is strongly expressed in microglia as well as in reactive astrocytes and OLs. The hypothesis of this project is that peroxynitrite, a highly toxic reactive nitrogen species formed by reaction of nitric oxide and superoxide, plays an important role in the death of preOLs that occurs in PVL. Our preliminary results suggest that the toxicity of activated microglia to OLs is dependent upon the formation of peroxynitrite. Moreover, we have begun to characterize the mechanisms by which peroxynitrite is toxic to cells, and have found that this substance appears to activate the poly(ADP-ribose) polymerase (PARP) suicide pathway in preOLs that has been well-characterized in other cell types. Interestingly, we have also obtained evidence that peroxynitrite toxicity to mature OLs and preOLs involves activation of arachidonic acid metabolism, although by distinct pathways. These results suggest a greater complexity to the activation of the PARP pathway by peroxynitrite, at least in some cells, than has been appreciated. The specific aims of this project are to: 1) characterize the mechanisms of injury to OLs triggered by activation of microglia; 2) characterize the pathway(s) of injury to preOLs activated by peroxynitrite; 3) test for a role for peroxynitrite in hypoxic/ischemic injury and inflammatory injury to white matter of the developing brain. These studies will help to elucidate the molecular mechanisms of injury to developing white matter pertinent to the pathogenesis of PVL, and provide a foundation for the design of rational treatments for this disorder.

脑室白细胞（PVL）是早产儿中脑瘫的主要病理。在PVL中受伤的主要细胞类型是少突胶质细胞（OL）。由于PVL的峰值发病率是髓鞘化发作之前的，因此PVL似乎是涉及前髓的OLS（preols）的病变，而不是成熟的髓磷脂碱性蛋白表达OLS。 我们现在知道，小胶质细胞是PVL病变的重要组成部分，并且可诱导的一氧化氮合酶在小胶质细胞以及反应性星形胶质细胞和OLS中强烈表达。该项目的假设是，过氧亚硝酸盐是一种由一氧化氮和超氧化物反应形成的剧毒的反应性氮种，在PVL中发生的普雷紫酚的死亡中起着重要作用。我们的初步结果表明 活化的小胶质细胞对OLS取决于过氧亚硝酸盐的形成。此外，我们已经开始表征过氧亚硝酸盐对细胞有毒的机制，并发现该物质似乎激活了在其他细胞类型中良好特征的Preols中的聚（ADP-核糖）聚合酶（PARP）自杀途径。有趣的是，我们还获得了证据表明，过氧亚硝酸盐对成熟OLS的毒性和Preols涉及蛛网膜烯酸代谢的激活，尽管通过不同的途径。这些结果表明 至少在某些细胞中，过氧亚硝酸盐激活PARP途径的复杂性比已被欣赏的更复杂。该项目的具体目的是：1）表征由小胶质细胞激活引发的OLS损伤机制； 2）表征过氧亚硝酸盐激活的pre醇的损伤途径； 3）测试过氧亚硝酸盐在缺氧/缺血性损伤和发育不良大脑的炎症性损伤中的作用。这些研究将有助于阐明与PVL发病机理相关的损伤的分子机制，并为理性设计提供了基础 治疗这种疾病。