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.

脑室周围白质软化症（PVL）是早产儿脑性瘫痪的主要病理基础。PVL中受损的主要细胞类型是少突胶质细胞（OL）。因为PVL的发病高峰期在髓鞘形成开始之前，所以PVL似乎是涉及髓鞘形成前OL（preOL）的病变，而不是成熟的、表达髓鞘碱性蛋白的OL。 我们现在知道小胶质细胞是PVL病变的重要组成部分，并且诱导型一氧化氮合酶在小胶质细胞以及反应性星形胶质细胞和OL中强烈表达。该项目的假设是，过氧亚硝酸盐，一种由一氧化氮和超氧化物反应形成的高毒性活性氮物种，在PVL中发生的preOL死亡中起重要作用。我们的初步结果表明， 激活的小胶质细胞对OL的依赖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，并发现这种物质似乎激活了在其他细胞类型中已被充分表征的前OL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OL和前OL的毒性涉及花生四烯酸代谢的激活，尽管是通过不同的途径。这些结果表明 至少在某些细胞中，过氧亚硝酸盐激活PARP途径的复杂性比已经认识到的要大。本项目的具体目的是：1）表征由小胶质细胞激活触发的OL损伤机制; 2）表征由过氧亚硝酸盐激活的前OL损伤途径; 3）测试过氧亚硝酸盐在发育中大脑白色物质缺氧/缺血损伤和炎症损伤中的作用。这些研究将有助于阐明PVL发病机制中发育白色物质损伤的分子机制，并为设计合理的PVL治疗方案提供基础。 治疗这种疾病。