Free radical injury to developing oligodendrocytes

描述：脑室周围白质软化症(PVL)是脑室周围白质软化的主要病理基础。 早产儿脑性瘫痪的潜在损害和一种关键细胞类型 损伤的是少突胶质细胞。出于这个原因，它是重要的 为了了解少突胶质细胞中存在的死亡机制，可能是 在PVL中激活。调查人员和其他人已经开发出方法来 基于免疫泛素的相对纯培养的少突胶质细胞的生长 无血清限定培养液。通过使用这些文化，他们发现 前少突胶质细胞和未成熟少突胶质细胞比 成熟少突胶质细胞耗竭引起的氧化应激反应 细胞内的谷胱甘肽。这种损伤被自由基清除剂阻断。 并伴随着细胞内氧自由基的积聚。近期 研究表明，12-脂氧合酶在该通路中起着关键作用 从细胞内谷胱甘肽的耗尽到细胞死亡。此外, 本项目和项目2的初步研究，以及 其他研究人员认为，抗氧化酶的表达可能是 在成熟的少突胶质细胞中上调。总体假设是， 是前少突胶质细胞和未成熟少突胶质细胞的特性 有助于提高他们对氧化侮辱的敏感度；这些 包括抗氧化酶表达不足和酶活性增加 12-脂氧合酶。我们的长期目标是理解 谷胱甘肽耗竭和氧化应激导致死亡的事件 前少突胶质细胞和未成熟少突胶质细胞，以及 少突胶质细胞对这种形式的损伤的抵抗力。特定目标 1.测定少突胶质细胞在特定阶段的敏感性 发展为各种来源的氧化应激。具体目标2： 确定氧化应激易感性的下降是否与 少突胶质细胞谱系的发育进展是由于上调 一种或多种抗氧化酶的。具体目标3：确定是否 氧化应激诱导需要激活12-脂氧合酶活性 少突胶质细胞毒性。通过这项工作，调查人员将获得 关于发展如何改变脆弱性的基本信息 少突胶质细胞对氧化应激的反应。

DESCRIPTION: Periventricular leukomalacia (PVL) is the principal pathological lesion underlying cerebral palsy in premature infants, and a key cell-type injured in this lesion is the oligodendrocyte. For this reason, it is important to understand the mechanisms of death present in oligodendrocytes that might be activated in PVL. The investigators and others have developed methods for growing oligodendrocytes in relatively pure culture based on immunopanning and serum-free defined medium. Using these cultures they have found that preoligodendrocytes and immature oligodendrocytes are more vulnerable than mature oligodendrocytes to oxidative stress caused by depletion of intracellular glutathione. This injury is blocked by free radical scavengers and is accompanied by intracellular oxygen free radical accumulation. Recent work suggests a critical involvement of 12-lipoxygenase in the pathway leading from depletion of intracellular glutathione to cell death. In addition, preliminary studies for this project and Project 2, in addition to studies by other investigators, suggest that the expression of antioxidant enzymes may be upregulated in mature oligodendrocytes. The overall hypothesis is that there are specific properties of preoligodendrocytes and immature oligodendrocytes that contribute to their enhanced sensitivity to oxidative insults; these include an underexpression of antioxidant enzymes and increased activity of 12-lipoxygenase. The long-term objective is to understand the sequence of events that lead from glutathione depletion and oxidative stress to the death of preoligodendrocytes and immature oligodendrocytes, as well as the basis for the resistance of mature oligodendrocytes to this form of injury. Specific Aim 1: To determine the sensitivity of oligodendrocytes at specific stages of development to a variety of sources of oxidative stress. Specific Aim 2: To determine whether the decline in vulnerability to oxidative stress with developmental progression in the oligodendrocyte lineage is due to upregulation of one or more antioxidant enzymes. Specific Aim 3: To determine whether activation of 12-lipoxygenase activity is required for oxidative stress-induced oligodendrocyte toxicity. Through this work the investigators will gain fundamental information about how development alters the vulnerability of oligodendrocytes to oxidative stress.