Mediators of Oxidative Damage in Oligodendrocytes

少突胶质细胞氧化损伤的介质

基本信息

批准号：
6372562
负责人：
ANTHONY LORENTZ GARD
金额：
$ 25.29万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-30 至 2005-08-31
项目状态：
已结题

项目摘要

This project tests the central hypothesis that increased oligodendroglial oxidative stress promotes dysmyelination of the aging CNS through specific mediators of membrane lipid peroxidation (MLP) that are subject to environmental regulation. The studies will employ an in vitro approach to identify mechanisms of oxidative injury and glioprotection in the oligodendrocyte (OC)-myelin unit, modeled with myelinogenic OCs grown to maturity in isolation from other cell types. Experiments in Aim 1 will determine the identity of proteins of the myelin membrane and associated microtubule cyrtoskeleton adducted by 4- hydroxynonenal (HNE), a highly reactive cytotoxic effector of MLP- mediated injury implicated in neurodegenerative diseases of aging. They will further examine the peturbing effect of HNE on the amount and integrity of myelin-like membrane biogenesis, microtubule assembly and microtubule-dependent translocation of myelin basic protein mRNA to the myelin compartment in living cells. Experiments in Aim 2 will identify the capacity of specific environmental signals instrumental to differentiation and/or maintenance of the OC-myelin unit to regulate anti-oxidant defenses in myelinogenic OCs. They will identify specific diffusible factors and non-diffusible homotypic and heterotypic cell-cell interactions that suppress the generation of reactive oxygen species and cellular injury, using a menadione model for oxyradical production, and determine whether regulation occurs to stimulate glutathione biosynthesis and/or oxyradical-detoxifying enzyme activities. Experiments in Aim 3 will determine the capacity of estrogens and melatonin, both recognized as natural neuroprotectants with antioxidant activity, and non-pschycotropic cannabinoid to protect myelinogenic OCs against HNE and reactive oxygen species evoked by oxyradical generators and pro-oxidants of neuropathologic significance to aging (glutamate, beta-amyloid peptide. Successful completion of these aims will indicate biochemical loci where therapeutic intervention may suppress acute and chronic forms of oxidative stress in OCs and reduce morbidity consequent to dysmelination in normal and pathologic aging.

该项目检验了一个核心假设，即增加寡胶质氧化应激会通过受环境调节的特定膜脂质过氧化（MLP）的特定介体促进衰老中枢神经系统的衰老衰老。该研究将采用一种体外方法来鉴定少突胶质细胞（OC） - 肌蛋白单位中氧化损伤和神经保护的机制，该单位以与其他细胞类型分离为成熟的髓磷脂OC模型。 AIM 1中的实验将确定髓磷脂膜的蛋白质与4-羟基烯烯（HNE）合并的蛋白质和相关的微管Cyrtoskeleton（HNE），这是MLP介导的损伤的高反应性细胞毒性效应子，与神经性疾病有关。他们将进一步研究HNE对髓磷脂样膜生物发生，微管组装和微管依赖性易位髓磷脂基本蛋白mRNA对活细胞中髓磷脂室的易位。 AIM 2中的实验将确定特定环境信号的能力，可为OC-膜蛋白单元的分化和/或维护以调节骨髓蛋白OC中的抗氧化剂防御能力。他们将使用Menadione模型来抑制特定的可扩散因子以及不可扩张的同源性和异型细胞 - 细胞相互作用，这些相互作用抑制了活性氧和细胞损伤的产生，并使用Menadione模型进行了氧横向生产模型，并确定调节是否发生在刺激谷胱甘肽生物合成和/或Oxyradical Decladical-Oxyradical-detoxecify enzyzyme enzyzyme enzyzyseme enzyzyseme。 AIM 3中的实验将确定雌激素和褪黑激素的能力，均被认为是具有抗氧化剂活性的天然神经保护剂，以及非Pschycotropic Cannabinoid contranabinoid contrabinal and beta-nne sy-decokations and beta temagiantlo to to hne的骨髓毒素OC，又被神经毒性显着（GLUTAMATIC）引起的活性（GLUTAMATIDS）这些目标的成功完成将表明生化基因座，在这种情况下，治疗干预可能会抑制OC中的急性和慢性形式的氧化应激，并降低正常和病理衰老中差异的发病率。