ASTROCYTE MITOCHONDRIA AND NEUROTOXICITY

描述：(改编自《调查者摘要》)异质性 对神经毒性化学物质的区域和细胞反应 然而，人们认识到，选择性脆弱性的细胞基础是 人们对此知之甚少。在系统发育较老的区域中的某些核 对几种化学上无关的物质都非常敏感 神经毒药。其中许多化学物质扰乱了线粒体 谷胱甘肽(GSH)的稳态和能量代谢。这是假设的 星形细胞线粒体(MT)谷胱甘肽的区域差异 动态平衡导致脑干中特定数量的星形胶质细胞 易受化学诱导的能量缺乏综合症的影响。化学品 人们普遍认为它们对能量新陈代谢起作用，然而， 并不是对所有线粒体都有同样的影响。神经毒物，如1，3- 二硝基苯(DNB)产生的损害与在 “急性能量剥夺综合征”(AEDs)或特发性线粒体 疾病也会影响谷胱甘肽的状态。虽然相当强调的是 在这些综合征中被置于能量代谢的改变，地区性， 细胞和亚细胞的谷胱甘肽稳态在很大程度上 已被忽略。谷胱甘肽和谷胱甘肽的相互关系及相互依赖 能量代谢是复杂的，需要进一步研究 尊重选择性神经毒剂的脆弱性。中心假说 将通过解决以下具体问题来测试该提案 问题： 1)在区域、细胞和亚细胞方面有什么区别 谷胱甘肽状态和动态平衡？ 2)细胞抗氧化状态的调节是否会改变区域 线粒体对神经毒物诱导的氧化应激的易感性？ 3)星形胶质细胞线粒体是否选择性地代谢DNB并呈现 自身容易受到谷胱甘肽耗尽的影响 线粒体通透性转换孔？ 产生不同星形细胞损伤的体外和体内模型 将有助于确定mtGSH在AEDs病因学中的作用。 拟议的研究将提供有关氧化机制的信息。 导致特定脑细胞群丧失的应激 在暴露于神经毒性化学物质之后。这项工作将导致 更好地了解选择性脆弱性及其在 神经毒性综合症。

DESCRIPTION: (Adapted from the Investigator's Abstract) Heterogeneity in regional and cellular responses to neurotoxic chemicals has long been recognized, however, the cellular basis for selective vulnerability is poorly understood. Certain nuclei in the phylogenetically older regions of the brain are exquisitely sensitive to several chemically unrelated neurotoxicants. Many of these chemicals perturb mitochondrial glutathione (GSH) homeostasis and energy metabolism. It is hypothesized that regional differences in astrocytic mitochondrial (mt) glutathione homeostasis render specific populations of astrocytes in the brainstem vulnerable to chemically induced energy deprivation syndromes. Chemicals that are widely believed to act on energy metabolism, nevertheless, do not affect all mitochondria equally. Neurotoxicants such as 1,3- dinitrobenzene (DNB) which produce damage similar to those observed in "Acute Energy Deprivation Syndromes" (AEDS) or idiopathic mitochondrial diseases also affect glutathione status. While considerable emphasis has been placed on altered energy metabolism in these syndromes, regional, cellular and subcellular glutathione homeostasis have been largely ignored. The relationships and interdependencies between glutathione and energy metabolism are complex and require further investigation with respect to selective neurotoxicant vulnerability. The central hypothesis of this proposal will be tested by addressing the following specific questions: 1) What are the differences in regional, cellular and subcellular glutathione status and homeostasis? 2) Does modulation of cellular antioxidant status alter regional mitochondrial susceptibility to neurotoxicant-induced oxidative stress? 3) Do astrocytic mitochondria selectively metabolize DNB and render themselves vulnerable to glutathione depletion via opening of the mitochondrial permeability transition (MPT) pore? In vitro and in vivo models that produce distinct astrocytic lesions will aid in determination of the role of mtGSH in the etiology of AEDS. The proposed studies will provide information on mechanisms of oxidative stress which contribute to the loss of specific brain cell populations following exposure to neurotoxic chemicals. This work will lead to better understanding of selective vulnerability and its role in neurotoxic syndromes.