ASTROCYTE MITOCHONDRIA AND NEUROTOXICITY

描述：（改编自研究者摘要） 在区域和细胞对神经毒性化学物质的反应中， 然而，人们认识到，选择性脆弱性的细胞基础是 不太了解。某些细胞核在胚胎发育较早的区域 大脑的大脑对一些化学上无关的 神经毒剂这些化学物质中的许多干扰线粒体 谷胱甘肽（GSH）稳态和能量代谢。据推测 星形胶质细胞线粒体谷胱甘肽的区域差异 体内平衡使脑干中的特定星形胶质细胞群 易受化学诱导的能量剥夺综合症的影响化学品 被广泛认为是影响能量代谢的， 并不是对所有线粒体都有同样的影响。神经毒素，如1，3- 二硝基苯（DNB）产生的损害类似于在 “急性能量缺乏综合征”（AEDS）或特发性线粒体 疾病也影响谷胱甘肽的状态。虽然相当重视 在这些综合征中，区域性， 细胞和亚细胞谷胱甘肽的稳态在很大程度上 忽视谷胱甘肽与 能量代谢是复杂的，需要进一步研究， 选择性神经毒素的脆弱性。核心假设 将通过解决以下具体问题来检验这一建议的有效性 问题： 1)区域、细胞和亚细胞的差异是什么 谷胱甘肽状态和体内平衡 2)细胞抗氧化状态的调节是否改变了局部 线粒体对神经毒素诱导的氧化应激的敏感性？ 3)星形胶质细胞线粒体是否选择性代谢DNB， 他们自己容易通过开放谷胱甘肽耗尽 线粒体通透性转换孔（MPT）？ 产生不同星形胶质细胞病变的体外和体内模型 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压力 神经毒性化学物质的影响这项工作将导致 更好地了解选择性脆弱性及其在 神经毒性综合征

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.