Neuroinflammation and developmental vulnerability to manganese toxicity

项目摘要 基底节区黑质-纹状体多巴胺系统对环境损伤高度敏感 神经毒素。暴露于高水平的必需元素锰(Mn)会引起神经元 这一脑区以及皮质和皮质下结构的损伤。这种神经毒性的结果 代表了一系列神经影响，从认知和行为障碍 儿童接触饮用水中的锰，高剂量锰致帕金森病(锰中毒) 成年人的职业性暴露。然而，尚不清楚生命早期接触锰的情况会如何增加。 一生中对其他神经毒性挑战的易感性。鱼藤酮等农药会影响 线粒体功能是被认为放大重金属影响的环境神经毒素之一 金属，如锰，会增加神经退行性疾病的风险。锰对神经的敏化能力 农药暴露对组织的损害可能涉及胶质细胞的持续性炎症变化。锰- 神经胶质细胞中神经炎性基因的诱导表达受转录因子的调节， 核因子-κB，促进神经元损伤。然而，信号机制 小胶质细胞和星形胶质细胞之间调节这种破坏性的胶质表型的机制尚不清楚。 这种信息的缺乏阻碍了科学和医学在理解关键信号通路方面的进展 这可能会使个人在联合暴露于 环境神经毒素，包括锰和杀虫剂。为了解决这个问题，我们假设MN 发育期暴露刺激小胶质细胞间的NF-κB依赖的炎症信号 和星形胶质细胞，导致持续的神经胶质激活，从而增强对神经毒性损伤的易感性 在衰老过程中。这一假设将在三个具体目标中进行检验，这三个目标将1)确定锰如何 幼鱼发育期间暴露促进神经胶质细胞的炎性激活并调节 鱼藤酮对衰老过程中神经元损伤的影响，2)确定关键的炎症信号通路 调节锰和鱼藤酮对神经损伤影响的小胶质细胞，以及3) 表征小胶质细胞和星形胶质细胞之间介导神经元的细胞间信号因子 接触锰和鱼藤酮时的损伤。为了实现这些具体目标，我们将使用 我们实验室在两次打击模型中产生的独特的小胶质细胞特异性NF-κB基因敲除小鼠 确定青少年接触锰是如何改变神经毒性损伤的神经毒性损伤易感性和胶质细胞激活的 暴露于环境农药鱼藤酮后的衰老，鱼藤酮是一种系统性线粒体复合体 抑制剂。我们期望这种强大的转基因模型的使用将能够确定 神经炎性基因依赖于NF-κB激活的特异性分子信号事件 神经胶质细胞对发育期锰暴露的反应，这可能增加对神经毒性的易感性 在衰老过程中的侮辱。

Project Summary The nigro-striatal dopamine system in the basal ganglia is highly sensitive to damage from environmental neurotoxins. Exposure to elevated levels of the essential element manganese (Mn) causes neuronal injury to this brain region, as well as cortical and subcortical structures. The results of this neurotoxicity represent a continuum of neurological effects ranging from cognitive and behavioral impairment in children exposed to Mn in drinking water, to Mn-induced parkinsonism (manganism) from high-dose occupational exposure in adults. However, it is not clear how early life exposures to Mn might increase susceptibility to other neurotoxic challenges throughout life. Pesticides such as rotenone that affect mitochondrial function are amongst the environmental neurotoxins thought to amplify the effects of heavy metals such as Mn to increase risk for neurodegenerative disease. The capacity of Mn to sensitize neural tissue to damage from pesticide exposure may involve persistent inflammatory changes in glial cells. Mn- induced expression of neuroinflammatory genes in glial cells is regulated by the transcription factor, Nuclear Factor Kappa B (NF-κB), which promotes neuronal injury. However, the signaling mechanisms between microglia and astrocytes that regulate this damaging glial phenotype are not well understood. Lack of this information hinders scientific and medical progress in understanding key signaling pathways that may render individuals more susceptible to neurological disease following combined exposures to environmental neurotoxins, including Mn and pesticides. To address this question, we postulate that Mn exposure during development stimulates NF-κB-dependent inflammatory signaling between microglia and astrocytes, resulting in persistent glial activation that enhances susceptibility to neurotoxic injury during aging. This hypothesis will tested in three Specific Aims that will 1) Determine how manganese exposure during juvenile development promotes inflammatory activation of glial cells and modulates the effects of rotenone on neuronal injury during aging, 2) Identify critical inflammatory signaling pathways in microglia that modulate the effects of manganese and rotenone on neurological injury, and 3) Characterize the intercellular signaling factors between microglia and astrocytes that mediate neuronal injury during exposure to manganese and rotenone. To accomplish these Specific Aims, we will use unique microglia-specific NF-κB knockout mice generated in our laboratory in a `two-hit' model to determine how juvenile exposure to Mn alters glial activation and susceptibility to neurotoxic injury during aging following exposure to the environmental pesticide, rotenone, a systemic mitochondrial complex I inhibitor. It is our expectation that use of this powerful transgenic model will enable the determination of specific molecular signaling events underlying NF-κB-dependent activation of neuroinflammatory genes in glial cells in response to developmental exposure to Mn that may increase susceptibility to neurotoxic insults during aging.