Neuroinflammation and developmental vulnerability to manganese toxicity

项目摘要 位于基底神经节的黑质-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）会导致神经元损伤。 该大脑区域以及皮质和皮质下结构的损伤。这种神经毒性的结果 代表了从认知和行为障碍， 饮用水中锰暴露的儿童，从高剂量锰诱发的帕金森病（锰中毒） 成人职业暴露。然而，尚不清楚早期生活中锰的暴露如何增加 对其他神经毒性挑战的易感性。农药，如鱼藤酮， 线粒体功能是环境神经毒素之一，被认为可以放大重金属的影响。 金属如锰增加神经退行性疾病的风险。锰致敏神经元的能力 暴露于杀虫剂对组织的损害可能涉及神经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调节， 核因子κ B（NF-κB），促进神经元损伤。然而，信号机制 调节这种损伤性神经胶质表型的小神经胶质细胞和星形胶质细胞之间的关系还不清楚。 缺乏这些信息阻碍了科学和医学在理解关键信号通路方面的进展 这可能会使个人更容易患上神经系统疾病后，合并暴露于 环境神经毒素，包括锰和农药。为了解决这个问题，我们假设Mn 发育过程中的暴露刺激小胶质细胞之间的NF-κ B依赖性炎症信号传导 和星形胶质细胞，导致持续的胶质细胞活化，增强对神经毒性损伤的易感性 在老化过程中。这一假设将在三个具体目标，将1）确定如何锰 在幼年发育期间的暴露促进神经胶质细胞的炎性活化，并调节神经胶质细胞的增殖。 鱼藤酮对衰老过程中神经元损伤的影响，2）识别衰老过程中关键的炎症信号通路， 调节锰和鱼藤酮对神经损伤的影响的小胶质细胞，以及3） 表征小胶质细胞和星形胶质细胞之间介导神经元信号传导的细胞间信号传导因子 在锰和鱼藤酮暴露期间的损伤。为了实现这些目标，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敲除小鼠， 确定青少年暴露于锰如何改变神经胶质细胞活化和对神经毒性损伤的易感性， 暴露于环境杀虫剂鱼藤酮（一种系统性线粒体复合物I）后的衰老 抑制剂.我们期望使用这种强大的转基因模型将能够确定 NF-κ B依赖性神经炎性基因激活的特异性分子信号事件 在神经胶质细胞中，对锰的发育暴露的反应可能增加对神经毒性的易感性， 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.