Neuroinflammation and developmental vulnerability to manganese toxicity

神经炎症和发育对锰毒性的脆弱性

• 批准号: 10152595
• 负责人: RONALD TJALKENS
• 金额: $ 32.98万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152595
• 关键词: Address; Adolescent; Adult; Affect; Aging; Astrocytes; Basal Ganglia; Behavioral; Biology; Brain; Brain Injuries; Brain region; Cells; Child; Child Health; Childhood; Complex; Data; Development; Dose; Elements; Environmental Exposure; Event; Exposure to; Gene Expression; Genes; Goals; Health; Heavy Metals; Imaging Techniques; Impaired cognition; In Vitro; Individual; Inflammasome; Inflammatory; Inflammatory Response; Injury; Knock-out; Knockout Mice; Laboratories; Life; Luciferases; Manganese; Manganism; Mediating; Medical; Microglia; Mitochondria; Modeling; Molecular; Mus; NF-kappa B; Nervous System Trauma; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurologic Dysfunctions; Neurologic Effect; Neuronal Injury; Neurons; Neurotoxins; Occupational Exposure; Pathway interactions; Pattern; Pesticides; Phenotype; Predisposition; Public Health; Regulation; Reporter; Research; Risk; Rotenone; Signal Pathway; Signal Transduction; Structure; Testing; Tissues; Toxic effect; Transgenic Mice; Transgenic Model; Transgenic Organisms; Work; behavioral impairment; chemokine; cytokine; dopamine system; drinking water; early life exposure; expectation; gene environment interaction; glial activation; inhibitor/antagonist; nervous system disorder; neuroinflammation; neurotoxic; neurotoxicity; novel; pesticide exposure; relating to nervous system; response; transcription factor

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.

项目摘要 基底神经节中的黑人纹状体多巴胺系统对环境的损害高度敏感 神经毒素。暴露于基本元素（MN）的升高水平会引起神经元 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 代表神经系统效应的连续性，从认知和行为障碍中 儿童在饮用水中暴露于MN，从高剂量 成人占据。但是，目前尚不清楚生命早期对MN的暴露如何增加 一生对其他神经毒性挑战的敏感性。诸如藤酮等农药 线粒体功能是环境神经毒素之一，以扩大重量的影响 诸如MN之类的金属增加神经退行性疾病的风险。 MN对敏感神经元的能力 从农药暴露损害的组织可能涉及神经胶质细胞的持续炎症变化。 mn- 神经胶质细胞中神经炎症基因表达的表达受转录因子的调节， 核因子Kappa B（NF-κB），促进神经元损伤。但是，信号传导机制 在调节这种破坏性神经胶质表型的小胶质细胞和星形胶质细胞之间尚不清楚。 缺乏此信息阻碍了科学和医学进展，以理解关键信号通路 这可能会使个人更容易受到神经系统疾病的影响 环境神经毒素，包括MN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-κB依赖性炎症信号传导 和星形胶质细胞，导致持续的神经胶质激活，增强了神经毒性损伤的敏感性 在衰老期间。该假设将以三个特定目的进行测试，以确定锰如何 少年发育过程中的暴露会促进神经胶质细胞的炎症激活并调节 鱼藤酮对衰老期间神经元损伤的影响，2）确定关键的炎症信号通路 调节锰和鱼藤酮对神经系统损伤的影响的小胶质细胞，3） 表征介导神经元的小胶质细胞和星形胶质细胞之间的细胞间信号传导因子 暴露于锰和烤面包酮的过程中受伤。为了实现这些特定目标，我们将使用 我们实验室中以“两击”模型生成的独特的小胶质细胞特异性NF-κB敲除小鼠 确定少年暴露于MN如何改变神经胶质激活和对神经毒性损伤的敏感性 暴露于环境农药烤面包酮的衰老，一种全身线粒体复合物I 抑制剂。我们期望使用这种强大的转基因模型可以确定 神经炎症基因的NF-κB依赖性激活的基础的特定分子信号事件 在胶质细胞中，响应于MN的发育暴露，可能会增加对神经毒性的敏感性 衰老期间的侮辱。