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: 8959623
• 负责人: RONALD TJALKENS
• 金额: $ 29.35万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-14 至 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8959623
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Address; Adolescent; Adult; Aging; Air; Animals; Astrocytes; Basal Ganglia; Basal Ganglia Diseases; Behavioral; Brain; Cell Communication; Cells; Child; Child health care; Coculture Techniques; DNA; Data; Development; Diet; Elements; Epidemiology; Event; Exposure to; Genes; Genetic; Glial Fibrillary Acidic Protein; Health; Heavy Metals; Human; Impaired cognition; Individual; Inflammation; Inflammatory; Injury; Intoxication; Knockout Mice; Laboratories; Lead; Learning; Life; Link; Manganese; Mediating; Medical; Microglia; Modeling; Molecular; Mouse Strains; Mus; NF-kappa B; NOS2A gene; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurologic Dysfunctions; Neuronal Dysfunction; Neuronal Injury; Neurons; Neurotoxins; Nuclear; Pathogenesis; Pathway interactions; Pattern; Phenotype; Phosphotransferases; Predisposition; Puberty; Public Health; Regulation; Reporter; Risk; Role; Signal Pathway; Signal Transduction; Structure; TNF gene; Testing; Toxic effect; Transgenic Model; Transgenic Organisms; Weaning; Work; basal ganglia injury; base; behavioral impairment; biological adaptation to stress; chromatin protein; chromatin remodeling; drinking water; expectation; glial activation; improved; in vitro testing; in vivo; loss of function; nervous system disorder; neurochemistry; neuroinflammation; neurotoxic; neurotoxicity; novel; response

DESCRIPTION (provided by applicant): Neurotoxic injury to the developing CNS is linked to neurological disease in humans but mechanisms that may predispose to such conditions remain very poorly understood. Exposure to elevated levels of the essential element manganese (Mn) causes a spectrum of neurochemical and neuropathologic changes that can culminate in irreversible neuronal injury in subcortical and cortical structures. Children appear to be more vulnerable to Mn than adults and recent epidemiological evidence links high Mn in drinking water to cognitive and behavioral impairment in children but the basis for the apparent greater sensitivity of young individuals is not clear. Persistent inflammatory changes in glial cells may b a potential link between exposure to Mn early in life and heightened susceptibility to neurotoxic injury and neurological dysfunction during aging because neuroinflammation is now recognized as a central feature in the progression of manganism and other neurological disorders of the basal ganglia. It is the central hypothesis of this proposal that Mn exposure during development stimulates NF-kB-dependent intercellular signaling between microglia and astrocytes, resulting in ongoing neuroinflammation that enhances susceptibility to neurological dysfunction during aging. This hypothesis will be tested by three Specific Aims that will examine: the role of glial- specific NF-kB activation in promoting Mn-induced neurotoxicity during development and aging (Specific Aim 1), critical cell-cell interactions between astrocytes and microglia necessary for amplifying inflammatory activation and neuronal injury (Specific Aim 2), and transcriptional regulatory mechanisms in astrocytes mediating NF-kB-dependent induction of neuroinflammatory genes (Specific Aim 3). We will use a two-hit model in NF-kB-EGFP reporter mice and astrocyte-specific NF-kB knockout mice generated in our laboratory that expose animals to Mn from pre-weaning through puberty and then examine their susceptibility to the dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We except to identify temporal patterns of NF-kB activation in astrocytes and microglia that correlate with onset of neuroinflammation and that astrocyte-specific loss of function of NF-kB activity will mitigate the neurotoxic effects of Mn, both in developing mice and during aging. We also expect that exposure to Mn during juvenile development will lead to greater neurological dysfunction during aging due to persistent neuroinflammation that increases neuronal dysfunction, relative to mice without prior exposure to Mn. Collectively, the proposed Specific Aims will build upon previous work from our laboratory to address key mechanistic questions regarding critical cellular interactions between astrocytes and microglia that potentiate neuronal dysfunction caused by developmental exposure to Mn.

描述（由申请人提供）：对发育中的中枢神经系统的神经毒性损伤与人类的神经系统疾病有关，但可能诱发此类疾病的机制仍然知之甚少。暴露于高水平的必需元素锰 (Mn) 会导致一系列神经化学和神经病理学变化，最终导致皮质下和皮质结构发生不可逆的神经元损伤。儿童似乎比成人更容易受到锰的影响，最近的流行病学证据表明饮用水中的高锰与儿童认知和行为障碍有关，但年轻人对锰的敏感性明显更高的基础尚不清楚。神经胶质细胞中持续的炎症变化可能是生命早期接触锰与衰老过程中对神经毒性损伤和神经功能障碍的易感性增加之间的潜在联系，因为神经炎症现在被认为是基底节锰中毒和其他神经系统疾病进展的核心特征。该提案的核心假设是发育过程中接触锰会刺激 小胶质细胞和星形胶质细胞之间依赖 NF-kB 的细胞间信号传导，导致持续的神经炎症，从而增强衰老过程中神经功能障碍的易感性。这一假设将通过三个具体目标进行检验，这些目标将检查：神经胶质细胞特异性 NF-kB 激活在促进发育和衰老过程中锰诱导的神经毒性中的作用（具体目标 1）、星形胶质细胞和小胶质细胞之间放大炎症激活和神经元损伤所必需的关键细胞间相互作用（具体目标 2）以及星形胶质细胞介导的转录调节机制。 神经炎症基因的 NF-kB 依赖性诱导（具体目标 3）。我们将在我们实验室生成的 NF-kB-EGFP 报告小鼠和星形胶质细胞特异性 NF-kB 敲除小鼠中使用两次打击模型，使动物从断奶前到青春期暴露于锰，然后检查它们对多巴胺能神经毒剂 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 的敏感性。我们除了确定星形胶质细胞和小胶质细胞中与神经炎症发作相关的 NF-kB 激活的时间模式外，星形胶质细胞特异性 NF-kB 活性功能丧失将减轻锰对发育中小鼠和衰老过程中的神经毒性作用。我们还预计，与之前未接触锰的小鼠相比，在幼年发育期间接触锰将导致衰老过程中更大的神经功能障碍，因为持续的神经炎症会增加神经元功能障碍。总的来说，拟议的具体目标将建立在我们实验室之前的工作基础上，以解决有关星形胶质细胞和小胶质细胞之间关键细胞相互作用的关键机制问题，这些相互作用会加剧因发育暴露于锰而引起的神经元功能障碍。