Neuroinflammation and developmental vulnerability to manganese toxicity

神经炎症和发育对锰毒性的脆弱性

基本信息

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
项目类别：
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

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

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项目摘要

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）：对发展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，但可能易感此类疾病的机制仍然非常了解。暴露于基本元素（MN）的水平升高会导致神经化学和神经病理学的变化，这些变化可能导致皮层和皮质结构中不可逆的神经元损伤。儿童似乎比成年人更容易受到MN的影响，最近的流行病学证据将饮用水中的高水位与儿童的认知和行为障碍联系起来，但是年轻人显然更敏感的基础尚不清楚。神经胶质细胞的持续炎症变化可能会在衰老期间对MN的暴露与神经毒性损伤的易感性增强与神经功能障碍的敏感性之间存在潜在的联系，因为现在神经炎症现在被认为是锰制主义和其他神经神经神经神经神经神经神经神经病的疾病的核心特征。该提案的中心假设是，发育过程中的MN暴露会刺激 NF-KB依赖性小胶质细胞和星形胶质细胞之间的细胞间信号传导导致持续的神经炎症，从而增强了衰老期间神经功能障碍的敏感性。该假设将通过三个要研究的特定目的来检验：神经胶质特异性NF-KB激活在发育和衰老过程中促进MN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的关键细胞相互作用，在炎症激活和神经元损伤方面所必需的小胶质细胞和微胶质细胞之间所必需的小胶质细胞相互作用（特定的促进性2），以及特定的神经元损伤2），以及saver性的指数。 NF-KB依赖性神经炎症基因的诱导（特定目标3）。我们将在我们的实验室中产生的NF-KB-EGFP报告基因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，该小鼠将动物暴露于MN，从青春期中进行预断压，然后检查它们对多巴胺疗法的神经毒性毒性，1-甲基-4-磷酸1-菲尼斯特-1-----------1-2,2,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3yyyy。除了确定与神经炎症发作相关的星形胶质细胞和小胶质细胞中NF-KB激活的时间模式外，以及NF-KB活性的星形胶质细胞特异性功能的功能丧失将减轻MIC中MIC的神经毒性作用，既可以减轻发育中的小鼠和衰老过程中的神经毒性效应。我们还期望在少年发育过程中暴露于MN，由于持续的神经炎症会增加神经元功能障碍，因此在衰老期间会导致更大的神经功能障碍，相对于小鼠而没有事先暴露于MN。总的来说，提出的特定目标将基于我们实验室的先前工作，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理问题，这些问题会增强因MN的发育暴露而导致的神经元功能障碍。