Role of inflammation in manganese neurotoxicity: molecular mechanisms

炎症在锰神经毒性中的作用：分子机制

• 批准号: 7735836
• 负责人: NIKOLAY M FILIPOV
• 金额: $ 35.88万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-05 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7735836
• 关键词: Address; Applications Grants; Area; Astrocytes; Basal Ganglia; Basal Ganglia Diseases; Biophotonics; Blood Circulation; Body Burden; Brain; Brain region; Cells; Characteristics; Chemosensitization; Corpus striatum structure; Custom; Data; Disease; Encephalitis; Etiology; Exposure to; Funding; Gene Expression; Genetic Transcription; Globus Pallidus; Goals; Growth; Image; In Vitro; Individual; Industrial fungicide; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Investigation; Ligands; Lipopolysaccharides; MAPK14 gene; MAPK8 gene; Maneb; Manganese; Metals; Microglia; Modeling; Molecular; Mus; NADPH Oxidase; Nature; Nerve Degeneration; Neuroglia; Neurons; Nitric Oxide; Outcome; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathology; Patients; Peripheral; Phosphotransferases; Play; Poly I-C; Process; Production; Prostaglandins; Reporting; Research; Risk; Role; Route; Societies; Solid; Source; Specificity; Stimulus; Substantia nigra structure; Testing; Text; Thalamic structure; Time; Toll-like receptors; Training; Transgenic Mice; Tweens; Work; base; cell type; chemokine; cytokine; design; experience; gene function; high risk; in vivo; innovation; man; mouse model; neonate; neuroimmunology; neuroinflammation; neuron loss; neuropathology; neurotoxic; neurotoxicity; neurotoxicology; novel; novel strategies; prevent; public health relevance; response; toxicant; transcription factor

DESCRIPTION (provided by applicant): Excessive exposure to manganese (Mn) results in basal ganglia pathology and enhanced production of inflammatory mediators (cytokines, nitric oxide, prostaglandins) by activated glia in vitro. In preliminary in vivo studies we have shown that Mn exposure potentiates production of inflammatory molecules in brain and in circulation. We have also shown that this potentiation by Mn (i) is at the level of transcription, (ii) is accompanied by increased expression of early growth response factor 1 (Egr1), (iii) in vitro effects of Mn are dependent upon intracellular kinases and NADPH oxidase, and (iv) the enhancement of inflammation by Mn is independent of the nature of the activating inflammatory stimulus as increased cytokine production was observed when microglial cells were activated with different toll-like receptor (TLR) ligands. Finally, using biophotonic imaging, we also demonstrated that intrapallidal administration of Mn and an inflammagen leads to marked and sustained astrocyte activation. At present, there are no in vivo studies describing the nature of the interaction between Mn and an inflammagen nor are there studies describing the regional specificity and extent of the neuropathology associated with such an interaction. Moreover, there are no studies investigating the role of microglia vs. astrocytes in Mn neurotoxicity within the context on inflammation. We hypothesize that exposure to Mn will potentiate inflammation in mice challenged peripherally with an inflammagen in a brain region-specific manner, resulting in persistent neuroinflammation and selective neuronal loss in the basal ganglia. We also hypothesize that both astrocytes and microglia will contribute to the neuroinflammation, with microglia playing a dominant role earlier in the process. The project has the following Specific Aims: 1) determine, in a time-, brain region (striatum, globus pallidus, thalamus, substantia nigra)-, concentration-, and route of exposure- dependent fashion, the molecular alterations caused by peripheral Mn exposure alone or in combination with an inflammagen challenge; 2) determine in vivo the role that the three major kinases (p38, JNK, and ERK), Egr1, and NADPH oxidase play in the potentiation of brain inflammation following exposure to Mn and an in- flammagen; 3) determine the time-course, the degree of microglia and astrocyte activation, as well as cell- specific alterations in inflammatory molecules caused by exposure to Mn and an inflammagen. The proposed investigations will delineate the molecular mechanisms of the interaction between Mn and inflammagens in the induction of neurodegeneration and the role of microglia vs. astrocytes in the process. PUBLIC HEALTH RELEVANCE: The research proposed in this application is significant because it underscores the importance of assessing the contribution of peripheral inflammation to the neurotoxicity of Mn, thus allowing the identification of segments of the society who may at a greater potential risk when exposed to Mn. Namely, individuals with underlying inflammatory response at the time of exposure to Mn or individuals with increased body burdens of Mn, who are exposed to strong inflammatory stimuli.

描述（由申请方提供）：过量暴露于锰（Mn）导致基底神经节病理学和体外活化胶质细胞产生的炎症介质（细胞因子、一氧化氮、肾上腺素）增加。在初步的体内研究中，我们已经表明，锰暴露增强脑和循环中炎症分子的产生。我们还表明Mn的这种增强作用（i）在转录水平，（ii）伴随着早期生长反应因子1（Egr 1）表达的增加，（iii）Mn的体外作用依赖于细胞内激酶和NADPH氧化酶，和（四）Mn对炎症的增强作用与激活性炎症刺激物的性质无关，因为观察到细胞因子产生增加当小胶质细胞用不同的Toll样受体（TLR）配体激活时。最后，使用生物光子成像，我们还表明，苍白球内管理锰和inflammagen导致显着和持续的星形胶质细胞激活。目前，没有描述Mn和炎性因子之间相互作用的性质的体内研究，也没有描述与这种相互作用相关的神经病理学的区域特异性和程度的研究。此外，在炎症背景下，没有研究小胶质细胞与星形胶质细胞在Mn神经毒性中的作用。我们假设，暴露于锰将加强炎症在小鼠的周围挑战与inflammagen在大脑区域特异性的方式，导致持续的神经炎症和选择性神经元的损失在基底神经节。我们还假设星形胶质细胞和小胶质细胞都将有助于神经炎症，小胶质细胞在该过程的早期起主导作用。该项目有以下具体目标：1）确定，在一个时间，大脑区域（纹状体、苍白球、丘脑、黑质）-、浓度-和暴露途径依赖性方式，由单独的外周Mn暴露或与炎性因子激发组合引起的分子改变; 2）确定体内三种主要激酶的作用（p38、JNK和ERK）、Egr 1和NADPH氧化酶在暴露于Mn和in-flammagen后的脑炎症增强中起作用; 3）确定小胶质细胞和星形胶质细胞活化的时程、程度以及由暴露于Mn和炎性原引起的炎性分子的细胞特异性改变。拟议的调查将描绘Mn和inflamagens之间的相互作用的分子机制，在诱导神经变性和小胶质细胞与星形胶质细胞在这个过程中的作用。公共卫生关系：本申请中提出的研究是重要的，因为它强调了评估外周炎症对Mn神经毒性的贡献的重要性，从而允许识别当暴露于Mn时可能具有更大潜在风险的社会阶层。即，在暴露于Mn时具有潜在炎症反应的个体或暴露于强炎症刺激的Mn的身体负荷增加的个体。