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（由申请人提供）：过度暴露于锰（MN）会导致基底神经节病理学，并通过活化的胶质神经胶质在体外激活的胶质神经胶质（细胞因子，一氧化氮，前列腺素）的产生增强。在初步的体内研究中，我们表明MN暴露增强了大脑和循环中炎症分子的产生。我们还表明，Mn（i）的这种增强是在转录水平上，（ii）伴随着早期生长响应因子1（EGR1）的表达增加，Mn的体外效应依赖于细胞内激酶和NADPH氧化酶和NADPH氧化酶，以及（IV）在MN的炎症增强的增强中，该动态的增强是IMN的增强。用不同的Toll样受体（TLR）配体激活小胶质细胞。最后，使用生物光学成像，我们还证明了全囊内给药和炎症的炎症会导致星形胶质细胞的明显和持续的星形胶质激活。目前，尚无体内研究描述Mn与炎症之间相互作用的性质，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，尚无研究研究小胶质细胞与星形胶质细胞在炎症背景下MN神经毒性中的作用。我们假设暴露于MN会以脑区域特异性方式在外围用炎症挑战的小鼠增强炎症，从而导致基底神经节中持续的神经炎症和选择性神经元丧失。我们还假设，星形胶质细胞和小胶质细胞都会有助于神经炎症，而小胶质细胞在此过程的早期起着主要作用。该项目具有以下具体目的：1）确定在时间，大脑区域（纹状体，果胶，帕利德斯，丘脑，底底尼格拉） - 浓度 - 浓度和依赖性途径 - 单独或与炎症挑战的结合中所引起的分子变化，单独或与外周血MN暴露或结合在一起； 2）在体内确定三种主要激酶（P38，JNK和ERK），EGR1和NADPH氧化酶在暴露于Mn和Inflammagen后脑部炎症增强中的作用； 3）确定时间道，小胶质细胞和星形胶质细胞激活的程度，以及由暴露于MN和炎症引起的炎症分子的细胞特异性改变。拟议的研究将描述Mn和炎症剂之间在神经变性诱导中相互作用的分子机制，以及小胶质细胞与星形胶质细胞在此过程中的作用。公共卫生相关性：本申请中提出的研究非常重要，因为它强调了评估外围炎症对MN神经毒性的贡献的重要性，从而允许识别社会领域的细分市场，而社会的细分市场可能会在暴露于MN时面临更大的潜在风险。也就是说，暴露于MN或MN体重增加的个体时具有潜在的炎症反应的个体，暴露于强烈的炎症刺激中。