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）：过量接触锰 (Mn) 会导致基底神经节病变，并在体外通过激活的神经胶质细胞增加炎症介质（细胞因子、一氧化氮、前列腺素）的产生。在初步的体内研究中，我们发现锰暴露会增强大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) 是在转录水平，(ii) 伴随着早期生长反应因子 1 (Egr1) 表达的增加，(iii) Mn 的体外作用取决于细胞内激酶(iv) Mn 对炎症的增强与激活炎症刺激的性质无关，因为当用不同的 Toll 样受体 (TLR) 配体激活小胶质细胞时，观察到细胞因子产生增加。最后，利用生物光子成像，我们还证明苍白球内施用锰和炎症原会导致星形胶质细胞显着且持续的激活。目前，还没有体内研究描述锰和炎症原之间相互作用的性质，也没有研究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。此外，还没有研究调查小胶质细胞与星形胶质细胞在炎症背景下锰神经毒性中的作用。我们假设，暴露于锰会加剧以大脑区域特异性方式受到外周炎症原攻击的小鼠的炎症，导致基底神经节持续性神经炎症和选择性神经元损失。我们还假设星形胶质细胞和小胶质细胞都会导致神经炎症，其中小胶质细胞在此过程的早期起主导作用。该项目有以下具体目标：1) 以时间、大脑区域（纹状体、苍白球、丘脑、黑质）、浓度和暴露途径依赖的方式确定由外周锰引起的分子改变单独暴露或与炎症原激发相结合； 2) 体内确定三种主要激酶（p38、JNK 和 ERK）、Egr1 和 NADPH 氧化酶在接触 Mn 和炎症原后脑部炎症增强中所起的作用； 3) 确定小胶质细胞和星形胶质细胞活化的时间进程、程度，以及暴露于锰和炎症原引起的炎症分子的细胞特异性改变。拟议的研究将描述锰和炎症原在诱导神经变性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。公共健康相关性：本申请中提出的研究意义重大，因为它强调了评估周围炎症对锰神经毒性的影响的重要性，从而可以识别社会中哪些群体在接触锰时可能面临更大的潜在风险。即，接触锰时存在潜在炎症反应的个体或体内锰负荷增加的个体，这些个体暴露于强烈的炎症刺激下。