Protein radicals in microglia: environmental mechanisms of chronic neurotoxicity

小胶质细胞中的蛋白自由基：慢性神经毒性的环境机制

• 批准号: 8516506
• 负责人: Michelle L Block
• 金额: $ 29.61万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516506
• 关键词: 1-Methyl-4-phenylpyridinium; Abate; Affect; Aftercare; American; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antioxidants; Automobile Driving; Benign; Biochemistry; Biological Assay; Brain; Brain region; Cause of Death; Cell Count; Cells; Cessation of life; Characteristics; Chronic; Combined Modality Therapy; Conditioned Culture Media; Confocal Microscopy; Cytosol; Data; Development; Disease Progression; Elderly; Elements; Environmental Risk Factor; Etiology; Failure; Human; Hydrogen Peroxide; Immune; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Life; Lipopolysaccharides; Measures; Mediating; Membrane; Microglia; Modeling; Molecular; Morphology; Mus; NADPH Oxidase; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Injury; Neurons; Neurotoxins; Nuclear Protein; Oxidative Stress; Paraquat; Parkinson Disease; Pathogenesis; Patients; Phenotype; Production; Proteins; Reactive Oxygen Species; Recombinants; Research; Role; Sampling; Signal Transduction; Spin Trapping; Stimulus; Substantia nigra structure; TNFRSF5 gene; Techniques; Testing; Therapeutic Intervention; Time; Toxic Environmental Substances; Toxin; Western Blotting; Work; brain cell; cellular imaging; cytokine; dopaminergic neuron; in vivo; inhibitor/antagonist; insight; neuroinflammation; neuron loss; neurotoxic; neurotoxicity; new therapeutic target; novel; public health relevance; research study; response; tempol; therapeutic target; tool; toxicant; uptake

DESCRIPTION (provided by applicant): The etiology of Parkinson's disease (PD) is currently unknown and treatment is unable to halt disease progression. Microglias, the innate immune cells of the brain, are implicated in PD progression, but the mechanisms driving continuous and pathologically activated microglia are poorly understood. Environmental factors are associated with PD etiology and can chronically activate microglia to cause dopaminergic (DA) neuron damage. Microglial NADPH oxidase and reactive oxygen species have been strongly been implicated as key elements of toxic microglial activation, but how they regulate microglial function is largely unknown. Our overarching hypothesis is that environmental insult causes chronic neuroinflammation and consequent progressive DA neuron damage through changes in microglial protein radical biochemistry. Thus, beginning with the NF:2 p50 radical, we will test the specific hypothesis that paraquat, LPS, and MPTP/MPP+ cause microglial protein radicals that drive progressive neuroinflammation and DA neurotoxicity by: A) enhancing the production of neurotoxic pro- inflammatory factors (microglial priming); B) mediating the failure of microglia to resolve the pro- inflammatory response. Preliminary data indicate that microglia respond to pro-inflammatory toxins (LPS), direct neurotoxicants (MPTP/MPP+, reactive microgliosis), and dual-mode toxicants (paraquat) by changing their protein radical profile and increasing expression of the cytosolic NF:ss p50 radical. Thus, beginning with the NF:ss p50 radical, the specific aims are to: 1) identify the pro-inflammatory and priming characteristics of microglial protein radicals in vitro (NF:ss p50 radical); 2) characterize the role of the NF:ss p50 radical in progressive DA neuron damage in vivo; 3) determine the neuroprotective and anti-inflammatory effect of inhibiting NF:ss p50 radical formation. 1We expect to systematically demonstrate for the first time that the NF:ss p50 radical is a common mechanism of environmentally- induced deleterious microglial activation that fuels progressive DA neurotoxicity. These studies will define a new avenue of research in PD pathogenesis, ROS-signaling, and the role of environmentally-induced oxidative stress in neurodegenerative disease. Finally, this work will provide valuable insight into the identification and timing of novel therapeutic targets capable of slowing PD progression. PUBLIC HEALTH RELEVANCE These studies will define a new avenue of research in Parkinson's disease pathogenesis and the role of environmentally-induced oxidative stress in neurodegenerative disease. Finally, this work will provide valuable insight into the identification and timing of novel therapeutic targets capable of slowing Parkinson's disease progression.

描述（由申请人提供）：帕金森病（PD）的病因目前尚不清楚，治疗无法阻止疾病进展。小胶质细胞是大脑的先天免疫细胞，与帕金森病的进展有关，但驱动小胶质细胞持续和病理性激活的机制尚不清楚。环境因素与帕金森病的病因有关，可以长期激活小胶质细胞，导致多巴胺能 (DA) 神经元损伤。小胶质细胞 NADPH 氧化酶和活性氧已被强烈认为是有毒小胶质细胞激活的关键元素，但它们如何调节小胶质细胞功能在很大程度上尚不清楚。我们的首要假设是，环境损害通过小胶质细胞蛋白自由基生物化学的变化导致慢性神经炎症，进而导致进行性 DA 神经元损伤。因此，从 NF:2 p50 自由基开始，我们将检验以下具体假设：百草枯、LPS 和 MPTP/MPP+ 会通过以下方式引起小胶质细胞蛋白自由基，从而驱动进行性神经炎症和 DA 神经毒性：A) 增强神经毒性促炎因子的产生（小胶质细胞引发）； B) 介导小胶质细胞无法解决促炎症反应。初步数据表明，小胶质细胞通过改变其蛋白自由基谱和增加胞质 NF:ss p50 的表达来响应促炎毒素 (LPS)、直接神经毒物（MPTP/MPP+、反应性小胶质细胞增生）和双模式毒物（百草枯）激进的。因此，从NF：ss p50自由基开始，具体目标是：1）体外鉴定小胶质细胞蛋白自由基（NF：ss p50自由基）的促炎和启动特征； 2) 表征 NF:ss p50 自由基在体内进行性 DA 神经元损伤中的作用； 3)确定抑制NF:ss p50自由基形成的神经保护和抗炎作用。 1我们期望首次系统地证明 NF:ss p50 自由基是环境诱导的有害小胶质细胞激活的常见机制，可加剧进行性 DA 神经毒性。这些研究将为帕金森病发病机制、ROS 信号传导以及环境诱导的氧化应激在神经退行性疾病中的作用确定一条新的研究途径。最后，这项工作将为能够减缓帕金森病进展的新型治疗靶点的识别和时机提供有价值的见解。 公共卫生相关性 这些研究将为帕金森病发病机制和环境诱导的氧化应激在神经退行性疾病中的作用确定一条新的研究途径。最后，这项工作将为能够减缓帕金森病进展的新治疗靶点的识别和时机提供有价值的见解。