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: 8114977
• 负责人: Michelle L Block
• 金额: $ 37.51万
• 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/8114977
• 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; 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）：帕金森氏病（PD）的病因目前尚不清楚，治疗无法停止疾病的进展。小胶质细胞是大脑的先天免疫细胞，与PD进展有关，但是驱动连续和病理活化的小胶质细胞的机制知之甚少。环境因素与PD病因有关，并且可以长期激活小胶质细胞引起多巴胺能（DA）神经元损伤。小胶质细胞氧化酶和活性氧被强烈暗示是有毒小胶质细胞激活的关键要素，但是它们如何调节小胶质细胞功能在很大程度上尚不清楚。我们的总体假设是，环境侮辱会导致慢性神经炎症，从而通过小胶质细胞蛋白质自由基生物化学的变化而导致进行性DA神经元损害。因此，从NF：2 P50自由基开始，我们将测试以下特定假设：Paraquat，LPS和MPTP/MPP+引起的小胶质细胞蛋白质自由基，这些蛋白质驱动了进行性渐进性神经性神经炎和DA神经毒性，并通过：a）增强神经毒性的炎性促炎性因素（微层型启动）； b）介导小胶质细胞无法解决炎症反应的失败。初步数据表明，小胶质细胞对促炎毒素（LPS），直接神经毒性剂（MPTP/MPP+，反应性小胶质细胞增多）和双模式毒性（Paraquat）反应，通过改变其蛋白质自由基的特征和增加胞质NF：SS p50自由基的表达来反应。因此，从NF：SS P50自由基开始，具体目的是：1）在体外确定小胶质细胞蛋白自由基的促炎和启动特征（NF：SS P50自由基）； 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的神经保护作用和抗炎作用：SS P50自由基形成。 1我们期望有系统地证明NF：SS P50自由基是环境引起的有害小胶质细胞激活的一种常见机制，从而助长了渐进性DA神经毒性。这些研究将定义PD发病机理，ROS信号和环境诱导的氧化应激在神经退行性疾病中的作用的新途径。最后，这项工作将为能够减慢PD进展的新型治疗靶标的识别和时机提供宝贵的见解。 公共卫生相关性 这些研究将定义帕金森氏病发病机理研究的新途径以及环境诱导的氧化应激在神经退行性疾病中的作用。最后，这项工作将为能够放缓帕金森氏病进展的新型治疗靶标的识别和时机提供宝贵的见解。