Protein radicals in microglia: environmental mechanisms of chronic neurotoxicity

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PD进展有关，但驱动连续和病理激活的小胶质细胞的机制知之甚少。环境因素与PD病因学相关，并且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氧化酶和活性氧被认为是毒性小胶质细胞活化的关键因素，但它们如何调节小胶质细胞功能在很大程度上是未知的。我们的总体假设是，环境损伤导致慢性神经炎症和随之而来的进行性DA神经元损伤通过小胶质细胞蛋白质自由基生物化学的变化。因此，从NF：2 p50自由基开始，我们将检验以下特定假设：百草枯、LPS和MPTP/MPP+通过以下方式引起小胶质细胞蛋白自由基，所述小胶质细胞蛋白自由基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）介导小胶质细胞未能解决促炎反应.初步数据表明，小胶质细胞响应促炎毒素（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）通过改变其蛋白质自由基的档案和增加表达的胞质NF：SS p50自由基。因此，从NF：ss p50自由基开始，具体目的是：1）鉴定体外小胶质细胞蛋白自由基（NF：ss p50自由基）的促炎和引发特征; 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我们希望首次系统地证明NF：ss p50自由基是环境诱导的有害小胶质细胞活化的常见机制，其促进了进行性DA神经毒性。这些研究将为PD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提供新的研究途径。最后，这项工作将为能够减缓PD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以及环境诱导的氧化应激在神经退行性疾病中的作用开辟新的研究途径。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。

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.