Microglial Hv1 Proton Channel as a Mediator of Environmentally-Induced Neuroinflammation and Neurodegeneration

小胶质细胞 Hv1 质子通道作为环境诱发的神经炎症和神经变性的介质

• 批准号: 10584577
• 负责人: Jason R Richardson
• 金额: $ 59.31万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-04 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10584577
• 关键词: Animal Disease Models; Anti-Inflammatory Agents; Autopsy; Behavioral; Brain; Cells; Clinical Trials; Coupled; Data; Electrophysiology (science); Environment; Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Goals; Herbicides; Histone Acetylation; Human; Immune; In Vitro; Infection; Inflammasome; Inflammatory; Inflammatory Response; Knock-out; Knockout Mice; Link; Measures; Mediating; Mediator; Microglia; NADPH Oxidase; Nerve Degeneration; Neurodegenerative Disorders; Paraquat; Parkinson Disease; Pathway interactions; Patients; Pharmaceutical Preparations; Production; Protons; Reactive Oxygen Species; Regulation; Research; Risk; Role; Sampling; Signal Pathway; Signal Transduction; Techniques; Testing; Therapeutic; brain cell; chromatin immunoprecipitation; conditional knockout; dopaminergic neuron; driving force; experimental study; first responder; genetic approach; genetic inhibitor; in vivo; inhibitor; neuroinflammation; neuroprotection; neurotoxicity; novel; patch clamp; pharmacologic; protein aggregation; response; toxicant; transcription factor; voltage

Abstract Neuroinflammation is a driving force contributing to neurodegenerative diseases, including Parkinson's disease (PD). Microglia are the primary immune cell of the brain and are among the first responders to infection, toxic insult and aggregated proteins and contribute significantly to neuroinflammation and neurodegeneration. The microglial inflammatory response, including inflammasome activation, has been demonstrated to be significantly associated with PD. Paraquat (PQ) is a commonly used herbicide that has been linked to increased risk for PD. PQ-induced neurodegeneration is tightly coupled to the activation of microglia and appears to require priming of the microglial response. Therefore, factors that modulate the microglial inflammatory response could lead to neuroprotection and slow the progression of neurodegenerative diseases. However, to date, no anti- inflammatory drugs have proven successful in human clinical trials necessitating research on new targets. Hv1 (HVCN1) is a voltage-gated proton channel highly expressed on microglia in the brain and in other immune cells in the body. This proton channel regulates the activity of NADPH oxidase and production of reactive oxygen species in immune cells and especially microglia. Our preliminary data demonstrate that PQ directly increases Hv1 levels in microglia, possibly through an epigenetic mechanism involving histone acetylation. Further, our data demonstrate effects of PQ on the NLRP3 inflammasome that appear to be regulated by Hv1, providing a potential mechanism contributing to PQ-induced microglial priming. This proposal seeks to test the hypothesis that Hv1 regulates priming of microglia following PQ exposure through the NLRP3 inflammasome, leading to neuroinflammation and neurodegeneration. The Specific Aims of this project are to 1) Determine mechanisms of Hv1 regulation following paraquat exposure 2) Define the role of Hv1 in regulation of the NLRP3 inflammasome following paraquat exposure and 3) Determine the contribution of microglial Hv1 and the NLRP3 inflammasome in regulating neurodegeneration following paraquat exposure. Completion of these Aims will define regulatory mechanisms for Hv1 and determine the role of Hv1 in regulation of the NLRP3 inflammasome activation and their role in PQ-induced neuroinflammation and neurotoxicity. Together, these Aims will provide crucial information on the function of a novel regulator of neuroinflammation, Hv1, and determine whether targeting Hv1 may be a viable therapeutic strategy in toxicant-induced neurodegeneration.

摘要 神经炎症是导致包括帕金森病在内的神经退行性疾病的驱动力 （PD）。小胶质细胞是大脑的主要免疫细胞，并且是感染、毒性和免疫缺陷的第一反应者。 损伤和聚集蛋白质并显著促进神经炎症和神经变性。的 小胶质细胞炎症反应，包括炎性小体激活，已被证明是显著的， 与PD有关。百草枯（PQ）是一种常用的除草剂，与PD风险增加有关。 PQ诱导的神经退行性变与小胶质细胞的激活紧密相关，并且似乎需要启动 小胶质细胞的反应因此，调节小胶质细胞炎症反应的因素可能导致 神经保护和减缓神经退行性疾病的进展。然而，到目前为止，没有反- 炎性药物在人类临床试验中已被证明是成功的，需要对新靶点进行研究。HV1 （HVCN 1）是在脑中的小胶质细胞和其它免疫细胞中高度表达的电压门控质子通道 在体内该质子通道调节NADPH氧化酶的活性和活性氧的产生 免疫细胞，特别是小胶质细胞。我们的初步数据表明，PQ直接增加 小胶质细胞中的hv 1水平，可能通过涉及组蛋白乙酰化的表观遗传机制。此外，我们的 数据表明PQ对NLRP 3炎性小体的影响似乎受Hv 1调节，提供了一个 有助于PQ诱导的小胶质细胞启动的潜在机制。这一提议旨在检验这一假设 Hv 1通过NLRP 3炎性小体调节PQ暴露后小胶质细胞的启动，导致 神经炎症和神经变性。本项目的具体目标是：1）确定机制 2）确定Hv 1在调节NLRP 3炎性小体中的作用 3）确定小胶质细胞Hv 1和NLRP 3炎性小体的作用 在调节百草枯暴露后的神经退化方面的作用。这些目标的完成将定义监管 Hv 1的机制，并确定Hv 1在调节NLRP 3炎性小体活化中的作用， 它们在PQ诱导的神经炎症和神经毒性中的作用。这些目标将共同提供至关重要的 关于神经炎症新调节因子Hv 1功能的信息，并确定是否靶向Hv 1 可能是一个可行的治疗策略，在毒物诱导的神经变性。