Role of REV-ERB Proteins in Neuroinflammation and Alzheimer's Disease

REV-ERB 蛋白在神经炎症和阿尔茨海默病中的作用

• 批准号: 10580746
• 负责人: Erik Steven Musiek
• 金额: $ 41.81万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580746
• 关键词: APP-PS1; ARNTL gene; Acceleration; Agonist; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Amyloidosis; Brain; C3 gene; Cell physiology; Cells; Circadian Dysregulation; Circadian Rhythms; Clock protein; Complement; Complement 4b; Data; Diurnal Rhythm; Gene Expression; Genes; Genetic; Genetic Transcription; Gliosis; Goals; Hippocampus; Homologous Gene; Hour; Inflammation; Innate Immune System; Knockout Mice; Link; Mediating; Metabolic; Metabolism; Methods; Microglia; Modernization; Molecular; Mus; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Nuclear Receptors; Organ; Pathogenesis; Pathway interactions; Periodicity; Peripheral; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Play; Process; Proteins; Publishing; Regulation; Role; Senile Plaques; Signal Transduction; Societies; Synapses; Transcriptional Regulation; Transgenic Mice; Up-Regulation; Viral Vector; age related neurodegeneration; amyloid pathology; antagonist; cell type; circadian; circadian pacemaker; common symptom; complement C3 precursor; derepression; gene complementation; gene repression; glial activation; in vivo; mouse model; neuroinflammation; neuroprotection; novel; novel strategies; novel therapeutics; overexpression; oxidative damage; pharmacologic; prevent; small molecule; synaptic pruning; therapeutic target; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Role of REV-ERB Proteins in Neuroinflammation and Alzheimer’s Disease Circadian rhythm disruption is observed in Alzheimer’s Disease, and emerging data suggests that circadian dysfunction may contribute to the neurodegenerative process. However, mechanisms connecting circadian dysfunction to Alzheimer’s Disease-related neurodegeneration remain unclear. On a molecular level, core circadian clock genes mediate circadian rhythms, and also serve as critical transcriptional and metabolic regulators in a variety of organs, including the brain. We have shown that genetic disruption of the circadian clock by deletion of the master clock gene Bmal1 causes severe gliosis, oxidative damage, and synaptic degeneration in mouse brain, suggesting a link between core clock function and neurodegeneration. We have subsequently found that the deletion of REV-ERBα, a component of the core clock which is directly regulated by BMAL1, also causes spontaneous microglial activation and neuroinflammation. Our data shows that REV- ERBα expression is suppressed in the cortex of amyloid plaque-bearing APP/PS1 mice, a model of Alzheimer’s Disease, and in activated microglia. REV-ERBα and its homolog REV-ERBβ are nuclear receptors which, aside from their function in the circadian clock, have been implicated in regulation of inflammation and metabolism. We hypothesize that REV-ERBs serve to link the circadian clock to neuroinflammation and neurodegeneration. We will examine the cell-autonomous function of REV-ERBs in regulating microglial activation and neuroinflammation, and identify transcriptional pathways regulated by REV-ERBs in microglia. We will determine if REV-ERBs control microglial synaptic phagocytosis in the brain via transcriptional regulation of complement genes. Because they are nuclear receptors, REV-ERBs can be manipulated pharmacologically. Thus, we will examine the effects of cell type specific genetic deletion of REV-ERBs, or activation or inhibition of REV-ERB function with small molecule agonists, on neuroinflammation and neurodegeneration in a mouse model of Alzheimer’s Disease. These studies will shed new light on molecular mechanisms linking the circadian clock and Alzheimer’s Disease-related neurodegeneration, and illuminate the novel strategy of directly targeting the circadian clock for neuroprotection.

项目总结/摘要 REV-ERB蛋白在神经炎症和阿尔茨海默病中的作用 在阿尔茨海默病中观察到昼夜节律紊乱，新出现的数据表明，昼夜节律 功能障碍可能导致神经变性过程。然而，将昼夜节律 阿尔茨海默病相关的神经变性的功能障碍仍不清楚。在分子水平上， 生物钟基因介导昼夜节律，也是关键的转录和代谢基因。 包括大脑在内的各种器官的调节器。我们已经证明，昼夜节律的遗传干扰 主时钟基因Bmal 1的缺失导致严重的神经胶质增生、氧化损伤和突触损伤。 在小鼠大脑中的退化，表明核心时钟功能和神经退行性变之间的联系。我们有 随后发现，REV-ERBα的缺失，核心时钟的一个组成部分，直接调节， BMAL 1也会引起自发的小胶质细胞活化和神经炎症。我们的数据显示，REV- ERBα表达在携带淀粉样斑块的APP/PS1小鼠的皮质中受到抑制， 阿尔茨海默氏症，以及激活的小胶质细胞。REV-ERBα及其同源物REV-ERBβ是核受体 除了它们在生物钟中的功能外，它们还涉及炎症的调节， 新陈代谢.我们假设REV-ERB可以将生物钟与神经炎症联系起来， 神经变性我们将研究REV-ERBs在调节小胶质细胞中的细胞自主功能， 激活和神经炎症，并确定小胶质细胞中REV-ERB调控的转录途径。 我们将确定REV-ERBs是否通过转录调控来控制大脑中小胶质细胞的突触吞噬作用。 补体基因的调节。因为它们是核受体，REV-ERBs可以被操纵， - 是的因此，我们将研究REV-ERB的细胞类型特异性遗传缺失的影响，或 用小分子激动剂激活或抑制REV-ERB功能，对神经炎症和 阿尔茨海默病小鼠模型中的神经变性。这些研究将为分子生物学提供新的线索。 联系昼夜节律钟和阿尔茨海默病相关的神经退行性变的机制，并阐明 直接针对生物钟进行神经保护的新策略。