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

项目摘要/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 功能障碍可能会导致神经退化过程。然而，连接昼夜节律的机制 阿尔茨海默病相关神经变性的功能障碍仍不清楚。在分子水平上，核心 生物钟基因调节昼夜节律，也是转录和代谢的关键。 包括大脑在内的各种器官中的调节器。我们已经证明了昼夜节律的基因破坏 主时钟基因BMal1的缺失会导致严重的胶质细胞增生症、氧化损伤和突触 小鼠大脑的退化，表明核心时钟功能与神经退化之间存在联系。我们有 随后发现，REV-ERBα的缺失是核心时钟的一个组成部分，它是直接调节的 通过BMAL1，也会导致自发的小胶质细胞激活和神经炎症。我们的数据显示，牧师- 携带淀粉样斑块的APP/PS1小鼠大脑皮层ERBα表达受到抑制 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，它们还参与调节炎症和 新陈代谢。我们假设REV-ERB用于将生物钟与神经炎症和 神经退行性变。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受REV-ERBS调控的转录途径。 我们将确定REV-ERBS是否通过转录调控小胶质细胞突触吞噬作用 补体基因的调控。因为它们是核受体，所以REV-ERB可以被操纵 从药理上讲。因此，我们将研究REV-ERB的细胞类型特定基因缺失的影响，或 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。这些研究将为分子科学提供新的线索。 将生物钟与阿尔茨海默病相关的神经退化联系起来的机制，并阐明了 直接针对生物钟进行神经保护的新策略。

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.