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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

基本信息

批准号：
9974204
负责人：
Erik Steven Musiek
金额：
$ 39.01万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/9974204
关键词：
APP-PS1 ARNTL gene Agonist Alzheimer associated neurodegeneration Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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 (Brain)Homologous Gene Hour Inflammation Innate Immune System Knockout Mice Light 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 Pharmacology Play Process Proteins Publishing Regulation Repression Role Senile Plaques Signal Transduction Societies Synapses Transcriptional Regulation Transgenic Mice Up-Regulation Viral Vector age related neurodegeneration amyloid pathology cell type circadian circadian pacemaker common symptom complement C3 precursor gene complementation gene repression glial activation in vivo mouse model neuroinflammation neuroprotection novel novel strategies novel therapeutics overexpression oxidative damage prevent small molecule synaptic pruning therapeutic target transcriptome sequencing

项目摘要

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/文摘