Role of Glial Circadian Clock Dysfunction in the Pathogenesis of Alzheimer's Disease

胶质细胞生物钟功能障碍在阿尔茨海默病发病机制中的作用

• 批准号: 9700790
• 负责人: Erik Steven Musiek
• 金额: $ 22.11万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9700790
• 关键词: Aging; Alzheimer' s Disease; Amyloidosis; Brain; Cell Nucleus; Circadian Rhythms; Data Set; Databases; Deposition; Disease; Functional disorder; Gene Expression Profile; Genes; Genetic Techniques; Genetic Transcription; Hormone secretion; Hour; Inflammation; Intervention; Mus; Neurons; Pathogenesis; Pathology; Pathway interactions; Patients; Process; Role; Senile Plaques; Sleep; Small Nuclear RNA; System; aged; cell type; circadian pacemaker; glial activation; insight; new technology; new therapeutic target; novel; transcriptome; transcriptome sequencing

Project Summary This project is a supplement to R01AG054517, “Role of Glial Circadian Clock Dysfunction in the Pathogenesis of Alzheimer’s Disease“. Circadian rhythm dysfunction is a critical component of Alzheimer’s Disease (AD), though its impact on disease pathogenesis is not fully understood. We have shown that disrupting circadian rhythms in mice can causes glial cell activation, inflammation, and accelerate amyloid plaque pathology, though the mechanisms underlying these phenomena are not fully understood. In this supplement application, we propose to use a new technology, single-nucleus RNA sequencing (snRNA-seq), to elucidate the circadian transcriptomes of all cell types in the brain. We will also examine these cell-type-specific circadian transcriptomes in aged mice, and in a mouse mode of amyloid plaque deposition (APPPS1-21 mice), in order to determine how AD-related pathology can impact circadian transcription in different cell types in the brain. These studies will generate a definitive database of circadian transcription in most cell types in the brain, as well as changes which occur in aging and amyloidosis. This dataset will provide valuable insights into how the circadian systems influence glial and neuronal function, how this is perturbed in AD, and what pathways may represent new therapeutic targets for intervention.

项目概要 该项目是 R01AG054517“神经胶质昼夜节律时钟功能障碍在 阿尔茨海默病的发病机制“。昼夜节律功能障碍是阿尔茨海默病的一个重要组成部分 阿尔茨海默病（AD），尽管其对疾病发病机制的影响尚未完全了解。我们有 研究表明，扰乱小鼠的昼夜节律会导致神经胶质细胞活化、炎症和 加速淀粉样斑块病理学，尽管这些现象背后的机制尚不完全清楚 明白了。在这个补充申请中，我们建议使用一种新技术，单核RNA 测序（snRNA-seq），阐明大脑中所有细胞类型的昼夜节律转录组。我们将 还检查了老年小鼠中的这些细胞类型特异性昼夜节律转录组，并以小鼠模式 淀粉样斑块沉积（APPPS1-21 小鼠），以确定 AD 相关病理如何影响 影响大脑中不同细胞类型的昼夜节律转录。这些研究将产生明确的 大脑中大多数细胞类型的昼夜节律转录数据库，以及发生的变化 衰老和淀粉样变性。该数据集将为了解昼夜节律系统如何 影响神经胶质和神经元功能，AD 中神经胶质和神经元功能如何受到干扰，以及可能代表哪些通路 干预的新治疗目标。