Molecular genetic analyses of transcriptional dysregulation in Alzheimers disease

阿尔茨海默病转录失调的分子遗传学分析

• 批准号: 10662322
• 负责人: Jungsu Kim
• 金额: $ 75.56万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662322
• 关键词: Address; Affect; Age; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Animal Model; Brain; Candidate Disease Gene; Cell Line; Cell Lineage; Cells; Collaborations; Communities; Core Facility; Data; Data Set; Disease; Disease Progression; Down-Regulation; Electrophysiology (science); Frontal gyrus; Genes; Genetic Transcription; Genetic study; Gliosis; Goals; Human; Human Genetics; Immune response; Immune system; In Vitro; Inflammatory; Knock-in Mouse; Knockout Mice; Knowledge; Macrophage; Magnetic Resonance Imaging; Mediating; Metabolism; Methods; Microglia; Molecular; Molecular Genetics; Myelogenous; Neurons; Neurosciences Research; Pathogenesis; Pathology; Pathway interactions; Peptides; Phagocytes; Phagocytosis; Phenotype; Play; Positron-Emission Tomography; Proteins; Proteomics; Reporting; Role; SPI1 gene; Senile Plaques; Systems Biology; Testing; amyloid pathology; astrogliosis; chemokine; conditional knockout; cytokine; data resource; disease phenotype; epigenomics; experience; experimental study; genetic analysis; genetic risk factor; genome wide association study; genome-wide; immune function; in vitro activity; in vivo; induced pluripotent stem cell; innovative technologies; insight; knock-down; laboratory facility; lipid metabolism; monocyte; mouse model; multi-electrode arrays; multiple omics; new therapeutic target; protein aggregation; response; risk variant; selective expression; single-cell RNA sequencing; superresolution microscopy; therapy development; transcription factor; transcriptomics; uptake

Project Summary/Abstract Recently, multiple human genetic studies have identified the critical role of the immune system in the pathogenesis of Alzheimer’s disease (AD). For example, microglia phagocytose amyloid beta (Abeta) and regulate brain immune function by secreting cytokines and chemokines. Because previous studies have suggested both protective and detrimental effects of microglial activity in AD, how microglial AD risk genes, such as PU.1, affect microglial function still remains unclear. Therefore, investigating the role of AD genetic risk factors in microglia will provide critical insight into the pathobiology of the disease, potentially revealing key regulators of underlying disease mechanisms and novel therapeutic targets. An AD genetic risk factor, PU.1, is a critical transcription factor selectively expressed in microglia in the brain. We hypothesize that PU.1 affects several transcription pathways, Abeta metabolism and other AD-related pathologies by regulating their immune function. To test this hypothesis, we will apply several innovative technologies, including single-cell RNA-sequencing, quantitative proteomics, super-resolution microscopy, human-induced pluripotent stem cell-derived microglia and neurons, multi-electrode arrays, electrophysiology, and the simultaneous Positron Emission Tomography- Magnetic Resonance Imaging, in collaboration of multiple collaborators with extensive experience in these methods. In aim 1, we will determine how downregulating PU.1 affects microglial and neuronal phenotypes and perform unbiased transcriptomic and proteomic analyses to identify key downstream regulators. In aim 2, we will investigate the functional interaction between microglia and neurons using human induced pluripotent stem cells after regulating PU.1 expression. In aim 3, we will terminate how microglial PU.1 affects AD phenotypes when it is regulated before and after the onset of amyloid pathology.

项目概要/摘要 最近，多项人类遗传学研究已经确定了免疫系统在 阿尔茨海默病（AD）的发病机制例如，小胶质细胞吞噬β淀粉样蛋白（Abeta）和 因为之前的研究表明，通过分泌细胞因子和趋化因子来调节大脑免疫功能。 表明小胶质细胞活动对 AD 具有保护作用和应激作用，小胶质细胞 AD 风险基因，例如 PU.1对小胶质细胞功能的影响仍不清楚，因此，研究AD遗传危险因素的作用仍不清楚。 在小胶质细胞中的研究将为该疾病的病理学提供重要的见解，有可能揭示关键的调节因子 AD 遗传风险因素 PU.1 是一个关键的疾病机制和新的治疗靶点。 我们努力发现 PU.1 会影响多种大脑小胶质细胞。 通过调节免疫功能来调节转录途径、Abeta 代谢和其他 AD 相关病理。 为了验证这一假设，我们将应用多种创新技术，包括单细胞 RNA 测序、 蛋白质组学、超分辨率显微镜、人诱导多能干细胞衍生的小胶质细胞 和神经元、多电极阵列、电生理学和同步正电子发射断层扫描- 磁共振成像，与在这些方面拥有丰富经验的多个合作者合作 在目标 1 中，我们将确定下调 PU.1 如何影响小胶质细胞和神经表型以及 在目标 2 中，我们将进行公正的转录组和蛋白质组分析，以确定关键的下游调节因子。 使用人类诱导多能干细胞研究小胶质细胞和神经元之间的功能相互作用 在调节 PU.1 表达后，在目标 3 中，我们将终止小胶质细胞 PU.1 对 AD 表型的影响。 在淀粉样蛋白病理发生之前和之后受到调节。