The role of ABI3 in Alzheimers disease

ABI3 在阿尔茨海默病中的作用

• 批准号: 10621805
• 负责人: Jungsu Kim
• 金额: $ 75.57万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621805
• 关键词: Abeta clearance; Actins; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloidosis; Biochemical; Brain; Brain imaging; Brain region; CRISPR/Cas technology; Cell Culture Techniques; Cell physiology; Cells; Cellular Assay; Coculture Techniques; Code; Complex; Cytokinesis; Cytoskeletal Modeling; Disease; Electrophysiology (science); Endocytosis; Etiology; Family member; Gene Expression; Genes; Genetic study; Gliosis; Goals; Hippocampus; Human; Human Genetics; Immune response; Immunity; Impairment; In Vitro; Inflammatory; Knock-in Mouse; Knock-out; Knowledge; Late Onset Alzheimer Disease; Magnetic Resonance Imaging; Manuscripts; Mass Spectrum Analysis; Mediating; Microglia; Modeling; Mus; Nature; Neurons; Neurosciences; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phagocytosis; Pharmacology; Phenotype; Play; Positron-Emission Tomography; Proteome; Proteomics; RNA Interference; Reporting; Risk; Role; Senile Plaques; Synapses; System; Systems Biology; Testing; Variant; Wild Type Mouse; abeta accumulation; cancer cell; complement system; cytokine; druggable target; effective therapy; experimental study; genetic approach; genetic risk factor; genome editing; genome-wide; genome-wide analysis; immunoreactivity; induced pluripotent stem cell; innovative technologies; insight; interest; knock-down; migration; mouse model; neuropathology; new therapeutic target; novel; risk variant; single-cell RNA sequencing; superresolution microscopy; synaptic function; transcriptome; transcriptomics; uptake; β-amyloid burden

Project Summary/Abstract In recent large-scale genome-wide analysis studies, a rare coding variant was identified in Abelson interactor family member 3 (ABI3) gene and this variant is associated with increased risk of late-onset Alzheimer's disease (LOAD). ABI3 is highly conserved across multiple species, including humans and mice. Interestingly, it is highly expressed in microglia and relatively more abundant in the hippocampus, compared to the other brain regions. The overarching goal of this application is to understand the role of ABI3 in microglia function and the mechanisms by which ABI3 affects the pathogenesis of AD. We propose the following Specific Aims to test our hypotheses. In Aim 1, we will determine the effect of Abi3 deletion on Alzheimer's disease pathology using two mouse models. By performing unbiased transcriptomic and proteomic analyses, we will identify the potential key regulators of Abi3-mediated effects. We will conduct further functional and biochemical experiments to dissect the mechanism based on these findings. In Aim 2, we will investigate the function of Abi3 in microglia cells to understand cellular mechanisms by which Abi3 affects the pathogenesis of AD. We will utilize a genome editing approach to delete ABI3 gene in human microglial cells. In Aim 3, we will determine the effect of ABI3 rare- coding variant on AD pathology using ABI3 knock-in mouse model. We will perform brain imaging and electrophysiology experiments to assess the functional effects of ABI3 risk variant. In addition, we will assess neuropathological phenotypes in the brains. To identify the potential pathways and key regulators, we will perform transcriptome and proteome analyses. In addition, we will perform microglial cellular assays to determine the effects of ABI3 risk variant on microglia functions. Furthermore, we will use RNA interference approach to knock-down the genes of our interest to dissect the mechanism behind the ABI3 risk variant-mediated changes. The successful completion of this study will provide novel insights into the mechanisms of AD, in particular, microglial functions mediated by Abi3. Our long-term goal is to identify new druggable targets for the effective treatment of AD.

项目摘要/摘要 在最近的大型全基因组分析研究中，在阿伯森相互作用者中鉴定出罕见的编码变体 家庭成员3（ABI3）基因和该变体与晚期发病的阿尔茨海默氏病风险增加有关 （加载）。 ABI3在包括人类和小鼠在内的多种物种之间是高度保守的。有趣的是，这是高度的 与其他大脑区域相比，在小胶质细胞中表达，在海马中相对丰富。 此应用程序的总体目标是了解ABI3在小胶质细胞功能和 ABI3影响AD发病机理的机制。我们提出了以下特定目标，以测试我们的 假设。在AIM 1中，我们将使用两种ABI3缺失对阿尔茨海默氏病病理学的影响 鼠标模型。通过执行无偏的转录组和蛋白质组学分析，我们将确定潜在的密钥 ABI3介导的作用的调节剂。我们将进行进一步的功能和生化实验以剖析 基于这些发现的机制。在AIM 2中，我们将研究ABI3在小胶质细胞中的功能 了解ABI3影响AD发病机理的细胞机制。我们将利用基因组编辑 删除人类小胶质细胞中ABI3基因的方法。在AIM 3中，我们将确定ABI3稀有的效果 - 使用ABI3敲入小鼠模型对AD病理的编码变体。我们将执行大脑成像， 电生理实验评估ABI3风险变体的功能效应。此外，我们将评估 大脑中的神经病理表型。为了确定潜在的途径和关键调节器，我们将 执行转录组和蛋白质组分析。此外，我们将执行小胶质细胞测定法以确定 ABI3风险变体对小胶质细胞功能的影响。此外，我们将使用RNA干扰方法 敲除了我们感兴趣的基因，以剖析ABI3风险变体介导的变化背后的机制。 这项研究的成功完成将提供有关AD机制的新颖见解，特别是 ABI3介导的小胶质细胞功能。我们的长期目标是确定有效的新型可吸毒目标 AD的处理。