The role of ABI3 in Alzheimers disease

ABI3 在阿尔茨海默病中的作用

• 批准号: 10222074
• 负责人: Jungsu Kim
• 金额: $ 73.19万
• 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/10222074
• 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; Cytoskeleton; Disease; Electrophysiology (science); Endocytosis; Etiology; Family member; Gene Expression; Genes; Genetic study; Goals; Hippocampus (Brain); Human; Human Genetics; Immune response; Immunity; Impairment; In Vitro; Inflammatory; Knock-in Mouse; Knock-out; Knowledge; Late Onset Alzheimer Disease; Lead; Magnetic Resonance Imaging; Manuscripts; Mass Spectrum Analysis; Mediating; Microglia; Microscopy; Modeling; Mus; Nature; Neurons; Neurosciences; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phagocytosis; Pharmacology; Phenotype; Play; Positron-Emission Tomography; Proteome; Proteomics; RNA Interference; Reporting; Resolution; Risk; Role; Senile Plaques; Synapses; System; Systems Biology; Testing; Variant; Wild Type Mouse; abeta accumulation; base; cancer cell; complement system; cytokine; druggable target; effective therapy; experimental study; genetic approach; genetic risk factor; genetic variant; genome editing; genome-wide; genome-wide analysis; immunoreactivity; induced pluripotent stem cell; innovative technologies; insight; interest; knock-down; migration; mouse model; new therapeutic target; novel; risk variant; single-cell RNA sequencing; 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.

项目总结/摘要 在最近的大规模全基因组分析研究中，在Abelson相互作用子中发现了一种罕见的编码变体 家族成员3（ABI 3）基因，这种变异与晚发性阿尔茨海默病的风险增加有关 （加载）。ABI 3在多个物种中高度保守，包括人类和小鼠。有趣的是， 在小胶质细胞中表达，与其他脑区相比，在海马中相对更丰富。 本申请的首要目标是了解ABI 3在小胶质细胞功能中的作用，以及ABI 3在小胶质细胞功能中的作用。 ABI 3影响AD发病机制的机制。我们提出以下具体目标，以测试我们的 假设在目标1中，我们将使用两种方法确定Abi 3缺失对阿尔茨海默病病理学的影响 小鼠模型。通过无偏转录组学和蛋白质组学分析，我们将确定潜在的关键 Abi 3介导效应的调节剂。我们将进行进一步的功能和生化实验， 基于这些发现的机制。在目标2中，我们将研究Abi 3在小胶质细胞中的功能， 了解Abi 3影响AD发病机制的细胞机制。我们将利用基因组编辑 在人小胶质细胞中缺失ABI 3基因的方法。在目标3中，我们将确定ABI 3罕见的作用- 使用ABI 3敲入小鼠模型研究编码变体对AD病理学的影响。我们将进行脑部成像， 电生理学实验以评估ABI 3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监管机构，我们将 进行转录组和蛋白质组分析。此外，我们将进行小胶质细胞测定，以确定 ABI 3风险变异体对小胶质细胞功能的影响。此外，我们将使用RNA干扰方法， 敲低我们感兴趣的基因，以剖析ABI 3风险变体介导的变化背后的机制。 这项研究的成功完成将为AD的机制提供新的见解，特别是， Abi 3介导的小胶质细胞功能。我们的长期目标是确定新的药物靶点， 治疗AD。