The role of ABI3 in Alzheimers disease

项目摘要/摘要 在最近的大规模全基因组分析研究中，在Abelson交互作用分子中发现了一种罕见的编码变体 家族成员3(ABI3)基因和该变异与晚发性阿尔茨海默病风险增加相关 (加载)。ABI3在包括人类和小鼠在内的多种物种中高度保守。有趣的是，它是高度 在小胶质细胞中表达，与其他脑区相比，在海马区表达相对丰富。 本应用程序的首要目标是了解ABI3在小胶质细胞功能中的作用以及 ABI3影响AD发病机制的研究进展我们提出以下具体目标来测试我们的 假设。在目标1中，我们将使用两种方法来确定ABI3缺失对阿尔茨海默病病理的影响 老鼠模型。通过进行无偏见的转录组和蛋白质组分析，我们将确定潜在的关键 ABI3介导的效应的调节者。我们将进行进一步的功能和生化实验来解剖 基于这些发现的机制。在目标2中，我们将研究ABI3罕见编码变体的影响 用ABI3基因敲除小鼠模型研究AD的病理变化。我们将进行脑部成像和电生理学 评估ABI3风险变种的功能效应的实验。此外，我们还将评估神经病理学 大脑中的表型。为了确定潜在的途径和关键的调控因子，我们将分析转录组 蛋白质组被ABI3基因敲除和敲入改变。在目标3中，我们将进行小胶质细胞分析以 确定ABI3风险变异对小胶质细胞功能的影响。此外，我们将使用RNA干扰 敲除我们感兴趣的基因以剖析ABI3风险变量背后的机制的方法- 调解的变化。这项研究的成功完成将为我们提供新的洞察机制。 AD，尤其是ABI3介导的小胶质细胞功能。我们的长期目标是确定新的可用药靶点 为有效治疗阿尔茨海默病。

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 effect of the 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 analyze transcriptome and proteome altered by ABI3 knockout and knock-in. In Aim 3, 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.