Elucidating the Temporal, Spatial and Cellular Effects of Differential APOE Isoform Expression

阐明差异 APOE 亚型表达的时间、空间和细胞效应

• 批准号: 10331805
• 负责人: Tal Nuriel
• 金额: $ 57.23万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331805
• 关键词: Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Apolipoprotein E; Astrocytes; Behavioral; Bioenergetics; Bioinformatics; Biological; Biological Process; Brain; Brain region; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Development; Disease; Disease susceptibility; Event; Functional Magnetic Resonance Imaging; Genes; Genotype; Histologic; Hyperactivity; Image; Impaired cognition; Impairment; Individual; Investigation; Knock-in Mouse; Late Onset Alzheimer Disease; Lipids; Literature; Magnetic Resonance Imaging; Maps; Microglia; Molecular Biology; Mus; Nature; Neurons; Pathway interactions; Pattern; Physiology; Predisposition; Process; Protein Isoforms; Proteins; Publications; RNA; Regulation; Reporting; Research; Research Personnel; Resistance; Resolution; Risk; Role; Series; Site; System; Systems Biology; Technology; Time; Work; abeta accumulation; aged; base; behavior test; behavioral phenotyping; brain cell; cell type; conditional knockout; conditioned fear; design; entorhinal cortex; experimental study; genetic risk factor; human model; human old age (65+); improved; innovation; lipidomics; mass spectrometric imaging; metabolomics; mouse model; multiple omics; novel; novel therapeutic intervention; object recognition; prevent; theories; transcriptomics; unpublished works

Project Summary Carriers of the apolipoprotein E (APOE) ε4 gene are at a significantly increased risk for developing Alzheimer’s disease (AD). Although numerous theories have been proposed, the cause of this association remains unclear. My own research has uncovered novel effects of APOE4 expression on important processes in the brain, including neuronal activity, the endosomal-lysosomal system and bioenergetic regulation. However, substantial questions remain about when, where and how these systems are effected by differential APOE isoform expression. In order to answer these questions and gain a more comprehensive understanding of how differential APOE isoform expression affects vital brain processes and pathways, I propose a series of cutting-edge experiments, performed on a newly created APOE mouse model. By conducting behavioral experiments, histological examinations, imaging and an array of spatial multi-omics experiments, this project aims to define the temporal, spatial and cellular progression of differential APOE isoform effects in the brain. Each of these experiments will be performed on young (4-6 month-old), aged (14-16 month-old), and old (24-26 month-old) APOE2, APOE3 and APOE4-KI mice. In Aim 1, we will conduct a series of behavioral tests, including Barnes maze, novel object recognition, and fear conditioning, as well as a histological analysis for endosomal-lysosomal disruptions, bioenergetic deficits, and changes in AD pathology markers. We will also conduct a detailed imaging analysis using fMRI to observe activity and structural changes in these mice. In Aim 2, we will conduct an in- depth spatial multi-omics analysis on these mice, including spatial transcriptomics and spatial metabolomics/lipidomics. And in Aim 3, we will explore the cellular contributions to differential APOE isoform expression, including a novel bioinformatics approach and conditionally knockout of APOE from astrocytes and microglia in the APOE-KI mice. We anticipate that the full study proposed herein will uncover important APOE isoform effects on multiple brain processes and pathways in a systems-biology manner, which will dramatically increase our understanding of how APOE isoform differences affect an individual’s susceptibility to AD, potentially leading to new therapeutic strategies for AD, especially among APOE4 carriers.

项目概要 载脂蛋白 E (APOE) ε4 基因携带者患阿尔茨海默病的风险显着增加 疾病（AD）。尽管已经提出了许多理论，但这种关联的原因仍不清楚。 我自己的研究发现了 APOE4 表达对大脑重要过程的新影响， 包括神经元活动、内体-溶酶体系统和生物能调节。然而，实质性的 关于这些系统何时、何地以及如何受到不同的 APOE 异构体影响的问题仍然存在 表达。为了回答这些问题并更全面地了解如何差异化 APOE亚型表达影响重要的大脑过程和通路，我提出了一系列前沿的 实验是在新创建的 APOE 小鼠模型上进行的。通过进行行为实验， 组织学检查、成像和一系列空间多组学实验，该项目旨在定义 大脑中不同 APOE 亚型效应的时间、空间和细胞进程。这些中的每一个 实验将在年轻人（4-6个月大）、老年人（14-16个月大）和老年（24-26个月大）上进行 APOE2、APOE3 和 APOE4-KI 小鼠。在目标1中，我们将进行一系列行为测试，包括Barnes 迷宫、新物体识别和恐惧调节，以及内体-溶酶体的组织学分析 AD 病理标志物的破坏、生物能缺陷和变化。我们还将进行详细的成像 使用功能磁共振成像进行分析，观察这些小鼠的活动和结构变化。在目标 2 中，我们将进行一次in- 对这些小鼠进行深度空间多组学分析，包括空间转录组学和空间组学分析 代谢组学/脂质组学。在目标 3 中，我们将探索细胞对差异 APOE 亚型的贡献 表达，包括一种新的生物信息学方法和从星形胶质细胞中有条件地敲除 APOE 和 APOE-KI 小鼠的小胶质细胞。我们预计本文提出的完整研究将揭示重要的 APOE 异构体以系统生物学的方式对多个大脑过程和通路产生影响，这将显着 增加我们对 APOE 同工型差异如何影响个体对 AD 易感性的了解， 可能会带来新的 AD 治疗策略，尤其是 APOE4 携带者。