Biochemistry and Structural Modeling Core

项目总结(APOE U19核心B：生物化学和结构建模核心) 编码apoE蛋白的apoE基因是阿尔茨海默病最强的遗传风险因素 (Ad)。然而，不同的载脂蛋白E亚型如何影响衰老和阿尔茨海默病仍不清楚。这个项目的总体目标是 U19的建议是检验载脂蛋白E级联假说(ACH)，即生化和结构差异 载脂蛋白E亚型之间在细胞和系统的一系列事件中启动它们的不同效应 水平，最终影响包括阿尔茨海默病在内的与衰老相关的致病条件。测试这一点的一个障碍 假说是，该领域目前缺乏对生化和结构特性的详细了解 不同载脂蛋白亚型的天然脂结合状态--称为脂蛋白。核心B将提供 生物化学和结构建模服务，以支持其他U19项目/核心，帮助发现 脂蛋白的生化组成和原子细节结构。具体来说，我们将建立 分离脂蛋白并表征其大小分布、脂类成分和 翻译后修饰。我们还将开发集成来自分子的信息的方法 在项目1中进行了动力学模拟和结构实验，以建立原子详细的模型 脂蛋白所采用的结构的集合。核心将分析生成的数据以确定 预测不同载脂蛋白E亚型对衰老和AD的影响的信号。

PROJECT SUMMARY (APOE U19 Core B: Biochemistry and Structural Modeling Core) The APOE gene, which encodes the apoE protein, is the strongest genetic risk factor for Alzheimer’s disease (AD). However, it remains unclear how different apoE isoforms impact aging and AD. The overall goal of this U19 proposal is to test the ApoE Cascade Hypothesis (ACH) that the biochemical and structural differences between apoE isoforms initiate their differential effects on a cascade of events at the cellular and systems levels, ultimately impacting aging-related pathogenic conditions including AD. One hurdle to testing this hypothesis is that the field currently lacks a detailed understanding of the biochemical and structural properties of different apoE isoforms in their native, lipid-bound states—called lipoproteins. Core B will provide biochemistry and structural modeling services to support other U19 projects/cores, helping to uncover the biochemical composition and atomically-detailed structures of lipoproteins. Specifically, we will establish standard protocols for isolating lipoproteins and characterizing their size distribution, lipid composition, and post-translational modifications. We will also develop methods for integrating information from molecular dynamics simulations and structural experiments performed in Project 1 to build atomically-detailed models of the ensemble of structures that lipoproteins adopt. The Core will analyze the data generated to identify signatures that are predictive of the impact of different apoE isoforms on aging and AD.