Biochemistry and Structural Modeling Core

生物化学和结构建模核心

• 批准号: 10407937
• 负责人: Gregory R Bowman
• 金额: $ 58.15万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10407937
• 关键词: Adopted; Aging; Agreement; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Apolipoprotein E; Astrocytes; Biochemical; Biochemistry; Biology; Blood Vessels; Brain; Cell Culture Techniques; Cells; Characteristics; Collaborations; Complex; Computer Models; Conditioned Culture Media; Cryoelectron Microscopy; Data; Data Analyses; Development; Disease; Event; Foundations; Future; Genes; Genotype; Goals; Heterogeneity; Human; Light; Lipid Binding; Lipids; Lipoproteins; Methods; Microglia; Modeling; Molecular Conformation; Mus; Pathogenicity; Pattern; Plasma; Post-Translational Protein Processing; Property; Protein Isoforms; Proteins; Protocols documentation; Resources; Sampling; Service delivery model; Source; Structural Models; Structure; System; Techniques; Testing; Therapeutic; Tissue Sample; Variant; apolipoprotein E-3; apolipoprotein E-4; base; cell type; clinical predictors; design; experimental study; genetic risk factor; induced pluripotent stem cell; insight; molecular dynamics; particle; predictive signature; rare variant; single molecule; web portal

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.

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危险因素 （AD）。然而，目前尚不清楚不同的apoE亚型如何影响衰老和AD。这个项目的总体目标是 U19提案是为了验证ApoE级联假说（ACH），即生化和结构差异 在apoE亚型之间启动它们对细胞和系统级联事件的不同作用， 水平，最终影响与衰老相关的致病性疾病，包括AD。测试这个的一个障碍是 一个假设是，该领域目前缺乏对生物化学和结构特性的详细了解 不同的apoE亚型在其天然的，脂质结合状态-所谓的脂蛋白。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，帮助揭示 脂蛋白的生化组成和原子详细结构。具体来说，我们将建立 用于分离脂蛋白并表征其大小分布、脂质组成和 翻译后修饰。我们还将开发从分子水平整合信息的方法， 在项目1中进行的动力学模拟和结构实验，以建立原子详细的模型， 脂蛋白所采用的整体结构。核心将分析生成的数据， 预测不同apoE同种型对衰老和AD的影响的特征。