Biochemistry and Structural Modeling Core

生物化学和结构建模核心

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目摘要（APOE U19核心B：生物化学和结构建模核心）编码APOE蛋白的APOE基因是阿尔茨海默氏病的强大遗传危险因素（广告）。但是，尚不清楚不同的APOE同工型如何影响衰老和AD。总体目标 U19建议是测试生化和结构差异的APOE级联假设（ACH）在ApoE同工型之间，它们对细胞和系统的级联事件的差异作用启动水平，最终影响与衰老相关的致病条件，包括AD。测试这个障碍假设是该领域目前缺乏对生化和结构特性的详细理解其本地脂质结合状态的不同APOE同工型（称为脂蛋白）。核心将提供生物化学和结构建模服务，以支持其他U19项目/核心，有助于发现脂蛋白的生化组成和原子详细的结构。具体来说，我们将建立隔离脂蛋白并表征其大小分布，脂质组成和的标准方案翻译后修改。我们还将开发用于整合分子信息的方法在项目1中执行的动力模拟和结构实验，以构建原子详细模型的模型脂蛋白采用的结构合奏。核心将分析生成的数据以识别可以预测不同APOE同工型对衰老和AD的影响的签名。