STRUCTURAL/KINETIC ANALYSIS OF ABETA FIBRILLOGENESIS

ABETA 纤维发生的结构/动力学分析

• 批准号: 6353734
• 负责人: DAVID B. TEPLOW
• 金额: $ 1.54万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-10 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6353734
• 关键词: Alzheimer's disease; amyloid proteins; atomic force microscopy; circular dichroism; electron microscopy; laboratory rat; neuritic plaques; pathologic process; protein biosynthesis; protein structure; synthetic peptide

An increasingly diverse and compelling set of experimental observations supports the hypothesis that Abeta fibrillization starts a cascade of events which eventually results in AD. Although much is known about the primary structure of Abeta in plaques and about the core secondary structure of Abeta in fibrils, little is understand about the mechanisms by which nascent Abeta folds and assembles into fibrils. Identification and characterization of fibrillogenesis intermediates and determination of the kinetics of Abeta fibrillogenesis is crucial if thoughtful, focused efforts are to be made to develop therapeutic agents affecting the fibrillogenesis process. Informative studies in this area will not only significantly accelerate the pace of drug discovery for AD, but will also advance efforts to understand and treat other amyloidoses. Our long term goal is to test the above hypothesis in a series of three steps: 1) to elucidate in molecular detail the mechanisms in Abeta fibrillogenesis; 2) to develop chemical agents capable of blocking or reversing key steps in the fibrillogenesis pathway in vitro; and 3) to formulate and clinically test the efficacy of the agents developed in vitro. This proposal focuses on long term goal #1. The three specific aims proposed build on a number of exciting recent experimental findings. These include the discovery of a potential new therapeutic target, the amyloid protofibril: development of a powerful paradigm, using quasielastic light scattering spectroscopy, for the quantitative analysis of Abeta fibrillogenesis kinetics; and identification of a novel Abeta folding intermediate, the study of which could provide important information about the earliest stages of Abeta fibrillogenesis.

一组日益多样化和引人注目的实验观察 支持Abeta fietization启动级联反应的假设， 最终导致AD的事件。虽然我们对这一点了解很多， 斑块中Abeta的一级结构和围绕核心的二级结构 纤维中Abeta的结构，关于其机制知之甚少 新生的Abeta折叠并组装成纤维。识别 纤维形成中间体的表征和 Abeta纤维形成的动力学是至关重要的， 将努力开发影响这些疾病的治疗剂。 原纤维形成过程这方面的研究不仅 大大加快了AD药物发现的步伐，但也将 进一步了解和治疗其他淀粉样变性。我们的长期 目标是通过一系列三个步骤来验证上述假设：1） 从分子上详细阐明Abeta纤维形成的机制; 2） 开发能够阻断或逆转关键步骤的化学制剂， 体外纤维形成途径;以及3）配制和临床 测试体外开发的药剂的功效。该提案重点 长期目标#1所提出的三个具体目标是建立在以下几个方面的基础上： 令人兴奋的最新实验发现其中包括发现 潜在的新治疗靶点--淀粉样蛋白原纤维的研究进展 一个强大的范例，使用准弹性光散射光谱， 用于定量分析Abeta原纤维形成动力学;以及 鉴定一种新的Abeta折叠中间体， 可以提供关于Abeta早期阶段的重要信息 纤维形成