Membrane Mediated Amyloidogenesis

膜介导的淀粉样蛋白生成

• 批准号: 6544358
• 负责人: Paul H Axelsen
• 金额: $ 30.61万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6544358
• 关键词: Alzheimer's disease; X ray crystallography; amyloid proteins; apolipoprotein E; biophysics; cell aggregation; chemical aggregate; clinical research; disease /disorder etiology; human tissue; infrared spectrometry; interferometry; intermolecular interaction; lipid bilayer membrane; membrane structure; neural degeneration; nuclear magnetic resonance spectroscopy; oxidative stress; postmortem; protein folding; protein structure; protein structure function

DESCRIPTION (provided by applicant): The proposed research is a biophysical study of the process by which lipid membranes induce aggregation and pathologically mis-folded secondary structure in amyloid beta (Ab) proteins. It aims to define mechanistic links between two major themes in the pathogenesis of Alzheimer's disease: amyloid fibril formation and oxidative damage. It is hypothesized that these processes are linked through protein-lipid interactions, and we have developed novel instrumentation for characterizing these interactions. We are specifically proposing to (1) Determine the secondary structure of membrane-associated Af3 protein, (2) Correlate Ab folding and accumulation to membrane composition and source, and (3) Define potential consequences of Ab-induced oxidative membrane damage. This research addresses basic pathological mechanisms of Alzheimer's Disease by addressing the complex interrelationships between Ab fibril formation, lipid membranes, and oxidative damage in both synthetic membranes and membranes derived from pathologically afflicted human brain tissue. In this way, the concept of membrane-mediated amyloidogenesis will be developed on a molecular and pathologically-relevant level.

描述（由申请人提供）：拟议的研究是对脂质膜在淀粉样蛋白（AB）蛋白中诱导聚集和病理错误折叠的二级结构的过程的生物物理研究。它的目的是在阿尔茨海默氏病发病机理中定义两个主要主题之间的机械联系：淀粉样蛋白纤维形成和氧化损伤。假设这些过程是通过蛋白质 - 脂质相互作用链接的，并且我们开发了用于表征这些相互作用的新型仪器。 我们专门提议（1）确定与膜相关的AF3蛋白的二级结构，（2）将AB折叠和积累与膜组成和来源相关联，以及（3）定义AB诱导的氧化膜损伤的潜在后果。 这项研究通过解决了合成膜和从病理上折磨的人类脑组织中得出的合成膜和膜中的复杂相互关系来解决阿尔茨海默氏病的基本病理机制。这样，膜介导的淀粉样生成的概念将以分子和病理上的水平发展。