Elucidation and control of the molecular mechanism of amyloid fibril formation Applications for nano materials

阐明和控制淀粉样原纤维形成的分子机制纳米材料的应用

基本信息

批准号：
15602001
负责人：
HASEGAWA Kazuhiro
金额：
$ 2.3万
依托单位：
University of Fukui (2004)福井医科大学 (2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

The aims of this study are (1) establishment of general molecular model of amyloid fibril formation and dissociation via the study of beta-amyloid and beta2-microglobulin (β2-m) amyloid (2) elucidation of the effect of various biological molecules or chemical compounds on the common pathogenesis of each amyloidosis, and suggest a strategy for treatment (3) invention of the control method for the formation and dissociation of amyloid fibril, and their application to nanotechnology. Results : (1) six peptides correspond to six of the seven beta sheet in the native structure of β2-m, and examined their amyloidogenisity. Among the peptides examined, peptide(21-31) showed fibril formation. (2) in β2-m amyloid fibril formation, partial unfolding of β2-m is believed to be prerequisite to its assembly into Aβ2M amyloid fibrils. In this study, low concentrations of trifluoroethanol and sodium dodecyl sulfate was found to induce the amyloidogenic partial unfolding of β2-m and result in the extension of Aβ2M amyloid fibrils at a neutral pH. (3) Polyphenols or vitamin A related compounds are found to inhibit the fibril formation of β-amyloid fibrils and to destabilize the preformed fibrils in vitro. (4) a direct thermodynamic analysis of amyloid fibril formation using isothermal titration calorimetry was develpoed. This investigation enables us to measure the heat capacity and enthalpy, and to estimate the stability and structural information on the conformational change of amyloidogenic proteins during fibril formation. As the conclusion of this study, remarkable advance on the clarification of the molecular mechanism of fibril formation in vitro was obtained. Furthermore, useful characteristics of amyloid fibril formation and dissociation for the application to nanotechnology were discovered.

本研究的目的是（1）通过研究β-淀粉样蛋白和β2-微球蛋白（β2-m）淀粉样蛋白，建立淀粉样蛋白原纤维形成和解离的通用分子模型（2）阐明各种生物分子或化学物质的作用化合物对每种淀粉样变性的常见发病机制，并提出治疗策略（3）发明淀粉样原纤维形成和解离的控制方法及其在纳米技术中的应用。结果：(1) 6 个肽对应于 β2-m 天然结构中 7 个 β 片层中的 6 个，并检查了它们的淀粉样蛋白生成性。在所检查的肽中，肽 (21-31) 在 β2- 中显示出原纤维形成。在 m 淀粉样蛋白原纤维形成过程中，β2-m 的部分解折叠被认为是其组装成 Aβ2M 淀粉样蛋白原纤维的先决条件。十二烷基硫酸钠被发现可诱导 β2-m 的淀粉样蛋白部分解折叠，并导致 Aβ2M 淀粉样原纤维在中性 pH 下延伸 (3) 多酚或维生素 A 相关化合物可抑制 β-淀粉样原纤维的原纤维形成。并在体外破坏预先形成的原纤维的稳定性（4）使用等温滴定量热法对淀粉样原纤维形成进行直接热力学分析。这项研究使我们能够测量淀粉样蛋白在原纤维形成过程中的构象变化的稳定性和结构信息，这在阐明淀粉样蛋白的分子机制方面取得了显着进展。此外，还发现了淀粉样蛋白原纤维形成和解离的有用特征，可用于纳米技术。