A Small-Angle Scattering Study of the Self-Assembly of Amyloid Peptide Fragments and Copolymers

将研究淀粉样蛋白肽片段的变性机制和动力学，淀粉样蛋白肽片段是导致阿尔茨海默病和II型糖尿病等疾病的原因。我们将在新的钻石同步加速器上进行时间分辨X射线散射，以探测淀粉样β肽的短片段（5-7个氨基酸）产生的原纤维的生长过程。所选择的序列已被证明是关键的氟化。我们还将研究肽与聚乙二醇（PEG）的共聚物的自组装。PEG是一种水溶性聚合物，已被批准用于药物应用。PEG将连接到设计为与完整的致病肽结合的肽片段。我们预期它将为肽原纤维提供空间稳定性，形成一个涂层，防止聚集成更大的聚集体，如淀粉样蛋白疾病的症状所观察到的。我们将研究淀粉样肽和肽聚合物纤维的自组装的机制和动力学，以深入了解肽序列中如何发生fiferisation以及如何使用PEG共聚物来预防。此外，我们将研究溶剂，盐和pH值对聚集过程的影响，例如确保我们在pH值和盐的生理条件下研究絮凝作用。将分析小角X射线散射数据，以确定肽聚集体的大小和形状。将研究高浓度下液晶相的形成，以及与血流中遇到的流动相关的剪切流对齐。这些将涉及最先进的同步X射线散射和剪切粘度测量。

The mechanisms and kinetics of fibrillisation of fragments of the amyloid peptide responsible for diseases such as Alzheimers and type II diabetes will be investigated. We will perform time-resolved x-ray scattering at the new Diamond synchrotron in order to probe the growth processes of fibrils produced by short (5-7 amino acid) fragments of the amyloid beta peptide. The sequences selected have been shown to be critical in fibrillisation. We will also investigate the self-assembly of copolymers of the peptide with poly(ethylene glycol), PEG. PEG is a water soluble polymer that has been approved for pharmaceutical applications. The PEG will be attached to peptide fragments designed to bind to the full disease-causing peptide. We expect it will provide steric stability to peptide fibrils, forming a coating layer that prevents aggregation into larger aggregates as observed as a symptom of amyloid disease. We will study the mechanisms and kinetics of self-assembly of the amyloid peptide and peptide polymer fibrils to gain insights into how fibrillisation occurs in the peptide sequences and how it can be prevented using PEG copolymers. In addition, we will examine the effects of solvent, salt and pH on the aggregation process, for instance ensuring that we investigate fibrillisation under physiological conditions of pH and salt. The small-angle x-ray scattering data will be analysed to determine the size and shape of the peptide aggregates. The formation of liquid crystal phases at high concentrations will be investigated, as will shear flow alignment, relevant to flow encountered in the bloodstream. These will involve state-of-the-art simultaneous x-ray scattering and shear viscosity measurements.