Amyloid Fibrils, Spherulites and Beyond: Unravelling Mechanisms that Control Protein Aggregation

淀粉样蛋白原纤维、球晶及其他：揭示控制蛋白质聚集的机制

• 批准号: EP/H006028/1
• 负责人: Athene Donald DBE FRS
• 金额: $ 46.78万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FH006028%2F1
• 关键词: Amyloid; Fibrils; Spherulites; Beyond; Unravelling

When globular proteins become partially unfolded or completely misfolded from their native conformation they frequently aggregate into assemblies of many molecules. One of the key forms in which this aggregation occurs is the so-called amyloid fibril, a very regular packing of the molecules into long fibrils containing a significant amount of beta sheet. These fibrils are implicated in many of the diseases of old age and neurodegeneration, such as Alzheimer's and Parkinson's disease. However, this same structure is also found in benign situations, such as when milk proteins are heat-treated to lead to texture in foods such as yogurt and cheese. The amyloid fibril is not the only form of aggregate that can occur, and recent studies have identified suprafibrillar aggregates known as spherulites. These have also been found in diseased brain tissue, and are also known to form in the milk proteins. This project aims to try to uncover the factors that control when and how these different aggregates form, and what determines the balance between them. By working on model proteins such as insulin and Abeta (the protein associated with Alzheimer's disease) we aim to explore the role of the charge state of the protein and the presence of surfaces. The relevant surfaces include the introduction of nanoparticles as well as more macroscopic surfaces. Understanding the impact of nanoparticles for protein aggregation is another major thrust in healthcare which this project may help to address. If nanoparticles are shown to promote protein aggregation these studies will have far reaching implications for the cytotoxicity and toxicology of nanomaterials.

当球状蛋白质从其天然构象中部分展开或完全错误折叠时，它们经常聚集成许多分子的集合。这种聚集发生的关键形式之一是所谓的淀粉样原纤维，这是一种非常规则的分子堆积成长纤维的形式，其中包含大量的β-折叠。这些纤维与许多老年疾病和神经退行性疾病有关，例如阿尔茨海默氏症和帕金森氏症。然而，同样的结构也在良性情况下被发现，例如当牛奶蛋白质被加热处理以在酸奶和奶酪等食物中产生质地时。淀粉样原纤维并不是唯一可能出现的聚集体形式，最近的研究发现了被称为球晶的纤维上聚集体。在患病的脑组织中也发现了这些物质，并已知它们也在牛奶蛋白中形成。这个项目旨在揭示控制这些不同聚集体形成的时间和方式的因素，以及是什么决定了它们之间的平衡。通过对胰岛素和Abeta(与阿尔茨海默病相关的蛋白质)等模型蛋白质的研究，我们的目标是探索蛋白质的电荷状态和表面存在的作用。相关表面包括纳米颗粒的引入以及更宏观的表面。了解纳米颗粒对蛋白质聚集的影响是医疗保健领域的另一个主要推动力，该项目可能有助于解决这一问题。如果纳米粒子被证明能促进蛋白质聚集，这些研究将对纳米材料的细胞毒性和毒理学产生深远的影响。