Studies of amyloid beta and alpha-synuclein oligomerisation by microfluidic techniques

通过微流体技术研究淀粉样蛋白 β 和 α-突触核蛋白寡聚化

• 批准号: 2276768
• 金额: --
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2276768
• 关键词: Studies; amyloid; beta; alpha; synuclein

Alzheimer's (AD) and Parkinson's (PD) diseases are increasingly prevalent and currently incurable neurodegenerative disorders linked to the accumulation of proteinaceous pathogenic inclusions in the nerve system. Oligomerisation of misfolded amyloid beta and alpha-synuclein proteins is a key step in AD and PD-associated neurotoxicity. Therefore a detailed understanding of this phenomenon is crucial to find effective disease management and therapeutic strategies. However, despite the intensive effort put to understand aberrant protein oligomerisation and the downstream events, mechanistic details of oligomer-induced cellular toxicity are still missing. The project aims at characterising AD- and PD- relevant oligomers at a single-molecule level, to the level of depth and complexity inaccessible by conventional biophysical techniques before. The project outcomes will fill in the gap of knowledge in disease-linked oligomer formation, evolution, diversity, interactions with cellular binding partners and, importantly, implications in neurotoxicity. A set of microfluidic techniques combined with an advanced single-molecule optical detection strategy will be employed to address the challenges faced in biophysical oligomer characterisation studies, namely transient nature, heterogeneity and low abundance of the species. The work will be carried out in close collaboration with Fluidic Analytics Ltd, a company developing and commercialising novel microfluidic tools for protein biophysics. The project is highly interdisciplinary and lies in the areas of biophysics and soft matter physics, as well as chemical biology and biological chemistry.

阿尔茨海默病（AD）和帕金森病（PD）是越来越普遍的，目前无法治愈的神经退行性疾病，与神经系统中蛋白致病性包涵体的积累有关。错误折叠的淀粉样蛋白和α -突触核蛋白的寡聚化是AD和pd相关神经毒性的关键步骤。因此，详细了解这一现象对于找到有效的疾病管理和治疗策略至关重要。然而，尽管人们付出了巨大的努力来理解异常蛋白寡聚化及其下游事件，但寡聚体诱导细胞毒性的机制细节仍然缺失。该项目旨在在单分子水平上表征AD和PD相关的低聚物，达到以前传统生物物理技术无法达到的深度和复杂性水平。该项目的成果将填补与疾病相关的寡聚物形成、进化、多样性、与细胞结合伙伴的相互作用以及重要的神经毒性方面的知识空白。将采用一套微流体技术结合先进的单分子光学检测策略来解决生物物理低聚物表征研究中面临的挑战，即物种的瞬态性，异质性和低丰度。这项工作将与流体分析有限公司密切合作，该公司开发并商业化用于蛋白质生物物理学的新型微流体工具。该项目是高度跨学科的，涉及生物物理学和软物质物理学，以及化学生物学和生物化学领域。