多尺度微纳米手性界面Aβ聚集及纤维化调控机制研究

Amyloid-β (Aβ) degeneration is a significant hypothesis in the pathogenesis of Alzheimer’s disease (AD). It is particularly important to clarify the regulatory mechanism of physical and chemical properties of biological membranes on Aβ misfolding and fibrillation. In our previous work, we have investigated the chiral effect and the size effect of surface on the process of Aβ amyloidosis, and found that both two factors have strong influence on the process of Aβ aggregation and fibrillation. However, the above studies are still in their infancy. The mechanism of interaction between surface molecules and Aβ, the synergistic effects between chiral and size, and the cooperation of them together with other aspects such as hydrophilicity and surface charge in the conformational transition, aggregation and fibrillation of Aβ are still problems needed for further research. Base on the previous work, we intends to construct a series of multi-scale micro/nano chiral interface to further reveal the mechanism of synergistic effects between chiral and size, and the cooperation of all aspects on influencing the Aβ conformational transition, aggregation and fibrillation. Combined with cell experiments, we will work with professional biological and medical research groups to explore its application in the treatment of AD.

Aβ淀粉样变性是阿兹海默病(AD)发病机制的重要假说。阐明生物膜等分子界面的物化性质对Aβ错误折叠及纤维化的调控机制，对AD治疗及新药的研发具有重要指导意义。申请人前期研究发现生物膜的两个基本物化特性——手性和多尺度是影响Aβ纤维化动力学和聚集态的关键因素。但上述研究目前仍处于初级阶段，其相关机制及二者如何协同，如何与其它因素（如亲疏水性、表面电荷等）共同影响Aβ构象转变、聚集态及纤维化动力学尚不清楚。在前期工作基础上，本项目拟进一步构建多尺度微纳米手性界面来深入探讨生物膜的手性与多尺度及其它因素如亲疏水性、表面电荷等对Aβ构象转变、聚集及纤维化动力学的协同调控机制，并结合细胞实验与专业的生物和医学课题组合作初步探讨其在AD药物研发中的应用。

Aβ淀粉样变性是阿兹海默病(AD)发病机制的重要假说。阐明生物膜等分子界面的物化性质对Aβ错误折叠及纤维化的调控机制，对AD治疗及新药的研发具有重要指导意义。申请人前期研究发现生物膜的两个基本物化特性——手性和曲率尺寸是影响Aβ纤维化动力学和聚集态的关键因素。但上述研究目前仍处于初级阶段，其相关机制及二者如何协同，如何与其它因素（如亲疏水性、表面电荷等）共同影响Aβ构象转变、聚集态及纤维化动力学尚不清楚。在前期工作基础上，本项目进一步将分子手性、界面电荷及亲疏水性分别引入到微纳米结构表面，构筑一系列带有不同手性分子、不同电荷及亲疏水性的纳米生物界面，利用微纳米粒子的尺寸效应与曲率效应来研究分子手性在不同尺度的带有不同电荷及亲疏水性的微纳米界面上对Aβ构象转变、聚集与纤维化的影响，先后发现了纳米材料调控蛋白纤维化的界面手性效应、界面电荷效应及界面分子异构效应，并深入探索分子手性与界面尺度、配体疏水链长与界面电荷协同作用于Aβ构象转变、聚集与纤维化的分子机制，最后通过探索不同手性纳米粒子对Aβ诱导AD细胞模型中Aβ聚集损伤细胞存活率的影响，筛选出了能够阻止Aβ聚集损伤细胞的材料，为开发手性纳米材料用于AD治疗提供了基础支撑数据。