UNS: Design of Self-Assembling Peptides and their Conjugates as Amyloid Inhibitors

建议编号：1510099随着人口老龄化，阿尔茨海默氏症(AD)和其他与年龄相关的神经退行性疾病将继续影响更多的人的生活，没有治愈的方法。淀粉样β蛋白(Abeta)多肽的聚集被认为是阿尔茨海默病(AD)中神经细胞功能障碍和丢失的原因之一，因此抑制Abeta聚集对AD新疗法的开发具有重要意义。然而，现有的抑制剂效力不足以作为有效的治疗方法。本项目旨在开发一种新型的多肽-纳米颗粒抑制剂，具有更好的生物相容性、酶抗性和抗Abeta聚集和毒性的递送特性。本研究的目标是(I)开发一类新型的β-折叠自组装肽(SAP)和SAP-纳米颗粒结合物作为淀粉样β蛋白(Abeta)抑制剂，具有更好的抑制能力、酶降解和血脑屏障(BBB)通透性；以及(Ii)建立实用的设计原则，能够一致地解释SAP衍生物和Abeta肽之间的功能相互作用对淀粉样蛋白聚集、毒性和抑制的序列/结构依赖性。为了实现这些目标，将首先开发从头开始的计算辅助设计工具来从大量的肽库中筛选和识别SAP，然后通过实验确定SAP在Abeta抑制和Abeta诱导的细胞毒性中的作用。然后，将开发SAP-纳米颗粒结合物，通过相互控制纳米颗粒和结合多肽的界面性质来解决SAP的毒性、降解性和BBB渗透问题。最后，将开发一个多尺度计算平台来整合实验和计算数据，以建立SAP聚集性、膜通透性和细胞毒性之间的序列/结构依赖关系，最终帮助确定一套序列和结构属性可调的SAP衍生抑制剂的迭代设计规则。这些多肽抑制剂可能对其他神经退行性疾病有潜在的用途，多肽材料也可以代表新的基于蛋白质的自组装纳米/生物材料，用于其他生物医学应用。该项目的跨学科性质提供了一个独特的机会来培训和教育所有水平的学生学习结构生物学、生物信息学和工程设计的概念和工具。将通过本科生/研究生课程、影响较大的期刊、会议报告、暑期讲习班/实习和其他外联活动来传播从该提案中获得的知识。

PI: Zheng, Jie Proposal Number: 1510099With the aging population, Alzheimer's (AD) and other age-related neurodegenerative diseases will continue to impact more lives with no cure available. Aggregation of amyloid-beta (Abeta) peptides is thought to contribute to dysfunction and loss of nerve cells in AD, so inhibition of Abeta aggregation holds considerable promise for the development of new therapies for AD. However, the existing inhibitors are not potent enough to be used as effective treatments. This project aims to develop a new class of peptide-nanoparticle inhibitors of improved biocompatibility, enzymatic resistance, and delivery properties against Abeta aggregation and toxicity. The objectives of this research are to (i) develop a new class of beta-sheet-forming self-assembling peptides (SAPs) and SAP-nanoparticle conjugates as amyloid-beta (Abeta) inhibitors with improved inhibitory ability, enzymatic degradation, and blood-brain barrier (BBB) permeability; and (ii) establish practical design principles that can consistently explain the sequence/structural dependence of functional interactions between SAP derivatives and Abeta peptides on amyloid aggregation, toxicity, and inhibition. To achieve these goals, de novo computation-aided design tools will be first developed to screen and identify SAPs from a large pool of peptide library, followed by experimental determination of the role of SAPs in Abeta inhibition and Abeta-induced cell toxicity. Then, SAP-nanoparticle conjugates will be developed to solve the issues of toxicity, degradation, and BBB permeation of SAPs by mutually controlling interfacial properties of both nanoparticles and conjugated peptides. Finally, a multiscale computational platform will be developed to integrate experimental and computational data to establish the sequence/structure-dependent relationship among aggregation property, membrane permeability, and cell toxicity of SAPs, and finally help to determine a set of rules for iterative design of SAP-derived inhibitors with tunable sequence and structural properties. The peptide inhibitors could be potentially useful for other neurodegenerative diseases, and peptide materials can also represent new protein-based self-assembled nano-/bio-materials for other biomedical applications. The interdisciplinary nature of the project provides a unique opportunity to train and educate all-level students to learn the concepts and tools in structural biology, bioinformatics, and engineering design. The knowledge derived from the proposal will be disseminated through undergraduate/graduate courses, high-impact journals, conference presentations, summer workshops/internships, and other outreach activities.