Photo-initiated Disassembly of Fibrils: Application to Amyloids and Hydrogels

原纤维的光引发分解：在淀粉样蛋白和水凝胶中的应用

• 批准号: 8717043
• 负责人: Beatrice Nicole Markiewicz
• 金额: $ 3.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8717043
• 关键词: Adopted; Affect; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid Fibrils; Architecture; Attention; Biological; Biological Models; Characteristics; Charge; Deposition; Disease; Dissociation; Effectiveness; Environment; Gel; Generations; Health; Higher Order Chromatin Structure; Human; Hydrogels; Hydrophobic Interactions; Investigation; Length; Light; Link; Literature; Lysine; Mechanics; Methodology; Methods; Molecular Conformation; Morphology; Motivation; Mutate; Mutation; Nature; Non-Insulin-Dependent Diabetes Mellitus; Parkinson Disease; Peptides; Pharmaceutical Preparations; Phase; Play; Positioning Attribute; Process; Property; Proteins; Regenerative Medicine; Side; Stimulus; Structure; Surface; System; Techniques; Testing; Therapeutic; Therapeutic Human Experimentation; Time; Tissue Engineering; Work; amylin (22-27); amyloid formation; base; biological research; biomaterial compatibility; design; innovation; interest; interfacial; irradiation; islet amyloid polypeptide; lysine analog; monomer; mutant; nanomaterials; novel; polypeptide; protein misfolding; research study; scaffold; self assembly; small molecule; stem

DESCRIPTION (provided by applicant): Protein self-assembly, the spontaneous organization of monomers into highly ordered structures, has become a significant aspect of biological research. A large portion is dedicated to understanding the self-assembly of insoluble amyloid deposits from misfolded proteins, which has been linked to incurable diseases, such as Alzheimer's, Parkinson's, and Type II Diabetes. At the same time, the investigation of protein/peptide self-assembly is also active in the design of biological architectures and scaffolds, such as peptide hydrogels, that have many new applications, ranging from regenerative medicine to the delivery of therapeutics. What is more interesting is that such protein/peptide assemblies, e.g. amyloids and hydrogels, share structural similarities, such as formation of highly ordered fibrils with cross β-sheet arrangements. Studies have shown that self-assembly is regulated by hydrophobic side chain interactions causing the assembly of a distinct hydrophobic core or cluster, which stabilize β-sheet arrangements. This proposal is founded on the idea that by introducing into the fibril interior a moiety which can produce a light activated charge, we can significantly weaken the hydrophobic interactions crucial to the assembly of aggregates, fibrils, or hydrogel matrices, and potentially disrupt these well-defined structures. This proposal will test this premise by using a photolabile lysine analog, dimethoxy-2-nitrobenzyloxycarbonyl (Lys(nvoc)), which is hydrophobic but yields a charged lysine upon photocleavage, to photo-trigger the dissociation of amyloids and other fibril forming peptide hydrogels. Introducing Lys(nvoc) in the place of other hydrophobic residues is expected to conserve the aggregation propensity prior to irradiation due to the aromatic nature of the photocage, while photocleavage will produce a charge at these positions to induce disassembly of fibrils. The results of these experiments will provide a novel way to manipulate the conformations of otherwise irreversible structures, potentially providing innovative and novel biological applications within amyloid related therapeutic research and/or the rational design of functional bionanomaterials.

描述（由适用提供）：蛋白质自组装，单体的赞助组织为高度有序的结构，已成为生物学研究的重要方面。很大一部分致力于了解错误折叠蛋白的不溶性淀粉样蛋白沉积物的自组装，该蛋白质与无法治愈的疾病有关，例如阿尔茨海默氏症，帕金森氏症和II型糖尿病。同时，蛋白质/肽自组装的投资在生物结构和脚手架的设计中也很活跃，例如肽水凝胶，这些肽水凝胶具有许多新的应用，从再生医学到治疗的提供。更有趣的是，这种蛋白质/肽组件，例如淀粉样蛋白和水凝胶具有结构相似性，例如形成具有横β-折叠布置的高度有序的原纤维。研究表明，自组装受疏水侧链相互作用的调节，导致组装不同的疏水核或簇，从而稳定β-折叠布置。该提议建立在这样的想法上，即通过将其引入原纤维内部一个可以产生光线的部分 激活的电荷，我们可以显着削弱对聚集体，原纤维或水凝胶材料的组装至关重要的疏水相互作用，并可能破坏这些定义明确的结构。该提案将通过使用光片赖氨酸类似物，Dimethoxy-2-硝基苯甲酰氧甲苯二醇（LYS（LYS（NVOC）））测试这一前提，该氧甲苯二甲氧甲苯甲苯甲酸（LYS（NVOC））是疏水性的，但在光方面产生了带电的赖氨酸，从而在光触发淀粉样蛋白和其他纤维纤维形式和其他纤维薄膜上触发了光触发。由于光结构的芳香性质，预计引入LYS（NVOC）代替其他疏水性保留率会保留辐照前的聚合承诺，而光电裂解将在这些位置产生电荷以诱导原纤维溶解。这些实验的结果将为操纵其他不可逆结构的构象提供一种新颖的方法，从而有可能在淀粉样蛋白相关的治疗研究和/或功能性生物植物材料的合理设计中提供创新和新颖的生物学应用。