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（由申请人提供）：蛋白质自组装，即单体自发组织成高度有序的结构，已成为生物学研究的一个重要方面。其中很大一部分致力于了解不溶性淀粉样蛋白沉积物的自组装，这些沉积物来自错误折叠的蛋白质，这与无法治愈的疾病有关，如阿尔茨海默氏症、帕金森病和II型糖尿病。与此同时，蛋白质/肽自组装的研究也活跃于生物结构和支架的设计，如肽水凝胶，有许多新的应用，从再生医学到治疗药物的输送。更有趣的是，这些蛋白质/肽组合，如淀粉样蛋白和水凝胶，具有结构上的相似性，例如形成具有交叉β片排列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，导致独特的疏水核或簇的组装，从而稳定β-片的排列。这个建议是建立在这样一个想法上的，即通过向纤维内部引入一个可以产生光的部分