Mimicry of Amyloid Oligomers

淀粉样蛋白寡聚物的模拟

• 批准号: 8239411
• 负责人: JAMES S NOWICK
• 金额: $ 27.7万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239411
• 关键词: Adopted; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Antibodies; Area; Basic Science; Behavior; Biochemical; Biological; Biological Models; Biophysics; Cells; Chemical Models; Creutzfeldt-Jakob Syndrome; Dendritic Spines; Development; Disease; Elements; Goals; Huntington Disease; Hydrogen Bonding; Hydrophobic Interactions; Inherited; Knowledge; Laboratories; Lead; Long-Term Depression; Long-Term Potentiation; Methodology; Modeling; Mus; NMR Spectroscopy; Neurobiology; Neurodegenerative Disorders; Neurons; Peptides; Prion Diseases; Prions; Process; Property; Proteins; Rattus; Research; Slice; Sorting - Cell Movement; Structure; Synapses; Techniques; Testing; X-Ray Crystallography; amyloid structure; beta pleated sheet; crosslink; density; dimer; falls; insight; interest; mimicry; molecular assembly/self assembly; neurotoxic; peptidomimetics; protein aggregate; protein aggregation; protein function; self assembly; tool

DESCRIPTION (provided by applicant): The aggregation of peptides and proteins is central to many devastating neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, and the prion diseases. Although amyloid fibrils have long been viewed as the hallmark of Alzheimer's and other neurodegenerative diseases, the oligomers formed by amyloidogenic peptides have begun to emerge as the more important neurotoxic species involved in Alzheimer's and other neurodegenerative diseases. The fibrils adopt layered beta-sheet structures. Although the structures of the oligomers are only beginning to emerge, they appear to also involve beta-sheet formation and may involve layering and related hydrophobic interactions. The development of robust model systems to mimic the structure of amyloid oligomers offers the promise of not only providing insights into the structures and biological activities of amyloid oligomers, but also providing new tools with which to control peptide and protein interactions involving beta-sheet formation. This project will approach the problem of stabilizing small oligomeric beta-sheets by developing interstrand and intersheet crosslinks tailored to stabilize interactions between beta-sheets. These crosslinks will be developed using macrocyclic beta-sheets developed in the PI's laboratory. The macrocyclic beta-sheets form hydrogen-bonded dimers that further self-assemble through hydrophobic interactions to form sandwich-like structures. Intersheet crosslinks will be developed to stabilize the layered structures and control self-assembly. Intrasheet crosslinks will be developed to achieve parallel beta-sheet structures. Macrocyclic beta-sheets containing these crosslinks will be used to mimic the structure of the amyloid beta-peptide dimer. The structures of the mimics of amyloid oligomers will be evaluated by NMR spectroscopy, X-ray crystallography, and other biophysical techniques. The ability of these molecules and molecular assemblies to mimic amyloid beta-peptide oligomers will be evaluated by using oligomer-specific antibodies and neuronal cells to compare their behavior to natural amyloid beta-peptide oligomers. The effect of promising amyloid oligomer mimics on long-term potentiation, long-term synaptic depression, and dendritic spine density at synapses will be studied in mouse hipocampal slices and rat organotypic slices. PUBLIC HEALTH RELEVANCE: Oligomers of peptides and proteins are involved in many devastating neurodegenerative disorders, including Alzheimer's disease and the prion diseases. This proposal seeks to understand and control oligomer formation through the use of chemical model systems. The knowledge that is gained through these studies may eventually lead to new therapies for these diseases.

描述（由申请人提供）：肽和蛋白质的聚集是许多破坏性神经变性疾病的核心，包括阿尔茨海默病、亨廷顿病和朊病毒病。虽然淀粉样蛋白原纤维长期以来被视为阿尔茨海默氏症和其他神经退行性疾病的标志，但由淀粉样蛋白生成肽形成的寡聚体已经开始作为参与阿尔茨海默氏症和其他神经退行性疾病的更重要的神经毒性物质出现。原纤维采用层状β-片层结构。虽然低聚物的结构才刚刚开始出现，但它们似乎也涉及β-折叠的形成，并可能涉及分层和相关的疏水相互作用。开发强大的模型系统来模拟淀粉样蛋白低聚物的结构，不仅提供了对淀粉样蛋白低聚物的结构和生物活性的了解，而且还提供了控制涉及β-折叠形成的肽和蛋白质相互作用的新工具。本项目将通过开发适合于稳定β-折叠之间相互作用的链间和折叠间交联来解决稳定小寡聚β-折叠的问题。将使用PI实验室开发的大环β-片开发这些交联。大环β-折叠形成氢键二聚体，其通过疏水相互作用进一步自组装以形成类β-结构。将开发层间交联以稳定层状结构并控制自组装。将开发膜内交联以实现平行β-折叠结构。含有这些交联的大环β-折叠将用于模拟淀粉样β-肽二聚体的结构。淀粉样蛋白低聚物的模拟物的结构将通过NMR光谱学、X射线晶体学和其他生物物理技术进行评估。将通过使用寡聚体特异性抗体和神经元细胞来评价这些分子和分子组装体模拟淀粉样β肽寡聚体的能力，以将它们的行为与天然淀粉样β肽寡聚体进行比较。将在小鼠海马切片和大鼠器官型切片中研究有前景的淀粉样蛋白寡聚体模拟物对长时程增强、长时程突触抑制和突触处树突棘密度的影响。 公共卫生相关性：肽和蛋白质的寡聚体参与许多破坏性神经退行性疾病，包括阿尔茨海默病和朊病毒疾病。该建议试图通过使用化学模型系统来理解和控制低聚物的形成。通过这些研究获得的知识可能最终导致这些疾病的新疗法。