Project 3: Assembly and structures of Abeta peptides.

项目3：Abeta 肽的组装和结构。

• 批准号: 9089801
• 负责人: WILLIAM DEGRADO
• 金额: $ 29.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9089801
• 关键词: Aging; Amides; Amino Acid Sequence; Amino Acids; Amyloid; Amyloid beta-Protein; Arctic Regions; Azides; Brain; Cells; Chemicals; Collaborations; Disease; Environment; Evolution; Fiber; Growth; Human; Hydration status; Hydrogen Bonding; In Vitro; Individual; Kinetics; Methods; Molecular Conformation; Molecular Structure; Monitor; Morphology; Mus; Mutation; Nerve Degeneration; Neurons; Nitriles; Pathology; Patients; Pattern; Peptides; Population; PrP; Presenile Alzheimer Dementia; Prions; Process; Reporting; Research Personnel; Role; Route; Series; Shapes; Spectrum Analysis; Staining method; Stains; Structure; System; Testing; Thioamides; Time; Tissue Sample; Toxic effect; Vertebral column; amyloid formation; crosslink; design; guanidinium; in vitro testing; in vivo; monomer; mutant; novel; particle; peptide A; peptidomimetics; research study; synuclein; tau Proteins; tool

Summary: Project 3 DeGrado An expanding body of evidence argues that besides PrP, A¿, tau and synuclein can become prions and cause neurodegeneration. We seek to understand the assembly of prion precursors into oligomers and fibers, and to correlate the formation of specific conformational forms with toxicity and transmissibility. The small size of A¿ makes it an attractive molecule to study with respect to conversion into prions that are presumably oligomers. We propose to determine the steps required for A¿ to acquire a self-propagating conformation that templates the assembly of additional monomers into oligomers and possibly fibers. The molecular structures of the key intermediates in this process are poorly understood, and it is not known whether the transmissible particle has the parallel cross-beta structure seen in fibers. While it is generally accepted that A¿ oligomers rather than fibers represent the toxic species, the relationship between toxicity and the size, conformation, and dynamics of the oligomers is unknown. We will develop new chemical tools to probe and dissect the steps of aggregation and amyloid formation. We will develop novel chemical strategies to rapidly trigger A¿ association and follow the evolution of its conformation over time. We also will design peptide mimetics and foldamers that enhance or inhibit assembly by stabilizing specific intermediates, allowing one to obtain better defined populations for building correlations between structure, transmissibility and toxicity. Finally, we will develop crosslinking strategies that can be used to obtain a footprint of the conformational ensemble of synthetic versus natural A¿, PrP, and tau at various levels of assembly.

摘要：项目3 Degrado 不断扩大的证据表明，除了PRP，A a，Tau和Synuclein以外，还可以成为病毒 神经变性。我们试图了解将主要前体组装成低聚物和纤维，并 将特定构象形式的形成与毒性和传播相关联。小小 将转化为大概是低聚物的王室进行研究的吸引力分子。 我们建议确定A获取自传播构象所需的步骤 将其他单体组装成低聚物和可能的纤维。钥匙的分子结构 在此过程中的中间体对 在纤维中看到的平行交叉β结构。虽然普遍认为，a的低聚物而不是 纤维代表有毒物种，毒性与大小，构象和动态之间的关系 低聚物的含量是未知的。我们将开发新的化学工具来探测和剖析 聚集和淀粉样蛋白形成。我们将开发新的化学策略来快速触发A域的关联 并遵循其构象的演变。我们还将设计肽模拟物和折叠剂 通过稳定特定的中间体来增强或抑制组装，从而获得更好的定义 结构，传播和毒性之间建筑相关性的种群。最后，我们将发展 交联策略可用于获得合成构象合奏的足迹 在各个级别的组装中，与天然a。，prp和tau。