AB MONOMER STRUCTURE AND ASSEMBLY

AB 单体结构和组装

• 批准号: 7469482
• 负责人: Michael Thomas Bowers
• 金额: $ 28.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 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/7469482
• 关键词: AP40; Accounting; Affect; Alzheimer' s Disease; Amino Acid Substitution; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyotrophic Lateral Sclerosis; Arts; Binding; Brain; C-terminal; Cerebrospinal Fluid; Condition; Coupled; Dissociation; Electrostatics; Excision; Family; Human; Hydrophobic Interactions; Isoleucine; Isomerism; Lactams; Length; Mass Spectrum Analysis; Measurement; Measures; Methods; Minor; Modeling; Modification; Molecular; Parkinson Disease; Peptides; Plasma; Play; Positioning Attribute; Process; Proteins; Relative (related person); Research; Role; Sampling; Senile Plaques; Side; Sodium Chloride; Solutions; Spectrometry; Staging; Structure; Tail; Temperature; Time; Work; abeta oligomer; aspartyllysine; base; carbene; familial Alzheimer disease; interest; ion mobility; molecular dynamics; monomer; nervous system disorder; neurotoxic; neurotoxicity; oxidation; secretase; size; therapeutic target

The objective of this research is to understand, on a molecular level, the folding and assembly of Abeta-protein alloforms. Recent results indicate small, soluble oligomers of Abeta are responsible for initiating a pathological cascade resulting in Alzheimer's disease (AD). Abeta42 has been shown to be the primary neurotoxic agent even though Abeta40 is nearly 10 times more abundant. Single-point amino-acid substitutions at positions 22 and 23 in Abeta42 account for a variety of familial forms of AD. It is our hypothesis that Abeta monomers and small oligomers are important therapeutic targets and characterization of their structure and mechanisms of folding and assembly are critical research objectives. Here we propose to apply, for the first time, the powerful methods of ion mobility spectrometry coupled with mass spectrometry (IMS-MS) to the problem of Abeta folding and assembly. These methods provide accurate measures of monomer and oligomer cross sections and oligomer-size distributions. When coupled with high-level molecular dynamics modeling, monomeric structure with atomic detail is obtained. The method is ultrasensitive, routinely working with picomoles of sample or less. These methods can be readily extended to other neurological diseases like ALS and Parkinson's disease that share the misfolding/aggregation motif with AD. The specific aims of this research are (1) to structurally characterize Abeta monomers and to determine how these structures change with single-amino-acid substitution, oxidation or other simple sequence modification, (2) to structurally characterize Abeta monomer fragments and determine how these structures change with sequence length, single-amino-acid substitutions or other modifications, and (3) to measure oligomer-size distributions and oligomer structures for the early stages of assembly in Abeta and modified forms of Abeta40 and Abeta42.

这项研究的目的是在分子水平上了解abeta蛋白的折叠和组装。 同种异体。最近的结果表明，Abeta的小而可溶的寡聚体负责启动一种 导致阿尔茨海默病(AD)的病理性级联反应。Abeta42已经被证明是主要的 神经毒剂，尽管Abeta40的含量几乎是Abeta40的10倍。单点氨基酸取代 Abeta42的第22位和第23位导致了多种家族性阿尔茨海默病。我们的假设是阿贝塔 单体和小低聚物是重要的治疗靶点和表征其结构和 折叠和组装机制是关键的研究目标。在这里，我们建议第一次申请 随着时间的推移，离子迁移率谱与质谱联用(IMS-MS)的强大方法应用于 Abeta折叠和组装的问题。这些方法提供了单体和齐聚物的准确测量 横截面和齐聚物尺寸分布。当与高级分子动力学模型相结合时， 得到了具有原子细节的单体结构。这种方法极其灵敏，经常与 样品的皮摩尔或更少。这些方法可以很容易地扩展到其他神经疾病，如 ALS和帕金森病与AD有共同的错误折叠/聚集基序。 这项研究的具体目的是(1)对Abeta单体进行结构表征，并确定如何 这些结构通过单一氨基酸取代、氧化或其他简单的序列修饰而改变， (2)对Abeta单体片段进行结构表征，并确定这些结构如何随 序列长度、单一氨基酸取代或其他修饰，以及(3)测量齐聚物大小 Abeta40和Abeta40和Abeta40修饰形式组装早期的分布和寡聚体结构 阿贝塔42岁。