Mechanism and structural basis of amyloid fibril formation by serum amyloid A

血清淀粉样蛋白A形成淀粉样蛋白原纤维的机制和结构基础

• 批准号: 7213180
• 负责人: WILFREDO COLON
• 金额: $ 23.29万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7213180
• 关键词: Abbreviations; Acids; Acute; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloid deposition; Amyloidosis; Arterial Fatty Streak; Atomic Force Microscopy; Binding; Binding Sites; Biochemical; Brain; Calcium; Calcium Binding; Cell Line; Cells; Cholesterol Homeostasis; Chronic; Circular Dichroism; Condition; Deposition; Disease; Family; Foundations; Glutaral; Goals; High Density Lipoproteins; High Pressure Liquid Chromatography; In Vitro; Individual; Inflammation; Inflammation Process; Inflammatory; Inflammatory Response; Kidney; Kinetics; Ligand Binding; Ligands; Light; Link; Lipids; Liver; Mass Spectrum Analysis; Metals; Methods; Modeling; Molecular; Molecular Profiling; Molecular Sieve Chromatography; Mouse Strains; Mus; Normal tissue morphology; Numbers; Organ; Patients; Phase; Plasma; Play; Positioning Attribute; Preventive; Process; Property; Protein Family; Protein Isoforms; Proteins; Rabies; Rate; Reaction; Research; Research Personnel; Resistance; Role; Serum amyloid A protein; Solutions; Spleen; Structure; Temperature; Testing; Therapeutic; Thioflavin T; Time; Tissues; Transmission Electron Microscopy; Zinc; Zinc deficiency; amyloid fibril formation; amyloid formation; analytical ultracentrifugation; base; crosslink; design; in vivo; light scattering; macrophage; monocyte; monomer; programs; sedimentation velocity; self assembly

DESCRIPTION (provided by applicant): Serum amyloid A (SAA) belongs to a highly conserved family of small proteins that appear to play a central role in cholesterol metabolism and the inflammatory response. SAA is mainly synthesized by the liver and secreted to the plasma where it binds to high density lipoprotein (HDL), but it is also expressed in normal and diseased tissue, including atherosclerotic plaques and the brains of patients with Alzheimer's disease. During chronic inflammation the concentration of SAA can increase up to 1000 fold, and sometimes form amyloid fibril deposits in major organs, leading to the usually fatal disease of amyloid A (AA) amyloidosis. There is no cure for AA amyloidosis, which is currently one of the most common systemic amyloid diseases worldwide. In mouse, AA amyloidosis can be induced by causing an inflammatory response. Nevertheless, a particular mouse strain (CE/J) contains a single isoform of SAA (SAA2.2) that is resistant to amyloid deposition in vivo during chronic inflammation, despite being 94% identical to the amyloidogenic SAA1.1 isoform. The goal of the proposed research is to study the amyloid formation mechanism of the mouse isoform SAA2.2 and the highly amyloidogenic mouse isoform SAA1.1 to understand the structural, biochemical, and biophysical basis for their different propensities for amyloid formation. Using various, analytical, biophysical, and biochemical methods, the aims of this application are to investigate (Aim 1) the mechanism of SAA2.2 and SAA1.1 amyloid formation, (Aim 2) the role of zinc, calcium, and HDL on the structure, stability and amyloid formation of SAA2.2 and SAA1.1, and (Aim 3) the structural basis for the high in vivo amyloidogenicity of SAA1.1. The long-term goal is to understand the structure, ligand-binding properties, and the molecular basis for the amyloidogenicity of SAA to allow the design of effective preventive or therapeutic approaches against AA amyloidosis. Considering the wide expression profile of SAA in normal and diseased tissue, and its large number of putative functions, it appears that SAA may not just be a marker for inflammation, but rather, may play an active role in the process of many inflammation- related diseases. Therefore, a better understanding of the biochemical and biophysical properties of SAA, as will result from the proposed studies, may shed some light towards understanding how it participates in the process of inflammation.

描述（由申请人提供）：血清淀粉样蛋白A（SAA）属于一个高度保守的小蛋白家族，在胆固醇代谢和炎症反应中似乎起着核心作用。 SAA主要由肝脏合成，并分泌到血浆中与高密度脂蛋白（HDL）结合的血浆，但在正常组织和患病的组织中也表达，包括动脉粥样硬化斑块和阿尔茨海默氏病的患者的大脑。在慢性炎症期间，SAA的浓度可以增加1000倍，有时会在主要器官中形成淀粉样蛋白原纤维沉积物，从而导致通常致命的淀粉样蛋白A（AA）淀粉样变性。无法治愈AA淀粉样变性，这是目前在全球最常见的系统性淀粉样蛋白疾病之一。在小鼠中，可以通过引起炎症反应来诱导AA淀粉样变性。然而，尽管在慢性炎症期间，特定的小鼠菌株（CE/J）含有单一的SAA（SAA2.2）同工型（SAA2.2），该同工型在体内具有抗淀粉样蛋白沉积，尽管与淀粉样蛋白基因生成的SAAA1.1同工相同。拟议的研究的目的是研究小鼠同工型SAA2.2和高度淀粉样蛋白生成小鼠同工型SAAA1.1的淀粉样蛋白形成机制，以了解其对淀粉样蛋白形成的不同支持的结构，生化和生物物理基础。使用各种，分析性，生物物理和生化方法，本应用的目的是研究（AIM 1）SAA2.2和SAA1.1淀粉样蛋白形成的机理，（AIM 2）锌，钙和HDL对SAA2.2和SAA1.1的结构，稳定性和淀粉样蛋白形成，以及（目标3）SAA1.1的体内淀粉样蛋白生成高的结构基础。长期的目标是了解SAA的淀粉样蛋白生成性的结构，配体结合特性以及分子基础，以设计有效的预防或治疗方法针对AA淀粉样变性。考虑到正常组织和患病组织中SAA的广泛表达谱，其假定功能大量，SAA似乎不仅是炎症的标记，而且可能在许多相关的炎症过程中起积极作用疾病。因此，正如拟议的研究所致，对SAA的生化和生物物理特性的更好理解可能会为了解其参与炎症过程的方式带来一些启发。