Polymorphism of ATTR amyloid fibrils from human tissue

人体组织 ATTR 淀粉样原纤维的多态性

• 批准号: 447874287
• 负责人: Professor Dr. Marcus Fändrich
• 金额: --
• 依托单位: Institut für Proteinbiochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/447874287?language=en
• 关键词: Polymorphism; ATTR; amyloid; fibrils; human

Systemic ATTR amyloidosis is a rare but serious disease that relies on the formation of pathogenic aggregates and amyloid fibrils in different organs. ATTR amyloid fibrils result from misfolding of the blood protein transthyretin or fragments thereof, with transthyretin assuming not its native tetrameric structure but an abnormal, pathogenic conformation. For the exact mechanistic understanding of this fundamental biochemical process and the possible design of specific ligands, the exact understanding of the pathogenic structure is essential. In this translational project, ATTR amyloid fibrils are extracted from patient tissue and their structure analyzed by cryo-electron microscopy. Cryo-electron microscopy is uniquely suited for the study of protein structures in biopsy material as it does not require isotope labels or crystals. In particular, the project aims to decipher the molecular basis of the development of various disease variants of ATTR amyloidosis and thus to create conditions for a better understanding of the pathogenic misfolding mechanism.

系统性ATTR淀粉样变性是一种罕见但严重的疾病，其依赖于不同器官中致病性聚集体和淀粉样纤维的形成。ATTR淀粉样蛋白原纤维由血液蛋白甲状腺素运载蛋白或其片段的错误折叠产生，甲状腺素运载蛋白呈现的不是其天然的四聚体结构，而是异常的致病构象。为了准确地理解这一基本的生化过程和可能的特定配体的设计，对致病结构的准确理解是必不可少的。在这个翻译项目中，从患者组织中提取ATTR淀粉样纤维，并通过冷冻电子显微镜分析其结构。冷冻电子显微镜是唯一适合于活检材料中的蛋白质结构的研究，因为它不需要同位素标记或晶体。特别是，该项目旨在破译ATTR淀粉样变性各种疾病变体发展的分子基础，从而为更好地理解致病性错误折叠机制创造条件。