Variation of the AL protein primary structure in two clinical variants of AL amyloidosis

AL 淀粉样变性两种临床变体中 AL 蛋白一级结构的变化

• 批准号: 422469078
• 负责人: Dr. Christian Haupt
• 金额: --
• 依托单位: Klinik für Hämatologie, Onkologie und Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/422469078?language=en
• 关键词: Variation; AL; protein; primary; structure

A key limitation of the research into AL amyloidosis arises from the fact that hardly any AL protein is known by its exact primary structure. Crucial features such as on posttranslational modifications and proteolytic cleavage remained therefore obscure. The detail aims will be: (i) to collect tissue, urine and serum from AL patients, (ii) to determine the primary structure of approximately 100 AL proteins, (iii) to analyze the light chains in serum and urine, (iv) to correlate AL protein properties with patient characteristics. Through this work we will test the hypothesis that proteolytic truncation or posttranslational modifications contribute to determining the pathogenicity of a given light chain, the organ tropism of the amyloid and the clinical outcome of the disease. This work will elucidate the natural diversity of AL proteins as an essential first step to reveal common principles in the mechanism of AL protein formation and thus in the etiology of AL amyloidosis in vivo. We will in particular test whether inclusion of these protein structural features improves the prediction of the clinical presentation of the affected patients or whether posttranslational modifications might underlie the development of different patient cohorts.

对AL淀粉样变性研究的一个关键限制来自于几乎没有任何AL蛋白的确切一级结构。因此，翻译后修饰和蛋白水解切割等关键特征仍然不清楚。具体目标为：（i）从AL患者收集组织、尿液和血清，（ii）确定大约100种AL蛋白的一级结构，（iii）分析血清和尿液中的轻链，（iv）将AL蛋白性质与患者特征相关联。通过这项工作，我们将测试的假设，即蛋白水解截断或翻译后修饰有助于确定一个给定的轻链的致病性，器官嗜性的淀粉样蛋白和疾病的临床结果。这项工作将阐明AL蛋白的自然多样性，作为揭示AL蛋白形成机制的共同原则的必要的第一步，从而在体内AL淀粉样变性的病因学。我们将特别测试这些蛋白质结构特征的纳入是否改善了对受影响患者临床表现的预测，或者翻译后修饰是否可能是不同患者队列发展的基础。