The molecular basis and functional consequences of IgG subclass glycosylation

IgG亚类糖基化的分子基础和功能后果

• 批准号: 395696317
• 负责人: Professor Dr. Falk Nimmerjahn
• 金额: --
• 依托单位: Lehrstuhl für Genetik - AG Falk Nimmerjahn
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/395696317?language=en
• 关键词: molecular; basis; functional; consequences; IgG

Carbohydrates (glycans) linked to proteins play essential roles in many aspects of life. However, their precise impacts on glycoprotein function and underlying molecular mechanisms are poorly understood, mainly due to their enormous structural variability and complexity. These features render the prediction of structure-function relationships of glycans a conceptually challenging task for which satisfying solutions have not yet been determined. Various international organizations (e.g. Euroglycoscience Forum, US National Research Council) independently recommend that substantial efforts have to be undertaken to improve our understanding of protein-carbohydrate interactions. An important prerequisite for this objective is the ability to control glycan biosynthesis. Thus glycoengineering of cells and expression hosts to achieve tight control of glycoprotein production are paramount for current and future investigations. An additional challenge in understanding the functional consequences of differential protein glycosylation especially for the human system is the fact that only a very limited number of model systems are available, allowing to place immunological/medical data within the framework of glycoscience, and vice versa. Indeed, integration of complementary scientific disciplines is mandatory to fully exploit the unique properties of protein linked glycans, and to evaluate their potential for future therapeutic approaches. By integrating the unique expertise of the group of Prof. Steinkellner in Vienna and Prof. Nimmerjahn in Erlangen, this research proposal tries to overcome these challenges. We will focus on human antibodies, which are highly variable glycoproteins and are an essential part of the immune system. By using a plant protein production system highly defined glycovariants of all human IgG subclasses will be generated which will also allow to obtain basic insights into the pathways of protein glycosylation. In addition, in vitro and novel humanized mouse model systems will be used to identify glycosylation dependent alterations in antibody activity in vivo.

与蛋白质相连的碳水化合物（聚糖）在生活的许多方面发挥着重要作用。然而，人们对它们对糖蛋白功能和潜在分子机制的精确影响知之甚少，这主要是由于它们巨大的结构变异性和复杂性。这些特征使得聚糖的结构-功能关系的预测成为一项概念上具有挑战性的任务，目前尚未确定令人满意的解决方案。各个国际组织（例如欧洲糖科学论坛、美国国家研究委员会）独立建议必须做出大量努力来提高我们对蛋白质-碳水化合物相互作用的理解。这一目标的一个重要先决条件是控制聚糖生物合成的能力。因此，对细胞和表达宿主进行糖工程以实现对糖蛋白生产的严格控制对于当前和未来的研究至关重要。了解差异蛋白糖基化的功能后果（特别是对于人类系统）的另一个挑战是，只有非常有限数量的模型系统可用，允许将免疫学/医学数据置于糖科学的框架内，反之亦然。事实上，为了充分利用蛋白质连接聚糖的独特特性，并评估其未来治疗方法的潜力，必须整合互补的科学学科。通过整合维也纳 Steinkellner 教授和埃尔兰根 Nimmerjahn 教授团队的独特专业知识，本研究计划试图克服这些挑战。我们将重点关注人类抗体，它们是高度可变的糖蛋白，是免疫系统的重要组成部分。通过使用植物蛋白生产系统，将生成所有人类 IgG 亚类的高度明确的糖变体，这也将允许获得对蛋白质糖基化途径的基本了解。此外，体外和新型人源化小鼠模型系统将用于识别体内抗体活性的糖基化依赖性改变。