GNE myopathy – Why is only muscle affected?

GNE 肌病 â 为什么只有肌肉受到影响？

• 批准号: 432537376
• 负责人: Dr. Sarah Konze
• 金额: --
• 依托单位: Research group Glycosylation Disorders in Neurology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/432537376?language=en
• 关键词: GNE; myopathy; Why; only; muscle

GNE myopathy is an inheritable disease caused by a dysfunction of the first enzyme in the sialic acid pathway. Sialic acids are the key sugars that terminate glycosylation of proteins and lipids and are therefore crucial for cellular interactions. Disruptions in the sialic acid pathway have been associated with common diseases such as cancer and with genetic defects causing neurological phenotypes. As sialic acid synthesis is ubiquitous, it remains unsolved why only the muscle is affected in GNE myopathy. To tackle this issue, I will combine my expertise in human induced pluripotent stem cells (hiPSC) with recent findings of the host group on a crucial role of the intermediate product of the sialic acid pathway, N-acetylmannosamine (ManNAc). In the proposed project I aim to investigate the molecular reason for the exclusively muscular phenotype of GNE myopathy and the peculiarity of ManNAc metabolism by addressing three Key Objectives: 1) Generation and functional characterisation of hiPSC-derived heart and skeletal muscle models from patients with GNE myopathy; 2) Glycoproteomic and metabolomic analysis of the GNE deficient heart and skeletal muscle models and 3) Metabolic repair of the biochemical and functional consequences of GNE deficiency .With this study I expect to elucidate the role of ManNAc and its putatively muscle-specific metabolism, which will aid diagnostics and therapeutic intervention in GNE myopathy. By finding an explanation for the tissue-specific mechanisms of sialic acid production, I furthermore aim to identify novel targets to correct disrupted sialic acid metabolism in other diseases.

GNE 肌病是一种遗传性疾病，由唾液酸途径中第一种酶的功能障碍引起。唾液酸是终止蛋白质和脂质糖基化的关键糖，因此对于细胞相互作用至关重要。唾液酸途径的破坏与癌症等常见疾病以及导致神经表型的遗传缺陷有关。由于唾液酸合成无处不在，因此为什么只有肌肉在 GNE 肌病中受到影响仍是未解之谜。为了解决这个问题，我将把我在人类诱导多能干细胞 (hiPSC) 方面的专业知识与宿主小组关于唾液酸途径中间产物 N-乙酰甘露糖胺 (ManNAc) 的关键作用的最新发现结合起来。在拟议的项目中，我的目标是通过解决三个关键目标来研究 GNE 肌病独特的肌肉表型的分子原因和 ManNAc 代谢的特殊性：1） GNE 肌病患者的 hiPSC 衍生心脏和骨骼肌模型的生成和功能表征； 2) GNE 缺乏的心脏和骨骼肌模型的糖蛋白组学和代谢组学分析，以及 3) GNE 缺乏的生化和功能后果的代谢修复。通过这项研究，我希望阐明 ManNAc 的作用及其假定的肌肉特异性代谢，这将有助于 GNE 肌病的诊断和治疗干预。通过寻找唾液酸产生的组织特异性机制的解释，我的目标还在于确定新的靶点来纠正其他疾病中受损的唾液酸代谢。