Regulation of developmental signaling pathways by glycosylation and deglycosylation

通过糖基化和去糖基化调节发育信号通路

• 批准号: 10624496
• 负责人: Hamed Jafar-Nejad
• 金额: $ 34.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10624496
• 关键词: Adult; Affect; Animals; Area; Bone Morphogenetic Proteins; Carbohydrates; Cell Surface Proteins; Development; Disease; Drosophila genus; Embryonic Development; Enzymes; Functional disorder; Glycobiology; Goals; Human; Impairment; Knowledge; Link; Maintenance; Modification; Molecular; Mus; Muscular Dystrophies; Mutation; Organism; Pathway interactions; Patients; Phenotype; Physiology; Play; Polysaccharides; Protein Glycosylation; Proteins; Regenerative Medicine; Regulation; Research; Research Design; Role; Signal Pathway; Signal Transduction; Structure; Tissues; Work; Xylose; body system; cell type; developmental disease; fly; glycosylation; human disease; insight; interest; notch protein; novel; novel therapeutic intervention; protein complex; receptor; sugar; tool; virtual

The majority of secreted and cell-surface proteins of all cell types studied so far are glycosylated, i.e. decorated with sugar molecules. These carbohydrate modifications play diverse structural and functional roles in organisms, and are involved in proper animal development and physiology. Mutations in various components of the glycosylation machinery have been shown to cause more than 100 human diseases, affecting virtually all organ systems. However, the glycan structures found on animal proteins are complex and heterogeneous, and each form of glycosylation can be found on tens to thousands of proteins. Therefore, it is difficult to understand the molecular mechanisms underlying the phenotypes observed in glycosylation disorders. The long-term goals of our research are to understand how carbohydrate modifications regulate animal development, to use this knowledge to provide insight into the pathophysiology of human glycosylation disorders, and to establish frameworks for novel therapeutic approaches in diseases caused or impacted by mutations affecting protein glycosylation. Our primary area of interest is the intersection between glycobiology and developmental signaling pathways, which are a small number of evolutionarily conserved, intercellular signaling mechanisms broadly used during embryonic development and adult maintenance of animals. One major focus of our research is on O-linked glycans attached to Notch proteins, which constitute the receptors for one of the most important developmental signaling pathways in animals. We have previously characterized the role of the enzymes involved in the addition of xylose-glycose-O glycans in the regulation of Drosophila development and Notch signaling. We have also studied the role of the first enzyme in this pathway (POGLUT1) in mice, and have linked POGLUT1 to two human diseases, a developmental disorder and a muscular dystrophy. In the current application, we propose to characterize the role of the enzymes downstream of POGLUT1 in mammalian development and Notch signaling. Moreover, we have found that an enzyme involved in removing N-linked glycans from proteins regulates another major signaling pathway (the bone morphogenetic protein or BMP pathway) in flies in a tissue-specific manner. Mutations in this enzyme (NGLY1) cause a multi-system developmental disorder in human patients, but the pathophysiology of the disease is not known. We propose to determine the molecular mechanisms underlying the regulation of the BMP pathway by NGLY1 in flies, and to determine which aspects of mammalian BMP signaling are regulated by this enzyme. In addition to providing insight into the roles of glycosylation in the regulation of major signaling pathways, these projects have the potential to establish novel tools to alter the activity of Notch and BMP signaling in disease contexts and in regenerative medicine.

到目前为止研究的所有细胞类型的大多数分泌和细胞表面蛋白都是糖基化的，即 用糖分子装饰。这些碳水化合物的修饰起着多样的结构和功能作用 在生物体中，参与适当的动物发育和生理学。各种突变 糖基化机制的成分已显示出100多种人类疾病， 几乎影响所有器官系统。但是，动物蛋白上发现的聚糖结构是复杂的，并且 在数十至数千种蛋白质上可以发现异质，并且每种形式的糖基化。因此，是 难以理解糖基化中观察到的表型的分子机制 疾病。我们研究的长期目标是了解碳水化合物修饰如何调节 动物发展，利用这些知识来洞悉人糖基化的病理生理学 疾病，并为造成或影响的疾病中新型治疗方法建立框架 影响蛋白质糖基化的突变。我们感兴趣的主要领域是糖生物学之间的交集 和发育信号通路，这是少数进化保守的细胞间 信号传导机制在胚胎发育和成人维持动物过程中广泛使用。一 我们研究的主要重点是构成受体的Notch蛋白的O连锁聚糖 对于动物中最重要的发育信号通路之一。我们以前已经表征了 酶在添加木糖 - 糖糖-O聚糖中所涉及的作用在果蝇调节中的作用 开发和缺口信号传导。我们还研究了第一种酶在该途径中的作用 （Poglut1）在小鼠中，并将Poglut1与两种人类疾病联系起来，一个发育障碍和一个 肌肉营养不良。在当前应用中，我们建议表征酶的作用 poglut1的下游在哺乳动物发育和缺口信号传导中。而且，我们发现 参与从蛋白质中去除N连接的聚糖的酶调节另一个主要信号通路（该途径 骨形态发生蛋白或BMP途径）以组织特异性方式以果蝇为单位。该酶突变 （ngly1）在人类患者中引起多系统发育障碍，但是 疾病尚不清楚。我们建议确定调节调节的分子机制 NGLY1在苍蝇中通过BMP途径，并确定调节哺乳动物BMP信号的哪些方面 通过这种酶。除了洞悉糖基化在主要信号传导调节中的作用 途径，这些项目有可能建立新的工具来改变Notch和BMP的活动 在疾病环境和再生医学中的信号传导。