Negative regulation of Jagged1 by glycosylation: towards a mechanism-based therapy for Alagille syndrome

摘要 Noch信号是一种细胞间的通讯机制，对胚胎发育和 成年动态平衡。为了在细胞之间传递信息，给定细胞上的Notch受体需要 被相邻细胞的配体激活。Notch途径的一种配体与BREAD 生物角色被称为Jagged1。人类Jagged1基因杂合性导致阿拉吉尔 综合征，是一种以胆管异常为特征的多系统发育障碍 以及心血管系统、肾脏和骨骼等其他器官系统的缺陷。这个 Alagille综合征的临床表现千差万别，即使在相同症状的患者中也是如此 突变。因此，已经提出了遗传修饰物在生物多样性中的重要作用。 这种疾病的病理生理学。此外，尚未建立以机制为基础的治疗方法 治疗阿拉格尔综合症。我们最近报道了一种Alagille综合征的小鼠模型，并 发现糖基转移酶基因Poglut1是表型的显性遗传抑制基因 在这个模型中。在这项提案中，我们将使用生化和细胞培养分析、转录图谱 和小鼠遗传学实验确定Jagged1糖基化调节的机制 确定Jagged1在胆管发育过程中的关键靶点。我们还将使用我们的 初步数据和小鼠模型作为建立Alagille病潜在治疗方法的基础 综合症。这些研究有可能为这一疾病的病理生理学提供新的见解。 疾病和Jagged1介导的信号调控的分子机制 糖基化。

Summary Notch signaling is a cell-to-cell communication mechanism critical for embryonic development and adult homeostasis. To communicate information between cells, Notch receptors on a given cell need to be activated by ligands from neighboring cells. One of the Notch pathway ligands with broad biological roles is called jagged1. Heterozygosity for the jagged1 gene in humans results in Alagille syndrome, which is a multisystem developmental disorder characterized by bile duct abnormalities and defects in other organs systems including the cardiovascular system, kidney and skeleton. The clinical presentation of Alagille syndrome is extremely variable, even in patients with identical point mutations. Accordingly, it has been proposed that genetic modifiers play an important role in the pathophysiology of this disease. Moreover, no mechanism-based treatment has yet been established for Alagille syndrome. We have recently reported a mouse model for Alagille syndrome and have identified the glycosyltransferase gene Poglut1 as a dominant genetic suppressor of the phenotypes in this model. In this proposal, we will use biochemical and cell culture assays, transcriptional profiling and mouse genetic experiments to determine the mechanism of jagged1 regulation by glycosylation and to identify critical targets of jagged1 during bile duct development. We will also use our preliminary data and mouse model as a basis to establish a potential therapeutic approach for Alagille syndrome. These studies have the potential to provide novel insight into the pathophysiology of this disease and the molecular mechanisms underlying the regulation of jagged1-mediated signaling by glycosylation.