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

总结 Notch信号传导是一种细胞间通讯机制，对胚胎发育至关重要， 成人体内平衡为了在细胞之间传递信息，给定细胞上的Notch受体需要 被邻近细胞的配体激活Notch途径配体之一，具有广泛的 生物学角色被称为锯齿状1。人类jagged1基因的杂合性导致Alagille 综合征，这是一种以胆管异常为特征的多系统发育障碍 以及包括心血管系统、肾脏和骨骼在内的其他器官系统的缺陷。的 Alagille综合征的临床表现是非常多变的，即使是在相同的点的患者中 突变。因此，已经提出，遗传修饰剂在遗传修饰中起重要作用。 这种疾病的病理生理学。此外，尚未建立基于机制的治疗方法 治疗阿拉吉尔综合症我们最近报道了Alagille综合征的小鼠模型， 确定了糖基转移酶基因Poglut 1作为表型的显性遗传抑制因子 in this model模型.在这个建议中，我们将使用生物化学和细胞培养分析，转录谱， 和小鼠遗传实验，以确定糖基化调节jagged1的机制， 并确定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基础，以建立Alagille的潜在治疗方法 综合征这些研究有可能为这种疾病的病理生理学提供新的见解。 疾病和潜在的调节jagged1介导的信号传导的分子机制， 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.