Targeting POGLUT1 to promote biliary development in Alagille syndrome

项目摘要/摘要 Alagille综合征(ALGS)是一种影响肝胆系统的遗传性、多系统发育障碍， 心血管系统、肾脏等器官。ALGS患者中观察到的最常见的表型是 肝脏胆管数量严重减少(称为胆管稀少)。与其他疾病相似 累及肝内胆管系统，胆管稀少及其后果常导致胆汁淤积。 ALGS患者的表型(如严重瘙痒)和终末期肝病。基因中的显性突变 被称为JAG1，它编码Notch信号通路中的一个配体，被认为是引起ALGS的原因 1997年，后来被证明对约95%的ALGS病例负有责任。然而，尽管有财富 对Notch通路的功能和调控的认识尽管已经过去了20多年 从在ALGS患者中发现JAG1以来，目前仍没有基于机制的治疗方法。这个 肝移植是治疗ALGS肝病和胆管缺乏症的唯一方法。然而， 肝脏供体短缺对这一患者群体构成了重大挑战。此外，其他人的参与 许多ALGS患者的器官系统--包括心血管和肾脏系统--使他们变得贫穷 肝脏移植的候选对象。此外，对于接受肝脏移植的人来说，更高的频率 观察心血管和肾脏并发症，以及免疫抑制的长期效果 治疗可能会有问题。因此，治疗方法的发展可以纠正或减轻 胆管缺乏和有助于避免或推迟移植是慢性胆管炎患者尚未满足的主要临床/医学需求 ALGS等疾病伴胆管缺如。根据我们最近公布的初步数据， 目前的应用建议进行临床前研究，以直接满足这一需求。我们已经建立了一只老鼠 通过移除C57BL/6遗传背景上的一个Jag1拷贝来建立ALGS模型。这种模式使我们能够 鉴定肝脏中Jag1杂合性的两个剂量敏感的遗传修饰物，它们可以拯救 胆管稀少和肝脏表型，无副作用。此外，我们的初步数据产生了 与一个行业合作伙伴合作表明，这些基因之一的表达在出生后减少 通过一种新方法的修饰剂可以显著改善我们的ALGS小鼠模型的肝脏表型。在 这项建议的两个目标，我们将确定最优剂量、长期利益和潜在的方面 我们的治疗策略对Jag1杂合子和其他遗传模式的ALGS的影响 肝脏受累和/或多器官受累。如果成功，我们的研究将为 在胆管缺乏模型中增强胆管树，将为临床研究铺平道路 或许有一天能帮助ALGS患者避免肝移植。

PROJECT SUMMARY/ABSTRACT Alagille syndrome (ALGS) is a genetic, multisystem developmental disorder affecting the liver biliary system, cardiovascular system, kidney and other organs. The most common phenotype observed in ALGS patients is a severe decrease in the number of bile ducts in the liver (called bile duct paucity). Similar to other diseases involving intrahepatic biliary system, bile duct paucity and its consequences often lead to cholestatic phenotypes (like severe itching) and end-stage liver disease in ALGS patients. Dominant mutations in a gene called JAG1, which encodes a ligand in the Notch signaling pathway, were identified as the cause of ALGS in 1997, and were later shown to be responsible for about 95% of ALGS cases. However, despite the wealth of knowledge on the function and regulation of Notch pathway and despite the passage of more than 2 decades from the discovery of JAG1 in ALGS patients, there is still no mechanism-based therapy for this disease. The only cure for ALGS liver disease and diseases of bile duct paucity is liver transplantation. However, the shortage in liver donor poses a significant challenge to this patient population. Moreover, involvement of other organ systems—including the cardiovascular and renal systems—in many ALGS patients makes them poor candidates for liver transplantation. Moreover, for those who do receive a liver transplant, a higher frequency of cardiovascular and kidney complications are observed, and the long-term effects of immunosuppressive therapy can be problematic. Therefore, development of therapies that can correct or decrease the degree of bile duct paucity and help avoid or delay transplant is a major unmet clinical/medical need of patients with ALGS and other diseases with bile duct paucity. Building on our recently published and preliminary data, the current application proposes preclinical studies to directly address this need. We have established a mouse model for ALGS by removing one copy of Jag1 on a C57BL/6 genetic background. This model allowed us to identify two dosage-sensitive genetic modifiers of the Jag1 heterozygosity in the liver, which can rescue the bile duct paucity and liver phenotypes without causing side effects. Moreover, our preliminary data generated in collaboration with an industry partner indicate that postnatal reduction in the expression of one of these modifiers by a novel approach can significantly improve the liver phenotypes in our ALGS mouse model. In the two Aims of this proposal, we will determine the optimal dosage, long-term benefits, and the potential side effects of our treatment strategy in Jag1 heterozygous and other genetic models of ALGS with more severe liver involvement and/or multiple organ involvement. If successful, our research will establish a strategy for augmentation of the biliary tree in bile duct paucity models and will pave the way for clinical studies which might one day help ALGS patients avoid liver transplantation.