DISSECTING THE LINK BETWEEN UREAGENESIS AND HEPATIC GLYCOGEN METABOLISM

项目概要/摘要 尿素循环障碍是常见的先天性肝脏代谢异常。随着治疗方法的改进 如氮清除剂，以防止氨水平升高，UCD患者增加 生存然而，即使没有高血氨症，UCD患者也可能有慢性肝病， 疾病UCD中的肝脏疾病可表现为血清转氨酶异常、肝肿大、肝硬化和肝硬化。 纤维化或肝细胞癌。在UCD中，慢性肝病的患病率最高， 维生素B2琥珀酸裂解酶缺乏症（ASLD）。重要的是，UCD如ASLD的肝脏疾病的原因是 未知，并且肝脏疾病尚未通过标准疗法预防。此外，没有治疗 专门针对ASLD或其他UCD的肝病的策略。 在ASLD和其他UCD中一个常见的组织病理学发现是过多的肝糖原沉积。 然而，肝糖原蓄积的机制及其对肝功能的影响 在UCD中是未知的。肝糖原沉积与肝糖原储存中的肝病有关 疾病和糖尿病糖原性肝病。因此，我们的中心假设是尿素循环功能障碍和 氨和其他有毒代谢物的积累会破坏肝脏的能量代谢，包括糖原 代谢，并在UCD中引起肝脏疾病。使用目前ASLD和其他远端 UCD由于尺寸小和寿命缩短而变得复杂。为了克服这一挑战， 为了促进我们提出的研究，我们已经操纵了ASLD和瓜氨酸血症的小鼠模型，以延长 寿命和促进生长。对于拟议的研究，我们将使用生化研究，遗传操作， 在这些小鼠模式中进行稳定同位素研究，以解决以下问题：1） ASLD肝糖原蓄积的生化基础？2)肝糖原正常化 水平预防ASLD的肝病？ 这些研究的见解有可能对我们理解 尿素循环障碍与肝糖原代谢的关系此外，结果可能 为患有UCD的患者提供慢性管理策略，并可能为新的治疗提供见解 这类疾病的治疗方法。从更广泛的角度来看，我们的研究可能会阐明 在更常见的葡萄糖代谢紊乱中有助于调节肝脏葡萄糖通量。

PROJECT SUMMARY/ABSTRACT Urea cycle disorders (UCDs) are common inborn errors of hepatic metabolism. With improved therapies such as nitrogen-scavenging agents to prevent elevated ammonia levels, patients with UCDs have increased survival. However, even in the absence of hyperammonemia, patients with UCDs may have chronic liver disease. Liver disease in UCDs can manifest as abnormal serum transaminases, hepatomegaly, hepatic fibrosis, or hepatocellular carcinoma. Among the UCDs, the highest prevalence of chronic liver disease occurs in argininosuccinate lyase deficiency (ASLD). Importantly, the cause for liver disease in UCDs such as ASLD is unknown, and liver disease has not been prevented by standard therapies. Moreover, there are no therapeutic strategies specifically targeting liver disease in ASLD or other UCDs. One common histopathologic finding in ASLD and other UCDs is excess hepatic glycogen deposition. However, the mechanism underlying hepatic glycogen accumulation and its consequences on hepatic function in UCDs are unknown. Hepatic glycogen deposition is associated with liver disease in glycogen storage disorders and diabetic glycogenic hepatopathy. Thus, our central hypothesis is that urea cycle dysfunction and accumulation of ammonia and other toxic metabolites disrupt hepatic energy metabolism, including glycogen metabolism, and cause liver disease in UCDs. Studies using current mouse models of ASLD and other distal UCDs have been complicated by the small size and shortened lifespan. To overcome this challenge and facilitate our proposed studies, we have manipulated mouse models of ASLD and citrullinemia to extend the lifespan and improve growth. For the proposed studies, we will use biochemical studies, genetic manipulation and stable isotope studies in these mouse modes to address the following questions: 1) What is the biochemical basis of hepatic glycogen accumulation in ASLD? 2) Does normalization of hepatic glycogen levels prevent liver disease in ASLD? Insights from these studies have the potential to have significant impact on our understanding of the relationship between urea cycle dysfunction and hepatic glycogen metabolism. In addition, the results may inform chronic management strategies for patients with UCDs and may lend insights into new treatment approaches for this group of disorders. On broader terms, our studies may elucidate mechanisms that contribute to the regulation of hepatic glucose flux in more common disorders of glucose metabolism.