DISSECTING THE LINK BETWEEN UREAGENESIS AND HEPATIC GLYCOGEN METABOLISM

项目摘要/摘要 尿素循环障碍(UCDs)是常见的肝脏代谢先天疾病。随着治疗方法的改进 如氮气清除剂，以防止氨水平升高，UCDs患者增加 生死存亡。然而，即使在没有高氨血症的情况下，UCDs患者也可能患有慢性肝脏。 疾病。UCDS的肝脏疾病可表现为血清转氨酶异常、肝脏肿大、肝脏 纤维化，或肝细胞癌。在非传染性疾病中，慢性肝病的发病率最高。 精氨酸琥珀酸裂解酶缺乏症(ASLD)。重要的是，像ASLD这样的UCDs的肝脏疾病的原因是 未知，肝病也不能通过标准疗法预防。此外，没有治疗的方法 针对ASLD或其他UCDs中的肝病的策略。 ASLD和其他UCDs的一种常见的组织病理学表现是肝糖原过度沉积。 然而，肝糖原蓄积的机制及其对肝功能的影响 在非传染性疾病中的作用是未知的。肝糖原沉积与肝病在糖原储存过程中的相关性 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扰乱了肝脏的能量代谢，包括糖原。 代谢，并导致UCDS的肝脏疾病。使用当前ASLD和其他远端小鼠模型的研究 UCD由于尺寸小和寿命短而变得复杂。为了克服这一挑战并 为了促进我们拟议的研究，我们操纵了ASLD和瓜氨酸血症的小鼠模型，以延长 延年益寿，促进增长。对于拟议的研究，我们将使用生化研究、遗传操作 在这些小鼠模式下进行稳定同位素研究，以解决以下问题：1)什么是 ASLD肝糖原蓄积的生化基础？2)肝糖原正常化 ASLD中的水平可以预防肝病吗？ 来自这些研究的见解有可能对我们对 尿素循环障碍与肝糖原代谢的关系此外，结果可能 为UCDs患者提供慢性管理策略，并可能为新的治疗方法提供见解 治疗这类疾病的方法。从更广泛的角度来看，我们的研究可能会阐明 在更常见的糖代谢紊乱中，有助于调节肝脏的葡萄糖流量。

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.