Dysregulation of Hepatic Energy Metabolism in Argininosuccinate Lyase Deficiency

项目摘要/摘要 尿素循环障碍是肝脏代谢的常见先天缺陷。通过改进的治疗方法，如 氮素清除剂为了防止氨水平升高，尿素循环障碍的患者 提高了存活率。然而，即使在没有高氨血症的情况下，尿素循环障碍的患者 (UCDS)可能患有慢性肝病。这种慢性肝病似乎更常见于 精氨酸琥珀酸裂解酶缺乏症(ASLD)与其他尿素循环障碍的比较。肝脏并发症 ASLD的范围从慢性肝细胞损伤、肝肿大、纤维化、肝硬变，可能还有肝细胞 癌症。ASLD和其他UCDs的肝脏疾病的发病机制尚不清楚，因此，有 没有针对这种并发症的特定治疗方法。 作为开发针对ASLD和其他UCDs肝病的治疗策略的第一步， 我们建议使用新开发的小鼠模型来研究肝病的生化基础。 这种疾病的肝细胞样细胞模型。因为这种酶，精氨酸琥珀酸裂解酶，整合了两种 细胞中的基本途径(尿素循环和柠檬酸循环)，我们假设能量失调 由柠檬酸循环中断引起，并导致ASLD的肝脏疾病。我们计划检验这一假设 通过研究解决以下问题：a)在小鼠的肝脏中是否存在线粒体功能障碍 ASL缺陷小鼠？B)柠檬酸循环障碍是否导致类肝细胞的能量失调 来自ASLD患者的细胞？ 总体而言，我们的研究将结合在体小鼠研究和在新的体外模型中的研究，以探讨 尿素循环、柠檬酸循环和能量失调之间的联系。我们的研究将使我们能够确定 未来ASLD和其他可能的肝病治疗策略研究的潜在终点 UCDS。此外，在这一提议中产生的肝细胞样细胞将是 对治疗靶点进行高通量筛查并解剖基因-表型 ASLD中的人际关系。最后，从更广泛的角度来看，这些研究有可能产生重要的见解 能量失调和尿素循环障碍在更常见形式的肝病中的作用。

PROJECT SUMMARY/ABSTRACT Urea cycle disorders are common inborn errors of liver metabolism. With improved therapies such as nitrogen-scavenging agents to prevent elevated ammonia levels, patients with urea cycle disorders have increased survival. However, even in the absence of hyperammonemia, patients with urea cycle disorders (UCDs) may have chronic liver disease. This chronic liver disease appears to be more common in argininosuccinate lyase deficiency (ASLD) as compared to other urea cycle disorders. The hepatic complications in ASLD range from chronic hepatocellular injury, hepatomegaly, fibrosis, cirrhosis, and possibly hepatocellular carcinoma. The pathogenesis for liver disease in ASLD and other UCDs remains unknown, and thus, there are no specific therapies that target this complication. As a first step towards developing therapeutic strategies targeting liver disease in ASLD and other UCDs, we propose to investigate the biochemical basis of liver disease using a mouse model and newly developed hepatocyte-like cell models for this disorder. Since the enzyme, argininosuccinate lyase, integrates two fundamental pathways (urea cycle and citric acid cycle) in the cell, we hypothesize that energy dysregulation results from citric acid cycle disruption and contributes to liver disease in ASLD. We plan to test this hypothesis by pursuing studies that address the following questions: a) Is there mitochondrial dysfunction in the liver of the ASL-deficient mice? b) Does citric acid cycle dysfunction contribute to energy dysregulation in hepatocyte-like cells derived from patients with ASLD? Overall, our studies will combine in vivo murine studies and studies in a new in vitro model to investigate the link between the urea cycle, citric acid cycle and energy dysregulation. Our studies will enable the identification of potential endpoints for future studies of therapeutic strategies for liver disease in ASLD and possibly other UCDs. Moreover, the hepatocyte-like cells generated in this proposal will be an important resource for performing high-throughput screening for therapeutic targets and for dissecting genotype-phenotype relationships in ASLD. Lastly, on broader terms, these studies have the potential to yield important insights into the role of energy dysregulation and urea cycle dysfunction in more common forms of liver disease.