Dysregulation of Hepatic Energy Metabolism in Argininosuccinate Lyase Deficiency

项目总结/摘要 尿素循环障碍是常见的先天性肝脏代谢缺陷。随着治疗方法的改进， 氮清除剂，以防止氨水平升高，尿素循环障碍的患者， 增加生存。然而，即使在没有高氨血症的情况下， （UCD）可能患有慢性肝病。这种慢性肝病似乎更常见于 与其他尿素循环障碍相比，维生素A琥珀酸裂解酶缺乏症（ASLD）。肝脏并发症 在ASLD中，范围从慢性肝细胞损伤、肝肿大、纤维化、肝硬化和可能肝细胞性 carcinoma. ASLD和其他UCD中肝病的发病机制仍然未知，因此， 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UCD的肝病治疗策略的第一步， 我们建议使用小鼠模型和新开发的 肝细胞样细胞模型。由于这种酶，即氨基琥珀酸裂解酶， 基本途径（尿素循环和柠檬酸循环）在细胞中，我们假设能量失调， 结果从柠檬酸循环中断，并有助于肝脏疾病的ASLD。我们计划验证这个假设 通过进行研究，解决以下问题：a）是否有线粒体功能障碍的肝脏， ASL缺陷小鼠？B）柠檬酸循环功能障碍是否有助于肝细胞样肿瘤中的能量失调？ 来自ASLD患者的细胞 总之，我们的研究将结合联合收割机体内小鼠研究和新的体外模型研究， 尿素循环，柠檬酸循环和能量失调之间的联系。我们的研究将使识别 ASLD和其他可能的肝病治疗策略的未来研究的潜在终点 UCD。此外，在该提议中产生的肝细胞样细胞将是用于 对治疗靶点进行高通量筛选， 在ASLD的关系。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功能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.