DISSECTING THE LINK BETWEEN UREAGENESIS AND HEPATIC GLYCOGEN METABOLISM

剖析尿生成与肝糖原代谢之间的联系

• 批准号: 10349428
• 负责人: Lindsay C Burrage
• 金额: $ 46.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10349428
• 关键词: Acetylation; Address; Adenoviruses; Alpha-glucosidase; Ammonia; Argininosuccinate lyase deficiency; Biochemical; Birth; Chronic; Cirrhosis; Citrullinemia; Complication; Data; Deposition; Diabetes Mellitus; Disease; Distal; Early Diagnosis; Energy Metabolism; Enzymes; Functional disorder; Generations; Genetic Transcription; Glucose; Glucose Metabolism Disorders; Glycogen; Glycogen (Starch) Synthase; Glycogen Phosphorylase; Growth; Hepatic; Hepatic Tissue; Hepatomegaly; Hereditary Disease; High Prevalence; Human; Hyperammonemia; Impairment; Individual; Infant; Life; Link; Liver; Liver Cirrhosis; Liver Dysfunction; Liver Fibrosis; Liver Glycogen; Liver diseases; Longevity; Metabolic; Modeling; Mus; Mutant Strains Mice; Natural History; Nitrogen; Pathology; Patient Care; Patients; Phosphorylation; Post-Translational Protein Processing; Prevalence; Primary carcinoma of the liver cells; Protein-Restricted Diet; Proteins; Regulation; Serum; Testing; Therapeutic; Tissues; Transaminases; United States; Urea cycle disorders; Virus; Work; chronic liver disease; comorbidity; diabetic; enzyme activity; genetic manipulation; glucose output; glycogen metabolism; glycogenolysis; human tissue; improved; insight; liver metabolism; mouse model; novel; prevent; stable isotope; targeted treatment; therapeutic target; urea cycle

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.

项目摘要/摘要 尿素周期疾病（UCD）是肝代谢的常见先天错误。有改进的疗法 例如氮扫描剂以防止氨水升高，UCD患者增加了 生存。但是，即使没有高症血症，UCD的患者也可能患有慢性肝 疾病。 UCD中的肝病可能表现为异常的血清跨激酶，肝肿大，肝癌 纤维化或肝细胞癌。在UCD中，发生慢性肝病的最高患病率是 在Argininoscinate裂解酶缺乏症（ASLD）中。重要的是，诸如ASLD之类的UCD的肝病的原因是 标准疗法尚未阻止未知和肝病。而且，没有治疗性 专门针对ASLD或其他UCD的肝病的策略。 在ASLD和其他UCD中，一种常见的组织病理学发现是过量的肝糖原沉积。 但是，肝糖原积累的基础机制及其对肝功能的后果 在UCD中是未知的。肝糖原沉积与糖原储存中的肝病有关 疾病和糖尿病性糖原性肝病。因此，我们的中心假设是尿素周期功能障碍和 氨和其他有毒代谢产物的积累破坏肝能代谢，包括糖原 代谢，并在UCD中引起肝病。使用当前ASLD和其他远端的小鼠模型的研究 UCD的尺寸小和寿命缩短使UCD复杂化。克服这一挑战和 促进我们提出的研究，我们操纵了ASLD和柑橘类血症的小鼠模型，以扩展 寿命并改善增长。对于拟议的研究，我们将使用生化研究，遗传操作 以及在这些鼠标模式中稳定的同位素研究以解决以下问题：1）什么是 ASLD中肝糖原积累的生化基础？ 2）进行肝糖原的标准化 水平预防ASLD中的肝病？ 这些研究的见解有可能对我们对 尿素周期功能障碍与肝糖原代谢之间的关系。此外，结果可能 为UCD患者提供慢性管理策略，并可能对新治疗有所了解 这组疾病的方法。从广义上讲，我们的研究可能阐明 在葡萄糖代谢的更常见疾病中的肝葡萄糖通量调节。