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

基本信息

批准号：
10561730
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
项目类别：
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/10561730
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 novel therapeutic intervention prevent stable isotope targeted treatment therapeutic target urea cycle

项目摘要

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.

项目概要/摘要尿素循环障碍（UCD）是肝脏代谢的常见先天性错误。随着治疗方法的改进例如使用氮清除剂来防止氨水平升高，UCD 患者的数量增加生存。然而，即使没有高氨血症，UCD 患者也可能患有慢性肝病疾病。 UCD 中的肝病可表现为血清转氨酶异常、肝肿大、肝纤维化或肝细胞癌。在 UCD 中，慢性肝病的患病率最高精氨基琥珀酸裂解酶缺乏症（ASLD）。重要的是，UCD（例如 ASLD）肝病的原因是未知，并且标准疗法尚未预防肝病。而且，目前还没有治疗方法专门针对 ASLD 或其他 UCD 肝病的策略。 ASLD 和其他 UCD 的一种常见组织病理学发现是肝糖原沉积过多。然而，肝糖原积累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疾病相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扰乱肝脏能量代谢，包括糖原代谢，并导致 UCD 中的肝脏疾病。使用当前 ASLD 和其他远端小鼠模型进行的研究由于尺寸小和寿命短，UCD 变得更加复杂。为了克服这一挑战并为了促进我们提出的研究，我们操纵了 ASLD 和瓜氨酸血症的小鼠模型，以延长寿命并改善生长。对于拟议的研究，我们将使用生化研究、基因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 肝糖原积累的生化基础？ 2) 肝糖原正常化吗水平可以预防 ASLD 患者的肝病吗？这些研究的见解有可能对我们对这一问题的理解产生重大影响。尿素循环障碍与肝糖原代谢的关系。此外，结果可能为 UCD 患者提供长期管理策略，并可能为新治疗提供见解针对这组疾病的方法。从更广泛的角度来看，我们的研究可能会阐明以下机制：有助于在更常见的葡萄糖代谢疾病中调节肝脏葡萄糖通量。