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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：
10094421
负责人：
Lindsay C Burrage
金额：
$ 46.1万
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/10094421
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

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.

项目总结/文摘