Wilson Disease: Regulation of Steatosis by Methionine Metabolism

威尔逊病：蛋氨酸代谢调节脂肪变性

基本信息

批准号：
8046345
负责人：
Valentina Medici
金额：
$ 15.34万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8046345
关键词：
Address Adenosine Adenosylhomocysteinase Affect Animal Model Basic Science Betaine Biochemical California Chelating Agents Cirrhosis Copper DNA DNA Methylation DNA Methyltransferase DNA Methyltransferase Inhibitor DNA Modification Methylases Data Decitabine Disease Elements Environment Enzymes Epigenetic Process Fatty Liver Fatty acid glycerol esters Fibrosis Figs - dietary Gene Expression Gene Expression Regulation Genes Genetic Goals Hepatic Hepatocyte Hepatolenticular Degeneration Hepatology Homocysteine Homocystine In Vitro Lentivirus Vector Lipids Liver Liver diseases Measurement Mediating Mentors Metabolic Metabolic Pathway Metabolism Methionine Methionine Metabolism Pathway Methods Methylation Milk Modification Molecular Mus National Institute of Diabetes and Digestive and Kidney Diseases Orphan Disease Outcome Pathogenesis Pathway interactions Phase Physicians Postdoctoral Fellow Prevention Principal Investigator Process Program Development Rare Diseases Reaction Regulation Research Resources Role S-Adenosylhomocysteine S-Adenosylmethionine Scientist Staging Subfamily lentivirinae Techniques Testing Time Training Training Programs Triglycerides Universities Very low density lipoprotein base career career development endoplasmic reticulum stress graduate student improved in vitro activity in vivo inhibitor/antagonist insight lipid biosynthesis lipid metabolism methyl group mouse model non-alcoholic fatty liver programs public health relevance research study skills small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in Hepatology, oriented to basic science research. The principal investigator has scientific background on Wilson Disease and now will expand upon her scientific skills through a unique integration of resources. This program will promote the understanding of the molecular mechanisms relating copper overload to steatosis in Wilson Disease, with the ultimate objective to explore new therapies for this rare disease based on the modification of these aberrant underlying processes. Dr. CH Halsted and Dr. JC Rutledge will mentor the principal investigator's scientific and career development. They are recognized leaders in the fields of methionine and lipid metabolism and they have trained numerous postdoctoral fellows and graduate students. The research will focus on the inhibitory effect exerted by copper accumulation on the enzyme S-adenosylhomocysteine (SAH) hydrolase. Preliminary data demonstrate that SAH hydrolase inhibition is followed by significant reduction of the hepatic S-adenosylmethionine (SAM):SAH ratio, a marker of methylation status, and later time-dependent homocysteine increase. The proposed experiments will entail the use of a copper chelator to reduce hepatic copper concentration and improve SAH hydrolase activity, thereby demonstrating the direct effect of copper on this enzyme, and further inhibition of SAH hydrolase both in vivo (with DZA) and in vitro (with shRNA carried by lentivirus) and provision of methyl groups as supplemental betaine, a compound known to correct aberrant methionine metabolism. An assortment of biochemical, molecular, and cellular techniques, including epigenetic methods will be used to study methionine and lipid metabolism. The specific aims include: 1) Establishing relationships among copper accumulation, hepatic steatosis, and aberrant methionine metabolism, 2) Determining if the methyl donor betaine can improve lipid metabolism in tx-j mice and in primary hepatocytes from the same animal model, and 3) Determining if steatosis in Wilson disease is mediated by epigenetic regulation of expressions of genes relevant to lipid synthesis. This will be the first detailed analysis of the mechanisms of hepatic steatosis based on the metabolism of methionine in this rare disease. The University of California Davis provides an ideal setting for training physician- scientists by incorporating expertise from diverse resources into customized programs. Such an environment maximizes the potential for the principal investigator to establish a scientific niche from which an academic career can be constructed. The successful outcome of the proposed experiments will promote an understanding of the metabolic processes underlying the pathogenesis of steatosis in Wilson disease, an orphan disease (included in the NIDDK action plan for Liver Disease Research) whose genetic background is well-established but whose metabolic etiopathogenesis is unclear. The study will also provide insights into the role of copper and methionine metabolism in more common diseases, such as non-alcoholic fatty liver disease. PUBLIC HEALTH RELEVANCE: Wilson disease, an autosomic recessive disorder due to hepatic copper excess, is frequently characterized by fat accumulation in the liver. We will study the interaction between copper and hepatic methionine metabolism with the ultimate objective to explore new therapies based on modification of these underlying processes. The study will also provide insights into the role of copper and methionine metabolism in more common diseases, such as non-alcoholic fatty liver disease.

描述（由申请人提供）：该提案描述了一个为期 5 年的肝病学学术职业发展培训计划，面向基础科学研究。首席研究员拥有威尔逊病的科学背景，现在将通过独特的资源整合来扩展她的科学技能。该计划将促进对威尔逊病中铜超载与脂肪变性相关的分子机制的理解，最终目标是在修改这些异常的潜在过程的基础上探索这种罕见疾病的新疗法。 CH Halsted 博士和 JC Rutledge 博士将指导首席研究员的科学和职业发展。他们是蛋氨酸和脂质代谢领域公认的领导者，培养了众多博士后和研究生。该研究将重点关注铜积累对S-腺苷高半胱氨酸（SAH）水解酶的抑制作用。初步数据表明，SAH 水解酶抑制后，肝脏 S-腺苷甲硫氨酸 (SAM):SAH 比率（甲基化状态的标志物）显着降低，随后随时间依赖性的同型半胱氨酸增加。拟议的实验将需要使用铜螯合剂来降低肝铜浓度并提高 SAH 水解酶活性，从而证明铜对该酶的直接影响，并在体内（使用 DZA）和体外进一步抑制 SAH 水解酶（慢病毒携带的shRNA）并提供甲基作为补充甜菜碱，一种已知可以纠正异常蛋氨酸代谢的化合物。包括表观遗传学方法在内的各种生化、分子和细胞技术将用于研究蛋氨酸和脂质代谢。具体目标包括：1) 建立铜积累、肝脂肪变性和异常蛋氨酸代谢之间的关系，2) 确定甲基供体甜菜碱是否可以改善 tx-j 小鼠和同一动物模型的原代肝细胞中的脂质代谢，以及 3 ) 确定威尔逊病中的脂肪变性是否是由与脂质合成相关的基因表达的表观遗传调节介导的。这将是首次对这种罕见疾病中基于蛋氨酸代谢的肝脂肪变性机制进行详细分析。加州大学戴维斯分校通过将不同资源的专业知识融入定制项目，为培训医师科学家提供了理想的环境。这样的环境最大限度地发挥了首席研究员建立科学利基的潜力，并以此为基础构建学术生涯。拟议实验的成功结果将促进对威尔逊病脂肪变性发病机制的代谢过程的理解，威尔逊病是一种孤儿疾病（包含在 NIDDK 肝病研究行动计划中），其遗传背景已明确，但其代谢发病机制尚不清楚。该研究还将深入了解铜和蛋氨酸代谢在非酒精性脂肪肝等更常见疾病中的作用。公众健康相关性：威尔逊病是一种由于肝铜过多引起的常染色体隐性遗传疾病，其特征通常是肝脏中脂肪堆积。我们将研究铜和肝脏蛋氨酸代谢之间的相互作用，最终目标是探索基于修改这些潜在过程的新疗法。该研究还将深入了解铜和蛋氨酸代谢在非酒精性脂肪肝等更常见疾病中的作用。