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Wilson Disease: Effect of High-Choline Feeding on Fetal and Offspring Mouse Liver

威尔逊病：高胆碱喂养对胎儿和子代小鼠肝脏的影响

基本信息

批准号：
8878248
负责人：
Valentina Medici
金额：
$ 7.83万
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：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878248
关键词：
ATP phosphohydrolase Address Adjuvant Adult Adult Children Affect Animal Model Biliary Caliber Cell Nucleus Choline Clinical Clinical Treatment Copper DNA DNA Methylation Data Development Diagnosis Diet Disease Dot Immunoblotting Elderly Embryo Environmental Risk Factor Epigenetic Process Excretory function Failure Fetal Liver Fetus Functional disorder Funding Future Gene Expression Gene Expression Profile Gene-Modified Genes Genomics Genotype Health Hepatic Hepatocyte Hepatolenticular Degeneration Heterogeneity Histology Human Individual Inflammation Inherited Investigation Lactation Life Liver Liver diseases Longevity Mental disorders Metabolism Methionine Methionine Metabolism Pathway Methylation Mus Nutritional Organ Partner in relationship Pathogenesis Pathway interactions Patients Phenotype Pregnancy Prevention Property RNA Sequence Analysis RNA Sequences Research Role S-Adenosylhomocysteine S-Adenosylmethionine Site Specimen Structure Supplementation Techniques Testing Transcript Weaning Wild Type Mouse base clinical efficacy dietary supplements early childhood epigenetic regulation feeding fetal genome wide methylation genome-wide improved insight liver injury methyl group methylome mouse model nervous system disorder novel offspring pregnant prevent programs protective effect research study transcriptome sequencing transmission process

项目摘要

DESCRIPTION (provided by applicant): Wilson disease (WD) is an inherited, autosomal recessive, copper (Cu) accumulation disorder, which is caused by the dysfunction of a Cu-transporting P-type ATPase that is crucial in the hepatocellular utilization and biliary excretion f Cu. WD is characterized by a remarkable heterogeneity in its clinical hepatic presentation. The failure to identify specific genotype-to-phenotype correlations could be due in part to the presence of epigenetic factors affecting phenotype expression. The HYPOTHESIS of the proposed research is that the gestational supply of dietary methyl groups modifies fetal DNA methylation mechanisms that regulate the expression of genes involved in liver damage in WD and persist through subsequent life of the offspring. We will test this hypothesis in the tx-j mouse model of WD, which we have previously characterized as showing global DNA hypomethylation and changes in the expression of genes related to hepatic methionine metabolism. Our SPECIFIC AIMS will be to test if 1) Specific Aim 1: maternal methyl status during pregnancy will affect transcriptome and methylome status in fetal liver; 2) Specific Aim 2: maternal methyl status during pregnancy will affect parameters of methionine metabolism and persisting changes in on hepatic global DNA methylation and gene expression in 4 month old offspring. The study will be conducted on livers of fetuses from tx-j and wild-type dams fed a choline-supplemented or control diets before mating and during gestation (Specific Aim 1), and on livers from offspring of tx-j and wild-type dams. The proposed experiments will use epigenetic techniques of dot-blot for global DNA methylation, RNA-sequencing analysis, and MethylC-seq analysis to determine the gene specific methylation status of CpG sites genome-wide. The anticipated findings are that aberrant fetal methionine metabolism and altered global and gene-specific DNA methylation will persist in offspring and be prevented by maternal dietary provision of choline. These findings will provide important evidence that WD is a condition characterized not only by Cu accumulation but also by global DNA hypomethylation which can be corrected by provision of methyl groups in the maternal diet. Positive results from this study will provide a rationale for the potential use of agents that modify gene methylation status in the prevention and/or treatment of clinical manifestations of WD. The present proposal is a novel departure based on current K08 progress and will form the basis for a subsequent R01 application to study methylation status over the lifespan of animal models and humans with WD by exploring the addition of dietary methyl donors such as choline to the traditional anti-Cu treatment in order to modify the disease course in difficult and less responsive cases and as adjuvant to traditional anti-Cu agents.

描述（由申请人提供）：威尔逊病（WD）是一种遗传性、常染色体隐性遗传的铜（Cu）蓄积性疾病，由铜转运P型ATP酶功能障碍引起，该酶在肝细胞利用和胆汁排泄Cu中至关重要。WD的特点是在其临床肝脏表现的显着异质性。未能确定特定的基因型与表型的相关性可能部分是由于存在影响表型表达的表观遗传因素。这项研究的假设是，妊娠期膳食甲基的供应改变了胎儿DNA甲基化机制，该机制调节了WD肝损伤相关基因的表达，并在后代的后续生活中持续存在。我们将在TX-J WD小鼠模型中测试这一假设，我们先前已将其表征为显示全球DNA低甲基化和与肝甲硫氨酸代谢相关的基因表达的变化。我们的具体目标是测试1）具体目标1：妊娠期间母体甲基状态是否会影响胎肝中的转录组和甲基化组状态; 2）具体目标2：妊娠期间母体甲基状态是否会影响蛋氨酸代谢参数以及4个月龄后代中肝脏整体DNA甲基化和基因表达的持续变化。本研究将对交配前和妊娠期间饲喂胆碱补充饲料或对照饲料（特定目的1）的tx-j和野生型母鼠的胎仔肝脏以及tx-j和野生型母鼠后代的肝脏进行研究。所提出的实验将使用用于全局DNA甲基化的斑点印迹、RNA测序分析和MethylC-seq分析的表观遗传学技术来确定全基因组CpG位点的基因特异性甲基化状态。预期的结果是，异常的胎儿甲硫氨酸代谢和改变的全球和基因特异性DNA甲基化将持续在后代和防止母亲的饮食提供胆碱。这些研究结果将提供重要的证据，WD是一种条件，其特征不仅是铜的积累，但也通过全球DNA低甲基化，这可以纠正提供甲基基团在母体饮食。本研究的阳性结果将为潜在使用修饰基因甲基化状态的药物提供理论依据。预防和/或治疗WD的临床表现。本提案是基于当前K 08进展的新的出发点，并且将形成后续R 01应用的基础，以通过探索将膳食甲基供体（例如胆碱）添加到传统抗Cu治疗中来研究WD动物模型和人的寿命期间的甲基化状态，以便在困难和响应性较低的情况下改变病程，并且作为传统抗Cu剂的辅助剂。