权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Epigenetic regulation of Wilson Disease

威尔逊病的表观遗传调控

基本信息

批准号：
9104634
负责人：
Valentina Medici
金额：
$ 34.57万
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：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104634
关键词：
ATP phosphohydrolase Adult Affect Age Animal Model Animals Biliary Brain Carnitine Chelating Agents Choline Clinical Collaborations Complement Copper Copper Chelation DNA DNA Methylation Development Diet Disease Electrons Epigenetic Process Europe Excretory function Failure Family Female Fetal Liver Fetus Functional disorder Gene Expression Genes Genomic DNA Genomics Genotype Goals Hepatic Hepatolenticular Degeneration Heterogeneity Human Immune Immunofluorescence Immunologic Impairment Institution International Life Liver Liver diseases Measurement Medical Methionine Metabolism Pathway Methylation Mitochondria Mus Nutritional Oxidative Phosphorylation Pathway interactions Patients Pattern Penicillamine Phenotype Plasma Reaction Recording of previous events Regulation Role Sampling Severities Siblings Site Slide Staining method Stains Techniques Testing Tissues Transcript United States Wilson disease protein acylcarnitine clinical phenotype cohort disease phenotype disease-causing mutation epigenetic regulation feeding fetal genome-wide indexing liver biopsy liver injury methyl group methylation pattern methylome mother nutrition mouse model neuropsychiatry offspring phenotypic data placental transfer prenatal prevent programs public health relevance research study response treatment response

项目摘要

DESCRIPTION (provided by applicant): Wilson disease (WD) is an autosomal recessive disorder of hepatic copper accumulation, which is caused by the dysfunction of a copper-transporting P-type ATPase that is crucial in the hepatocellular utilization and biliary excretion f copper. WD is characterized by a remarkable heterogeneity in its clinical hepatic severity and neuropsychiatric presentations. The failure to identify specific genotype-to-phenotype correlations could be due in part to the presence of epigenetic factors affecting phenotype expression. Our hypothesis is that WD phenotype and its potential response to anti copper treatment may be regulated by maternal dietary methyl group effects on offspring hepatic methionine metabolism and oxidative phosphorylation mechanisms. Our aims will be 1) To determine the effects of maternal methyl status on hepatic genomic methylation, transcript levels of oxidative phosphorylation pathway genes and mitochondrial function of offspring and their response to copper chelation in the tx-j mouse model of WD; 2) To characterize human liver DNA methylation and plasma acyl carnitines as markers of mitochondrial function in WD patients with different phenotypic presentation. We will test the first aim in the tx-j mouse model of WD, which we have previously characterized as showing global DNA hypo-methylation and changes in the expression of genes related to hepatic methionine metabolism, genomic DNA methylation, and liver injury. We will provide control or choline supplemented diets to heterozygous dams (Atp7b +/-) and study the effects of these diets on hepatic genomic DNA methylation and gene expressions and their response to copper chelating agents in 24 week wild type and homozygous (Atp7b - /-) tx-j offspring mice with hepatic copper accumulation. In addition, we will conduct global DNA methylation studies in unstained liver biopsy slides and DNA from tissue blocks from WD patients in collaboration with medical institutions in both the United States and Europe. We will focus particularly on mitochondrial function gene expression pathways which we have shown are affected in tx-j mice liver from fetal to adult life. The proposed experiments will entail the use of epigenetic techniques including methylome analysis by MethylC- seq and pyro-sequencing in liver to determine the methylation status of CpG sites genome-wide in mice, the use of immune staining of human liver biopsy slides for global DNA methylation patterns, methylome analysis for global DNA methylation quantification, and gene specific methylation analysis, and measurements of acylcarnitines in serum/plasma samples from WD subjects as indices of mitochondrial function. The anticipated findings are that aberrant methionine metabolism and altered gene-specific DNA methylation will be prevented by maternal dietary provision of choline in mice and that WD patient with different phenotypes will have different DNA methylation and mitochondrial impairment patterns.