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:
- 金额:$ 7.83万
- 依托单位:
- 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:
- 关键词:ATP phosphohydrolaseAddressAdjuvantAdultAdult ChildrenAffectAnimal ModelBiliaryCaliberCell NucleusCholineClinicalClinical TreatmentCopperDNADNA MethylationDataDevelopmentDiagnosisDietDiseaseDot ImmunoblottingElderlyEmbryoEnvironmental Risk FactorEpigenetic ProcessExcretory functionFailureFetal LiverFetusFunctional disorderFundingFutureGene ExpressionGene Expression ProfileGene-ModifiedGenesGenomicsGenotypeHealthHepaticHepatocyteHepatolenticular DegenerationHeterogeneityHistologyHumanIndividualInflammationInheritedInvestigationLactationLifeLiverLiver diseasesLongevityMental disordersMetabolismMethionineMethionine Metabolism PathwayMethylationMusNutritionalOrganPartner in relationshipPathogenesisPathway interactionsPatientsPhenotypePregnancyPreventionPropertyRNA Sequence AnalysisRNA SequencesResearchRoleS-AdenosylhomocysteineS-AdenosylmethionineSiteSpecimenStructureSupplementationTechniquesTestingTranscriptWeaningWild Type Mousebaseclinical efficacydietary supplementsearly childhoodepigenetic regulationfeedingfetalgenome wide methylationgenome-wideimprovedinsightliver injurymethyl groupmethylomemouse modelnervous system disordernoveloffspringpregnantpreventprogramsprotective effectresearch studytranscriptome sequencingtransmission 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(申请人提供):威尔逊病(WD)是一种常染色体隐性遗传性铜(Cu)蓄积性疾病,由铜转运 P 型 ATP 酶功能障碍引起,该酶对肝细胞利用和胆汁排泄铜至关重要。 WD 的特点是其临床肝脏表现具有显着的异质性。未能确定特定基因型与表型相关性的部分原因可能是影响表型表达的表观遗传因素的存在。本研究的假设是,妊娠期膳食甲基的供应改变了胎儿 DNA 甲基化机制,该机制调节与 WD 肝损伤有关的基因的表达,并在后代的后续生命中持续存在。我们将在 WD 的 tx-j 小鼠模型中测试这一假设,我们之前已将其描述为显示整体 DNA 低甲基化以及与肝脏蛋氨酸代谢相关的基因表达的变化。我们的具体目标将是测试 1) 具体目标 1:怀孕期间母亲的甲基状态是否会影响胎儿肝脏中的转录组和甲基化状态; 2) 具体目标2:妊娠期间母体甲基状态将影响4月龄后代的蛋氨酸代谢参数以及肝脏整体DNA甲基化和基因表达的持续变化。该研究将在交配前和妊娠期间饲喂补充胆碱或对照饮食的 tx-j 和野生型母鼠的胎儿肝脏(具体目标 1)以及 tx-j 和野生型母鼠的后代的肝脏上进行。拟议的实验将使用斑点印迹的表观遗传学技术进行全局 DNA 甲基化、RNA 测序分析和甲基 C-seq 分析,以确定全基因组 CpG 位点的基因特异性甲基化状态。预期的结果是,异常的胎儿蛋氨酸代谢以及改变的整体和基因特异性 DNA 甲基化将在后代中持续存在,并且可以通过母体饮食中提供胆碱来预防。这些发现将提供重要的证据,证明WD是一种不仅以铜积累为特征的疾病,而且还以整体DNA低甲基化为特征,而这种低甲基化可以通过在母体饮食中提供甲基来纠正。这项研究的积极结果将为潜在使用改变基因甲基化状态的药物提供依据。
预防和/或治疗WD的临床表现。目前的提案是基于当前K08进展的新出发点,并将为后续R01应用奠定基础,通过探索在传统抗铜治疗中添加膳食甲基供体(如胆碱)来研究WD动物模型和人类整个生命周期的甲基化状态,以改变困难和反应较差病例的病程,并作为传统抗铜药物的佐剂。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Wilson disease: At the crossroads between genetics and epigenetics-A review of the evidence.
- DOI:10.1016/j.livres.2017.08.003
- 发表时间:2017-09
- 期刊:
- 影响因子:0
- 作者:Kieffer DA;Medici V
- 通讯作者:Medici V
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Valentina Medici其他文献
Valentina Medici的其他文献
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{{ truncateString('Valentina Medici', 18)}}的其他基金
UC Davis CTSC TL1 Administrative Supplement to Recognize Excellence in Diversity, Equity, Inclusion, and Accessibility Mentorship
加州大学戴维斯分校 CTSC TL1 行政补充,以表彰在多样性、公平性、包容性和无障碍指导方面的卓越表现
- 批准号:
10604918 - 财政年份:2016
- 资助金额:
$ 7.83万 - 项目类别:
Wilson Disease: Regulation of Steatosis by Methionine Metabolism
威尔逊病:蛋氨酸代谢调节脂肪变性
- 批准号:
7893427 - 财政年份:2010
- 资助金额:
$ 7.83万 - 项目类别:
Wilson Disease: Regulation of Steatosis by Methionine Metabolism
威尔逊病:蛋氨酸代谢调节脂肪变性
- 批准号:
8261958 - 财政年份:2010
- 资助金额:
$ 7.83万 - 项目类别:
Wilson Disease: Regulation of Steatosis by Methionine Metabolism
威尔逊病:蛋氨酸代谢调节脂肪变性
- 批准号:
8465224 - 财政年份:2010
- 资助金额:
$ 7.83万 - 项目类别:
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