Characterizing the (epi)genetics of oxytocin response in clinical and animal models

临床和动物模型中催产素反应的（表观）遗传学特征

• 批准号: 9894649
• 负责人: SIMON G GREGORY
• 金额: $ 61.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-14 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894649
• 关键词: 3-Dimensional; Amygdaloid structure; Animal Model; Area; Behavioral; Biological Models; Brain; Brain region; C58/J Mouse; Candidate Disease Gene; Clinical; Clinical Trials; Communication; Cytosine; DNA; DNA Methylation; Data; Development; Disease; Dopamine; Drug usage; Epigenetic Process; Etiology; Eye; Funding; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genotype; Hippocampus (Brain); Hormones; Human; Impairment; Individual; Knockout Mice; Language Development; Lifestyle-related condition; Mediating; Mediator of activation protein; Methylation; Modification; Mouse Strains; Mus; Mutant Strains Mice; Neuromodulator; Neurotransmitters; Oxytocin; Oxytocin Receptor; Participant; Pathway interactions; Pattern; Phenotype; Play; Regulation; Research; Research Personnel; Research Support; Rewards; Role; SNP array; Sampling; Signal Transduction; Social Behavior; Social Interaction; Tissues; Translating; United States National Institutes of Health; Ventral Striatum; affiliative behavior; autism spectrum disorder; autistic children; behavioral phenotyping; behavioral response; density; developmental disease; efficacy trial; epigenetic regulation; epigenome; functional status; genetic predictors; genetic profiling; human model; improved; interest; methylome; mouse model; non-genetic; novel; promoter; psychosocial; repetitive behavior; response; social; social deficits; transcriptome; transcriptomics; treatment duration; treatment response

The autism spectrum disorders (ASDs) are a heterogeneous group of developmental disorders with specific core features, including impaired social interaction and abnormal repetitive behavior. Several ongoing studies, including our own, are assessing the use of the drug oxytocin to ameliorate social deficits in individuals with ASDs and other psychosocial disorders. We hypothesize that behavioral response to oxytocin treatment is mediated by genetic and epigenetic factors and that these factors, particularly epigenetic mediators of gene expression, may be pivotal to baseline response and/or may change during oxytocin exposure. This proposal will explore the role of the epigenome and genetic predisposition to oxytocin treatment response in longitudinal samples that have already been collected as part of an ongoing clinical trial in high and low functioning children with ASDs; we will investigate the transcriptome and epigenome (5mC and 5hmC) in regions of the brain and periphery of a mouse model of ASD known to have positive response to oxytocin treatment; we will also examine novel regulatory mechanisms of oxytocin's receptor OXTR via 5-hydroxy methyl cytosine. The data generated by these aims will not only serve to develop (epi)genetic predictors of oxytocin response, but they will inform other trials using oxytocin to treat psychosocial disorders.

自闭症谱系障碍（ASD）是一组异质性的发育障碍，具有特定的 核心特征，包括社交互动受损和异常重复行为。一些正在进行的研究， 包括我们自己的，正在评估使用药物催产素来改善患有 ASD和其他心理社会障碍。我们假设催产素治疗的行为反应是 通过遗传和表观遗传因素介导，这些因素，特别是基因的表观遗传介质， 表达，可能是关键的基线响应和/或可能在催产素暴露过程中发生变化。这项建议 将探讨表观基因组和遗传易感性的作用，催产素治疗反应的纵向 作为正在进行的高功能和低功能儿童临床试验的一部分， 与ASD;我们将研究转录组和表观基因组（5 mC和5 hmC）在大脑的区域， 已知ASD小鼠模型对催产素治疗有积极反应的外周;我们还将 研究催产素受体OXTR通过5-羟甲基胞嘧啶的新的调节机制。数据 这些目标产生的结果不仅有助于开发催产素反应的遗传预测因子， 将为其他使用催产素治疗心理社会障碍的试验提供信息。