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（ASDS）是一组具有特定的发育障碍 核心特征，包括社会互动受损和重复行为异常。正在进行的几项研究， 包括我们自己的包括我们自己的人正在评估使用药物催产素以改善患有的人的社会缺陷 ASD和其他社会心理疾病。我们假设对催产素治疗的行为反应是 由遗传和表观遗传因素介导的，这些因素，尤其是基因的表观遗传介体 表达可能是基线反应至关重要的，并且/或在催产素暴露期间可能会发生变化。这个建议 将探讨表观遗传组和遗传易感性对催产素治疗反应的作用 作为正在进行的高功能儿童正在进行的临床试验的一部分已经收集的样本 与ASD；我们将研究大脑区域的转录组和表观基因组（5MC和5HMC） 已知对催产素治疗的ASD小鼠模型的外围。我们也会 检查催产素受体OXTR的新型调节机制通过5-羟基甲基胞嘧啶。数据 这些目标产生的不仅将有催产素反应的（EPI）遗传预测因子 将向其他使用催产素治疗社会心理疾病的试验告知其他试验。