Long-term physiological and behavioral outcomes, epigenetic profiles and multigenerational phenotypes in a mouse ART model

小鼠 ART 模型中的长期生理和行为结果、表观遗传特征和多代表型

• 批准号: 9921459
• 负责人: MARISA S. BARTOLOMEI
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921459
• 关键词: ATAC-seq; Abnormal placentation; Accounting; Affect; Angelman Syndrome; Animal Model; Applications Grants; Assisted Reproductive Technology; Basic Science; Beckwith-Wiedemann Syndrome; Behavior; Behavioral; Biological Assay; Biological Models; Birth; Body mass index; Cardiac; Cardiovascular Abnormalities; Cardiovascular Physiology; Cells; Cesarean section; Child; Chromatin Structure; Congenital Abnormality; Country; Couples; DNA Methylation; Diagnosis; Disease; Embryo; Embryonic Development; Environmental Exposure; Epigenetic Process; European; Exhibits; Fertilization in Vitro; Fetal Tissues; Fetal Weight; Fetus; Fostering; Foundations; Frequencies; Future; Gene Expression; Gene Expression Regulation; Generations; Genes; Growth; Health; Heart Diseases; Hormonal; Human; Iatrogenesis; Individual; Infertility; Knowledge; Lead; Link; Low Birth Weight Infant; Maternal Age; Metabolic; Metabolic Diseases; Metabolism; Modeling; Modification; Molecular; Mus; Mutation; National Institute of Child Health and Human Development; Outcome; Phenotype; Physiological; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Premature Birth; Procedures; Reporting; Risk; Silver-Russell syndrome; Structure; Superovulation; Systemic blood pressure; Testing; Therapeutic; Tissues; United States; Validation; Variant; Weight; Weight Gain; Work; adverse outcome; behavioral outcome; behavioral phenotyping; design; embryo cryopreservation; embryo culture; epigenomics; experimental study; fetal; genome-wide; high throughput analysis; human data; imprint; improved; infertility treatment; mouse model; next generation; novel strategies; offspring; placental morphology; postnatal; prognostic; stillbirth; transcriptome sequencing; transmission process

Abstract Infertile couples are increasingly turning to Assisted Reproductive Technologies (ART) to treat their infertility. Of growing concern is that ART-conceived children are at increased risk for specific loss-of-imprinting disorders, congenital malformations, growth restriction, preeclampsia as well as postnatal cardiac and metabolic disorders. Given the difficulty of conducting studies using human embryos, a mouse model system, which anticipated some risks associated with ART, will be used to assess the effects of ART on placental morphology, imprinted gene regulation, growth, metabolic, cardiac and behavioral phenotypes of the offspring, and gene expression and chromatin structure genome-wide. Specific Aim 1 will assess the phenotypes, including growth, behavior metabolism and cardiovascular function, of ART-offspring in comparison to naturally-conceived controls. We will also interrogate imprinted gene regulation and gene expression, DNA methylation and chromatin structure using gene-specific and high throughput analyses. Moreover, the design of this aim will enable us to isolate, phenotype and match placenta to offspring to determine whether the placental phenotype can accurately predict health of in vitro fertilization (IVF)-derived offspring. Because we have previously reported a low frequency of epigenetic errors in multiple tissues of IVF-conceived offspring, we hypothesize that the germline cells also harbor epigenetic mutations. In Specific Aim 2, we will test this hypothesis by determining whether aberrant phenotypes observed in IVF offspring are transmitted to subsequent generations and, if so, assess the mechanism of this transmission. The result from these experiments will provide a trove of information regarding the linkage between epigenetic changes and health of offspring conceived by ART and whether placental phenotyping can predict offspring health. Our findings may also suggest experimental modifications to ART procedures that can improve offspring outcomes. !

摘要 越来越多的不孕不育夫妇转向辅助生殖技术(ART)治疗 他们的不孕不育。越来越令人担忧的是，艺术受孕的儿童患癌症的风险增加。 特定的印迹丢失障碍、先天性畸形、生长受限、先兆子痫 以及出生后的心脏和代谢紊乱。考虑到进行研究的困难 使用人类胚胎，一个小鼠模型系统，它预测了一些与 ART，将用于评估ART对胎盘形态、印记基因的影响 后代的调节、生长、代谢、心脏和行为表型，以及基因 全基因组的表达和染色质结构。特定目标1将评估表型， 包括生长、行为代谢和心血管功能 与自然构思的控制相比较。我们还将询问印记基因的调节 并利用基因表达、DNA甲基化和染色质结构等基因特异性高 吞吐量分析。此外，这个目标的设计将使我们能够分离、表型和 将胎盘与后代进行配对，以确定胎盘表型是否能准确 预测体外受精(IVF)衍生后代的健康状况。因为我们之前已经 据报道，在体外受精受孕的后代的多个组织中，表观遗传学错误的频率很低。 假设生殖系细胞也存在表观遗传突变。在具体目标2中，我们将 通过确定在体外受精后代中观察到的异常表型是否 传播给后代，如果是的话，评估这种传播的机制。 这些实验的结果将提供关于这种联系的大量信息 ART受孕后代的表观遗传学变化与健康之间的关系以及是否胎盘 表型可以预测后代的健康状况。我们的发现也可能表明我们是实验性的。 修改抗逆转录病毒治疗程序，以改善后代结局。 好了！