Project 2: Epigenetic, Behavioral, and Physiological Outcomes in a Mouse ART Model

项目 2：小鼠 ART 模型中的表观遗传、行为和生理结果

• 批准号: 10372962
• 负责人: MARISA S. BARTOLOMEI
• 金额: $ 38.49万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372962
• 关键词: Abnormal placentation; Accounting; Address; Adult; Angelman Syndrome; Animal Model; Animals; Assisted Reproductive Technology; Beckwith-Wiedemann Syndrome; Behavioral; Biological Models; Biopsy; Birth; Cardiac; Cesarean section; Child; Chromatin Structure; Conceptus; Conflict (Psychology); Congenital Abnormality; Country; Couples; DNA Methylation; Data; Development; Disease; Effectiveness; Embryo; Embryo Transfer; Embryonic Development; Endometrium; Environment; Environmental Exposure; Epigenetic Process; European; Experimental Designs; Fertilization in Vitro; Fetal Growth; Fetal Tissues; Fetal Weight; Fostering; Funding; Gene Expression Regulation; Genes; Genetic Screening; Goals; Growth; Health; Heart Diseases; Hormonal; Human; Iatrogenesis; Individual; Infertility; Intervention; Knockout Mice; Link; Low Birth Weight Infant; Marriage; Maternal Age; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Modification; Morphology; Mus; Outcome; Phenotype; Physiological; Placenta; Placentation; Pregnancy; Preimplantation Diagnosis; Procedures; Reproduction; Research; Risk; Role; Safety; Superovulation; Techniques; Testing; Therapeutic; Translating; Validation; Variant; Weight; Weight Gain; Woman; Work; adverse outcome; clinical implementation; embryo cryopreservation; embryo culture; embryo stage 2; experimental study; fetal; genome-wide; human data; imprint; improved; infertility treatment; insight; mouse model; novel strategies; offspring; outcome prediction; perinatal morbidity; placental morphology; postnatal; preimplantation; trophoblast; vasculogenesis

Abstract Assisted Reproductive Technologies (ART) are invaluable for the increasing number of women who require interventions to treat their infertility. Nevertheless, ART-conceived children are at increased risk for loss-of-imprinting disorders resulting from epigenetic errors, abnormal growth, congenital malformations, and postnatal cardiac and metabolic disorders. Such problems likely arise because ART procedures take place when the mammalian embryo is being epigenetically reprogrammed. Because it is difficult to conduct studies using human embryos, a mouse model system, which anticipated some risks associated with ART, will be used to assess the effect of ART interventions on placental morphology, imprinted gene regulation, growth, metabolic and cardiac phenotypes of the offspring, and epigenetic gene regulation, including DNA methylation and chromatin structure genome-wide. Presently, preliminary evidence suggests that frozen embryos transferred into unstimulated women have less perinatal morbidity than fresh cycles but conflicting data suggest adverse outcomes associated with frozen embryos. Specific Aim 1 will determine the effects of embryo vitrification and maternal hormonal environment on offspring outcome of IVF-generated embryos. Moreover, preimplantation genetic screening (PGS) is being increasingly employed in the absence of research assessing the consequences of blastomere biopsy. Specific Aim 2 will investigate the phenotypes and epigenetic profiles of the placenta and ART offspring derived when PGS is used. Finally, data from our human placental studies demonstrate alterations in DNA methylation in genes critical to early placentation, fetal growth, and adult metabolism. Specific Aim 3 will translate these data to our animal ART model to determine the role of specific genes in adverse outcomes associated with IVF. The role of Grb10 in IVF-associated changes in fetal growth, placentation, and vasculogenesis using a mouse model will be initially assessed. Results of these experiments will provide information regarding the linkage between epigenetic changes and health of offspring conceived by ART. These findings may also suggest experimental modifications to ART procedures that can improve offspring outcomes.

摘要 辅助生殖技术（ART）对于越来越多的女性来说是非常宝贵的。 需要干预治疗不孕症的妇女。然而，艺术构思 儿童患上由表观遗传学引起的印记丧失障碍的风险增加， 错误，异常生长，先天性畸形，以及出生后心脏和代谢 紊乱这些问题可能会出现，因为ART程序发生时， 哺乳动物的胚胎正在进行表观遗传重编程。因为很难 使用人类胚胎进行研究，这是一种小鼠模型系统， 与ART相关的风险，将用于评估ART干预对 胎盘形态，印迹基因调控，生长，代谢和心脏 后代的表型和表观遗传基因调控，包括DNA甲基化 和全基因组的染色质结构。目前，初步证据表明， 将冷冻胚胎移植到未受刺激的妇女中， 新的周期，但相互矛盾的数据表明，与冷冻相关的不良结果 胚胎具体目标1将确定胚胎玻璃化冷冻和母体 激素环境对IVF产生的胚胎的后代结果。此外，委员会认为， 植入前遗传筛查（PGS）越来越多地被用于缺乏 评估卵裂球活检结果的研究。具体目标2将 研究胎盘和ART后代的表型和表观遗传特征 使用PGS时导出。最后，我们的人类胎盘研究数据表明， 对早期胎盘形成、胎儿生长和发育至关重要的基因中的DNA甲基化改变， 成人新陈代谢具体目标3将这些数据转化为我们的动物ART模型， 确定特定基因在IVF相关不良结局中的作用。的作用 Grb 10在IVF相关的胎儿生长、胎盘形成和血管发生变化中的作用 使用小鼠模型进行初步评估。这些实验的结果将提供 关于表观遗传变化与后代健康之间联系的信息 这些发现也可能表明对ART的实验性修改 可以改善后代结果的程序。