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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的辅助生殖技术（ART）对于越来越多的需要干预措施来治疗其不孕症的妇女。然而，艺术构思儿童表观遗传导致损失损失疾病的风险增加错误，异常生长，先天性畸形以及产后心脏和代谢疾病。可能会出现此类问题，因为在哺乳动物的胚胎是表观遗传重编程的。因为很难使用人类胚胎（小鼠模型系统）进行研究，该系统预期一些与艺术相关的风险将用于评估艺术干预对胎盘形态，印迹基因调节，生长，代谢和心脏后代的表型和表观遗传基因调节，包括DNA甲基化和整个基因组的染色质结构。目前，初步证据表明转移到未刺激的妇女的冷冻胚胎比新的周期但矛盾的数据表明与冷冻有关的不利结果胚胎。特定的目标1将确定胚胎玻璃化和母体的影响 IVF生成的胚胎的后代结果的激素环境。而且，在不存在的情况下，植入前遗传筛查（PGS）正在越来越多地使用研究评估胚泡活检的后果的研究。具体目标2将研究胎盘和艺术后代的表型和表观遗传谱使用PGS时得出。最后，我们人类胎盘研究的数据证明对早期胎盘，胎儿生长和成人代谢。具体目标3将这些数据转化为我们的动物艺术模型确定特定基因在与IVF相关的不良结果中的作用。角色 IVF相关的GRB10胎儿生长，胎盘发生变化最初将评估使用鼠标模型。这些实验的结果将提供有关表观遗传变化与后代健康之间联系的信息由艺术构思。这些发现也可能暗示对艺术的实验修改可以改善后代结果的程序。