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）对于越来越多的人来说是无价的需要干预治疗不孕症的女性。尽管如此，艺术构思儿童因表观遗传导致的印记缺失疾病的风险增加错误、生长异常、先天畸形以及出生后心脏和代谢失调。此类问题可能会出现，因为 ART 程序发生时哺乳动物胚胎正在进行表观遗传重新编程。因为很难使用人类胚胎（一种小鼠模型系统）进行研究，该系统预期一些与 ART 相关的风险，将用于评估 ART 干预措施对胎盘形态、印记基因调控、生长、代谢和心脏后代的表型和表观遗传基因调控，包括 DNA 甲基化和全基因组染色质结构。目前，初步证据表明移植到未受刺激的女性体内的冷冻胚胎的围产期发病率低于新鲜周期但相互矛盾的数据表明与冷冻相关的不良后果胚胎。具体目标 1 将确定胚胎玻璃化冷冻和母体的影响激素环境对体外受精产生的胚胎后代结果的影响。而且，植入前遗传筛查（PGS）在缺乏评估卵裂球活检后果的研究。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 时得出。最后，我们的人类胎盘研究数据表明对早期胎盘、胎儿生长和发育至关重要的基因中 DNA 甲基化的改变成人新陈代谢。 Specific Aim 3 会将这些数据转化为我们的动物 ART 模型确定特定基因在 IVF 相关不良后果中的作用。角色 Grb10 在 IVF 相关胎儿生长、胎盘和血管发生变化中的作用将使用小鼠模型进行初步评估。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。这些发现也可能建议对 ART 进行实验性修改可以改善后代结果的程序。