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

基本信息

批准号：
10152633
负责人：
MARISA S. BARTOLOMEI
金额：
$ 32.74万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152633
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

项目摘要

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. !

抽象的不育夫妇越来越多地转向辅助生殖技术（ART）来治疗他们的不孕症。越来越关注的是艺术构想的儿童的风险增加特定的损失疾病，先天性畸形，生长限制，先兆子痫以及产后心脏和代谢疾病。考虑到进行研究的困难使用人类胚胎，鼠标模型系统，该系统预计与艺术将用于评估艺术对胎盘形态，印迹基因的影响后代和基因的调节，生长，代谢，心脏和行为表型表达和染色质结构全基因组。特定目标1将评估表型，包括生长，行为代谢和心血管功能，在Art-Offspring 与自然构造的对照进行比较。我们还将询问印迹基因调节以及使用基因特异性和高的基因表达，DNA甲基化和染色质结构吞吐量分析。此外，这个目标的设计将使我们能够隔离，表型和将胎盘与后代匹配，以确定胎盘表型是否可以准确预测体外受精（IVF）衍生的后代的健康。因为我们以前有报道了IVF构想后代多个组织中表观遗传误差的频率低，我们假设种系细胞还具有表观遗传突变。在特定的目标2中，我们将通过确定在IVF后代中观察到的异常表型来检验这一假设传输到随后的世代，如果是这样，请评估这种传播的机制。这些实验的结果将提供有关联系的信息在艺术构想的后代的表观遗传变化和健康之间表型可以预测后代健康。我们的发现也可能建议实验修改可以改善后代结果的艺术程序。呢