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. !

抽象的越来越多的不孕夫妇转向辅助生殖技术（ART）来治疗他们的不孕症。越来越令人担忧的是，通过 ART 受孕的孩子面临更高的患病风险特定印记缺失性疾病、先天性畸形、生长受限、先兆子痫以及产后心脏和代谢紊乱。鉴于进行研究的难度使用人类胚胎、小鼠模型系统，该系统预测了与 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表达和染色质结构。具体目标 1 将评估表型，包括 ART 后代的生长、行为代谢和心血管功能与自然构思的对照进行比较。我们还将探究印记基因调控以及基因表达、DNA 甲基化和染色质结构，使用基因特异性和高吞吐量分析。此外，这一目标的设计将使我们能够分离、表型和将胎盘与后代进行匹配，以确定胎盘表型是否能够准确预测体外受精 (IVF) 后代的健康状况。因为我们之前已经报道了体外受精后代的多个组织中表观遗传错误的频率较低，我们假设生殖细胞也含有表观遗传突变。在具体目标 2 中，我们将通过确定在 IVF 后代中观察到的异常表型是否与遗传给后代，如果是这样，评估这种传播的机制。这些实验的结果将提供有关链接的大量信息表观遗传变化与 ART 受孕后代的健康之间的关系以及胎盘是否表型分析可以预测后代的健康状况。我们的发现也可能表明实验修改 ART 程序可以改善后代的结局。！