Epimutations in Offspring Produced by Assisted Reproductive Technologies (ART)

辅助生殖技术 (ART) 产生的后代的表观突变

• 批准号: 8757199
• 负责人: John R MCCARREY
• 金额: $ 62.76万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8757199
• 关键词: Address; Age; Appearance; Assisted Reproductive Technology; Clinical; Couples; DNA Methylation; Data Set; Defect; Development; Disease; Embryo; Embryo Transfer; Embryonic Development; Epigenetic Process; Etiology; Frequencies; Future; Gametogenesis; Gene Expression; Gene Expression Profile; Genes; Genome; Genomics; Germ Lines; Gonadotropins; Health; Human; Human Biology; Incidence; Individual; Intracytoplasmic Sperm Injections; Knowledge; Lead; Maintenance; Methodology; Methods; Modification; Mus; Oocytes; Outcome; Pattern; Phenotype; Procedures; Process; Prospective Studies; Protocols documentation; Relative (related person); Reporting; Reproduction; Research; Resolution; Resources; Risk; Safety; Somatic Cell; Staging; Technical Expertise; Technology; Testing; Time; base; blastocyst; design; embryo culture; epigenome; epigenomics; experience; fetal; folliculogenesis; genome-wide; imprint; innovation; novel; offspring; preimplantation; programs; public health relevance; skills

DESCRIPTION (provided by applicant): This project is designed to obtain the first comprehensive assessment of epigenetic defects (epimutations) induced by the use of assisted reproductive technologies (ART) in the offspring produced. The genome-wide occurrence of abnormalities in DNA methylation patterns and gene expression patterns will be assessed in mice produced by intracytoplasmic sperm injection (ICSI) using cutting-edge, high-throughput epigenomic and genomic technologies. In addition, the etiology of ART-induced epimutations will be investigated by determining the precise timing of appearance of epimutations in mice produced by ART, as well as by discerning the relative contribution of each of three specific aspects of the ART process - gonadotropin stimulation of folliculogenesis, prolonged culture of preimplantation embryos, and embryo transfer - to the induction of epimutations. Finally, the fate of ART-induced epimutations will be examined to determine if these are consistently corrected by epigenetic reprogramming during either embryogenesis or gametogenesis. The significance of the research proposed in this application is that it will include high (single-base) resolution, comprehensive analyses of the disruptive effects of ART on epigenetic programming genome-wide, and it will facilitate controlled, prospective studies of the genesis, etiology, extent and fte of epimutations induced by ART, including parallel, simultaneous studies of the relative contribution(s) of multiple different aspects of the ART process to the induction of epimutations in the offspring produced. The proposed research is innovative and timely because we are now able to generate datasets of unprecedented scale and resolution describing abnormal epigenetic programming and gene expression in ART offspring, and we can use these to understand the genesis, consequences and fate of ART-induced epimutations in ways that will have significant implications for basic biology and human health. The resulting enhanced understanding of the etiology of ART-induced epimutations will inform future modifications of clinical ART protocols to minimize the induction of epimutations in ART-derived human offspring and thereby reduce the occurrence of epigenetic disorders in individuals produced by this technology.

描述(由申请人提供)：该项目旨在首次全面评估因使用辅助生殖技术(ART)而产生的后代的表观遗传缺陷(表观突变)。将使用尖端、高通量的表观基因组和基因组技术，在卵胞浆内单精子注射(ICSI)产生的小鼠中评估DNA甲基化模式和基因表达模式的全基因组异常发生。此外，将通过确定ART产生的小鼠表观突变的准确出现时间，以及辨别ART过程的三个特定方面--促性腺激素刺激卵泡发生、植入前胚胎的延长培养和胚胎移植--对表观突变诱导的相对贡献，来研究ART诱导表型突变的病因学。最后，将检查ART诱导的表观突变的命运，以确定是否在胚胎发生或配子发生期间通过表观遗传重新编程来一致地纠正这些命运。在本申请中提出的研究的意义在于它将包括高(单基)分辨率， 全面分析ART对全基因组表观遗传编程的颠覆性影响，将有助于对ART诱导的表观突变的起源、病因学、程度和FTE进行可控的前瞻性研究，包括平行、同时研究ART过程的多个不同方面对诱导后代表观突变的相对贡献(S)。这项拟议的研究具有创新性和及时性，因为我们现在能够产生前所未有的规模和分辨率的数据集，描述ART后代中异常的表观遗传编程和基因表达，并利用这些数据集来了解ART诱导的表观突变的起源、后果和命运，这将对基础生物学和人类健康产生重大影响。由此产生的对ART诱导的表观突变的病因学的理解将为未来临床ART方案的修改提供信息，以将ART衍生的人类后代的表观突变的诱导降至最低，从而减少由这项技术产生的个体表观遗传学疾病的发生。