The regulation of ovarian aging by H19 and let-7

H19和let-7对卵巢衰老的调控

• 批准号: 10120190
• 负责人: Amanda Nicole Kallen
• 金额: $ 36.01万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10120190
• 关键词: Acceleration; Address; Age; Aging; Aneuploidy; Area; Back; Binding; Binding Sites; Birth Rate; Cells; Child; Congenital Abnormality; DNA Damage; DNA Repair; DNA Repair Gene; Data; Defect; Development; Disease; Doxorubicin; Elderly; Estradiol; Estrogens; Etiology; Exposure to; Fertility; Functional disorder; Gatekeeping; Genes; Genomics; Germ Cells; Growth; H19 gene; Health; Hormones; In Vitro; Infertility; Investigation; Lead; Link; Long-Term Effects; Maintenance; Maternal Age; Maternal Health; Mediating; Messenger RNA; MicroRNAs; Mission; Molecular; Mothers; Mus; National Institute of Child Health and Human Development; Oocytes; Outcome; Ovarian; Ovarian Follicle; Ovarian aging; Ovary; Pathway interactions; Physiology; Play; Population; Pregnancy loss; Premature Menopause; Primordial Follicle; Process; Production; Public Health; RNA Interference; Regulation; Regulatory Pathway; Reproduction; Reproductive Health; Research Priority; Research Support; Role; Signal Pathway; Somatic Cell; Spontaneous abortion; Testing; Therapeutic; Time; Transfection; United States National Institutes of Health; Untranslated RNA; Woman; Women' s Health; Work; base; chemotherapeutic agent; child bearing; early pregnancy loss; fetal loss; folliculogenesis; granulosa cell; hormone regulation; innovation; insight; mullerian-inhibiting hormone; non-genomic; novel; offspring; oocyte quality; ovarian reserve; primary ovarian insufficiency; recruit; repaired; reproductive; reproductive senescence; response; transcriptome

PROJECT SUMMARY/ABSTRACT The mean age of first-time mothers is on the rise, with serious consequences for maternal health and that of their offspring. Older maternal age is strongly associated with birth defects, miscarriage, and infertility. These poor reproductive outcomes can frequently be traced back to defects in follicular and oocyte quantity and quality that occur with ovarian aging. A continuous decline in the quantity of ovarian follicles (i.e. the “ovarian reserve”) occurs during reproductive aging, as the pool of primordial follicles is continuously depleted. Additionally, oocyte quality declines as follicles and oocytes accumulate DNA damage over time, a process which accelerates even more rapidly when the ovary is exposed to gonadotoxins. There is therefore an urgent need to better understand the mechanisms that control follicular and oocyte quantity and quality in order to support the health of women and their children. The noncoding RNAs H19 and let-7 play essential roles in mammalian development, but little is known about their role in ovarian follicle growth and oocyte function. We have uncovered a plausible mechanism for noncoding-RNA-based regulation of follicular health via the H19/let-7 pair. We previously showed that H19 binds and antagonizes the miRNA let-7. We also demonstrated that in the absence of H19, ovarian AMH expression is decreased, follicular recruitment is accelerated, and fertility is compromised. We have observed that AMH has a functional let-7 binding site, suggesting a ncRNA-mediated mechanism for AMH regulation by H19 via let-7. Moreover, our preliminary data suggests altered response to DNA damage in the absence of H19. Thus, there is plausible mechanistic insight into, and strong support for, the role of H19 and let- 7 in the regulation of follicular/oocyte recruitment and function. In Aim 1, we will determine the role of H19 in E2- and AMH-mediated regulation of follicle quantity. In Aim 2, we will determine whether ovaries of H19KO mice are more susceptible to DNA damage than their WT counterparts. Lastly, for Aim 3, we will determine whether the abnormal follicular development and expression of DNA damage genes observed in H19KO mice is mediated via let-7 and identify changes in the transcriptome of somatic cells and oocytes related to loss of H19. Our approach is innovative because it represents a substantive departure from the status quo by defining noncoding RNAs (ncRNAs) as major regulators of oocyte quantity and quality, and has the potential to lead to novel, ncRNA-based treatments for a broad range of reproductive disease states.

项目概要/摘要 初为人母的平均年龄正在上升，这对孕产妇健康和女性健康造成严重影响 他们的后代。高龄产妇与出生缺陷、流产和不孕症密切相关。这些 不良的生殖结果通常可以追溯到卵泡和卵母细胞数量和质量的缺陷 是随着卵巢老化而发生的。卵泡数量（即“卵巢储备”）持续下降 发生在生殖衰老期间，因为原始卵泡池不断耗尽。此外，卵母细胞 随着时间的推移，卵泡和卵母细胞 DNA 损伤不断累积，质量下降，这一过程甚至会加速 当卵巢暴露于性腺毒素时，速度更快。因此迫切需要更好地理解 控制卵泡和卵母细胞数量和质量以支持妇女健康的机制 和他们的孩子。非编码 RNA H19 和 let-7 在哺乳动物发育中发挥重要作用，但很少 众所周知它们在卵泡生长和卵母细胞功能中的作用。我们发现了一个合理的 通过 H19/let-7 对进行基于非编码 RNA 的卵泡健康调节机制。我们之前展示过 H19 结合并拮抗 miRNA let-7。我们还证明，在没有 H19 的情况下，卵巢 AMH 表达降低，卵泡募集加速，生育能力受到损害。我们有 观察到 AMH 具有功能性的 let-7 结合位点，表明 AMH 存在 ncRNA 介导的机制 H19 通过 let-7 进行调节。此外，我们的初步数据表明，DNA损伤的反应发生了改变 缺少 H19。因此，对 H19 和 let- 的作用有合理的机制洞察和强有力的支持。 7 调节卵泡/卵母细胞募集和功能。在目标 1 中，我们将确定 H19 在 E2 中的作用- 以及 AMH 介导的卵泡数量调节。在目标 2 中，我们将确定 H19KO 小鼠的卵巢是否 比 WT 同类更容易受到 DNA 损伤。最后，对于目标 3，我们将确定是否 在 H19KO 小鼠中观察到的异常卵泡发育和 DNA 损伤基因表达是 通过let-7介导并识别与丢失相关的体细胞和卵母细胞转录组的变化 H19。我们的方法是创新的，因为它代表了对现状的实质性背离 将非编码 RNA (ncRNA) 定义为卵母细胞数量和质量的主要调节因子，并有潜力 导致针对多种生殖疾病状态的基于 ncRNA 的新型治疗方法。