The Regulation of Ovarian Aging by H19 and let-7

H19和let-7对卵巢衰老的调节

• 批准号: 10768346
• 负责人: Amanda Nicole Kallen
• 金额: $ 30.42万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10768346
• 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; Deterioration; Development; Doxorubicin; Elderly; Estradiol; Estrogens; Etiology; Exposure to; Fertility; Functional disorder; Gatekeeping; Genes; Genomics; Germ Cells; Growth; H19 gene; Health; Hormones; In Vitro; Infertility; Investigation; 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; Ovarian; Ovarian Follicle; Ovarian aging; Ovary; Pathway interactions; Physiology; Play; Population; Predisposition; 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; Tissues; United States National Institutes of Health; Untranslated RNA; Woman; Women' s Health; Work; chemotherapeutic agent; child bearing; early pregnancy loss; fetal loss; folliculogenesis; granulosa cell; innovation; insight; mullerian-inhibiting hormone; non-genomic; novel; offspring; oocyte quality; ovarian reserve; primary ovarian insufficiency; recruit; repaired; reproductive; reproductive outcome; reproductive senescence; reproductive system disorder; 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.

项目摘要/摘要 初次母亲的平均年龄正在上升，对物物健康和 他们的后代。较旧的物质年龄与先天缺陷，流产和不育症密切相关。这些 不良的繁殖结果经常可以追溯到卵形和卵母细胞数量和质量的缺陷 卵巢衰老发生。卵巢卵形的数量不断下降（即“卵巢储备”） 发生在生殖衰老期间，因为原始卵泡的库不断耗尽。另外，卵母细胞 质量随着时间的推移而下降，卵泡和卵母细胞丙烯酸DNA损伤，这一过程甚至可以丙烯酸 当卵巢暴露于性腺毒素时，会更快。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的机制以支持妇女的健康 和他们的孩子。未编码的RNA H19和Let-7在哺乳动物开发中起着重要的作用，但很少 知道它们在卵巢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对基于非编码RNA调节卵泡健康的机制。我们以前显示了 H19结合并拮抗miRNA let-7。我们还证明，在缺乏H19的情况下 改善了AMH的表达，卵泡募集得到加速，生育率受到损害。我们有 观察到AMH具有功能性let-7结合位点，这表明NCRNA介导的AMH机制 H19通过let-7进行调节。此外，我们的初步数据表明，对DNA损伤的反应改变了 缺乏H19。这是对H19和Let- 7在调节卵泡/囊肿的募集和功能中。在AIM 1中，我们将确定H19在E2-中的作用 和AMH介导的叶量调节。在AIM 2中，我们将确定H19KO小鼠的卵巢是否 比其WT对应物更容易受到DNA损伤。最后，对于AIM 3，我们将确定是否 在H19KO小鼠中观察到的DNA损伤基因的异常follic发育和表达 通过let-7介导，并确定与丢失有关的体细胞和卵母细胞的转录组的变化 H19。我们的方法具有创新性，因为它代表了与现状的实质性不同 将非编码RNA（NCRNA）定义为卵母细胞数量和质量的主要调节剂，并且有潜力 导致针对多种生殖疾病状态的新型，基于NCRNA的治疗方法。