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The Regulation of Ovarian Aging by H19 and let-7

H19和let-7对卵巢衰老的调节

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目总结/文摘