DNA methylation differences underlying female reproductive aging

女性生殖衰老背后的DNA甲基化差异

• 批准号: 10664473
• 负责人: Anna Kaitlyn Knight
• 金额: $ 12.57万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664473
• 关键词: Acceleration; Age; Aging; Apoptosis; Biological; Biological Aging; Biological Process; Biology of Aging; Cell Aging; Chronic Disease; Clinical Research; DNA Methylation; DNA Repair; Data; Development; Disease; Elderly; Embryo; Epigenetic Process; Etiology; Female; Fertilization in Vitro; Foundations; Funding; Future; Genes; Genome; Goals; Gonadal Steroid Hormones; Grant; Health; Implant; Individual; Life; Longevity; Maintenance; Manuscripts; Measures; Menopause; Metabolism; Methylation; Mutation; Oocytes; Ovarian Stimulations; Ovary; Participant; Pathway interactions; Pattern; Persons; Positioning Attribute; Process; Reporting; Reproductive system; Research Personnel; Risk; Sampling; Site; Telomere Shortening; Testing; Tissues; Training; Translational Research; United States National Institutes of Health; Woman; Work; Writing; age related; biobank; body system; career development; cell type; design; epigenome; epigenome-wide association studies; experience; falls; fertility preservation; granulosa cell; innovation; insight; methylation pattern; mullerian-inhibiting hormone; oocyte quality; ovarian reserve; preservation; reproductive; reproductive senescence; research and development; success; therapy development; training opportunity

PROJECT SUMMARY Reproductive aging occurs earlier than systemic aging as a person with ovaries’ ovarian reserve is depleted as they approaches menopause. There is considerable variability around when a person with ovaries reaches menopause, yet few contributing factors have been identified. Assessment of reproductive age involves measuring ovarian reserve and oocyte function, which has clearly-defined parameters in in vitro fertilization. As ovarian reserve declines, Anti-Mullerian hormone levels fall and women produce fewer oocytes after ovarian stimulation. Oocyte function also declines, as fewer mature oocytes are produced and have the capacity to be fertilized. The mechanisms of these age-related declines are unclear, but may involve changes in DNA methylation, which are known to occur with age and may reflect the biological processes underlying reproductive aging. We hypothesize that DNA methylation patterns will be associated with ovarian reserve and oocyte function, and that people with ovaries with poor ovarian reserve and oocyte function will experience epigenetic age acceleration and will accumulate more stochastic epigenetic mutations. To test this hypothesis, we will first perform an epigenome-wide association to examine DNA methylation patterns associated with each measure of ovarian reserve and oocyte function. Then, we will calculate epigenetic age and age acceleration, which are indicators of biological aging, and stochastic epigenetic mutations, which increase with age and may disrupt key biological pathways in an individual. If successful, this proposal will provide a better understanding of the genes and processes associated with reproductive aging, would allow for future development of targeted treatments to slow or reverse aging, and would help identify women at increased risk of chronic disease later in life. This proposal will provide focused training opportunities that will be crucial for my success as an independent, NIH-funded researcher. I will work with experts in the fields of aging biology and reproductive aging, epigenetic aging, and clinical and translational research. Finally, I will seek additional training in grant and manuscript writing. This training will position me to apply for future R01 funding and become an independent investigator.

项目摘要 生殖衰老比全身衰老更早，因为卵巢的卵巢储备的人被耗尽为 他们接近更年期。当一个卵巢达到的人到达时，有很大的可变性 更年期，但几乎没有发现贡献因素。生殖年龄的评估涉及 测量卵巢储备和卵母细胞功能，在体外受精中具有明确定义的参数。 随着卵巢保护 卵巢刺激。卵母细胞功能也会下降，因为产生的成熟卵母细胞少并具有 受精的能力。这些与年龄相关的下降的机制尚不清楚，但可能涉及变化 在DNA甲基化中，已知随着年龄的增长而发生的甲基化，可能反映了生物学过程 生殖衰老。我们假设DNA甲基化模式将与卵巢储备和 卵母细胞功能，卵巢储备和卵巢功能较差的卵巢的人会经历 表观遗传年龄的加速度和丙烯酸将更多的随机表观遗传突变。为了检验这一假设， 我们将首先执行整个表观基因组的关联，以检查与 卵巢储备和卵母细胞功能的每个度量。然后，我们将计算表观遗传年龄和年龄 加速度是生物衰老和随机表观遗传突变的指标，随着随着 年龄并可能破坏一个个体的关键生物学途径。如果成功，该提议将提供更好的 了解与生殖衰老相关的基因和过程，将允许未来 开发有针对性的治疗以减缓或逆转衰老，并将有助于确定妇女的风险增加 慢性疾病的后期。该提案将提供重点的培训机会，至关重要 我作为一名独立，NIH资助的研究员的成功。我将与衰老生物学领域的专家合作 以及生殖衰老，表观遗传衰老以及临床和翻译研究。最后，我将寻求更多 授予和手稿写作的培训。这项培训将使我申请将来的R01资金，并且 成为独立研究者。