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.

项目概要 生殖衰老比全身衰老更早发生，因为有卵巢的人的卵巢储备会随着以下原因而耗尽： 有卵巢的人接近更年期时，存在很大的差异。 更年期，但尚未发现对生育年龄的评估涉及的影响因素。 测量卵巢储备和卵母细胞功能，在体外受精中有明确的参数。 随着卵巢储备功能下降，抗苗勒氏管激素水平下降，女性产后卵母细胞减少 卵巢刺激也会导致卵母细胞功能下降，因为产生的成熟卵母细胞越来越少。 这些与年龄相关的受精能力下降的机制尚不清楚，但可能涉及变化。 DNA 甲基化，已知会随着年龄的增长而发生，可能反映了潜在的生物过程 我们发现DNA甲基化模式与卵巢储备和生殖衰老有关。 卵母细胞功能，卵巢储备和卵母细胞功能较差的卵巢患者会经历 表观遗传年龄加速并将积累更多随机表观遗传突变。 我们将首先进行全表观基因组关联，以检查与以下因素相关的 DNA 甲基化模式： 然后，我们将计算表观遗传年龄和年龄。 加速，这是生物衰老的指标，以及随机表观遗传突变，随着时间的推移而增加 如果成功，该提案将提供更好的方法。 了解与生殖衰老相关的基因和过程，将有助于未来 开发有针对性的治疗方法以减缓或逆转衰老，并有助于识别风险增加的女性 该提案将提供有针对性的培训机会，这对于以后的慢性疾病至关重要。 作为一名由美国国立卫生研究院 (NIH) 资助的独立研究人员，我将与衰老生物学领域的专家合作。 最后，我将寻求更多的研究。 资助和稿件写作培训将使我能够申请未来的 R01 资助和 成为一名独立调查员。