DNA methylation differences underlying female reproductive aging

项目摘要 生殖老化发生早于系统性老化，因为卵巢储备的人会随着年龄的增长而耗尽， 她们接近更年期。当一个有卵巢的人达到 更年期，但很少有贡献的因素已确定。生育年龄的评估包括 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。 随着卵巢储备功能的下降，抗苗勒管激素水平下降， 卵巢刺激卵母细胞的功能也会下降，因为产生的成熟卵母细胞较少， 能力被施肥。这些与年龄相关的下降的机制尚不清楚，但可能涉及改变 DNA甲基化，这是已知的发生与年龄，并可能反映了生物过程的基础 生殖老化我们假设DNA甲基化模式与卵巢储备功能相关， 卵母细胞功能，卵巢储备和卵母细胞功能差的卵巢患者将经历 表观遗传年龄加速，并将积累更多的随机表观遗传突变。为了验证这个假设， 我们将首先进行表观基因组范围的关联，以检查DNA甲基化模式与 卵巢储备和卵母细胞功能的每一项测量。然后，我们将计算表观遗传年龄和年龄 加速，这是生物老化的指标，和随机表观遗传突变，这增加与 年龄，并可能破坏个体的关键生物途径。如果成功的话，这一建议将提供一个更好的 了解与生殖衰老相关的基因和过程，将使未来 开发有针对性的治疗方法，以减缓或逆转衰老，并将有助于识别风险增加的女性 慢性病的风险。这项建议将提供重点突出的培训机会， 我作为一个独立的，国家卫生研究院资助的研究人员的成功。我将与衰老生物学领域的专家合作 以及生殖老化、表观遗传老化、临床和转化研究。最后，我将寻求更多的 资助和手稿写作培训。这次培训将使我能够申请未来的R01资金， 成为独立调查员。

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.