Thursday, November 21, 2024
11/21/2024
Project Summary The female reproductive system is the first system to experience age-dependent decline in mammals. In humans, this decline begins in one’s mid-thirties and continues to progress until menopause is reached at approximately 50 years of age. This age-dependent decline is characterized by many fertility complications that lead to negative outcomes for mother and fetus, such as prolonged time until conception, spontaneous abortion, chromosome abnormalities, preeclampsia, preterm birth, and birth defects. This phenomenon has become a significant health care concern, as an escalating number of women are postponing childbearing until advanced reproductive age, leading to increased reliance on artificial reproductive technologies (ART). Unfortunately, ART has yet to overcome the primary source of age-dependent fertility decline: oocyte quality. Despite the significant role oocyte quality plays in female reproductive aging, the molecular components that lead to its decline remain elusive. The long-term goal of this project is to identify novel molecular mechanisms that contribute to oocyte quality decline. The mammalian oocyte is an extremely long-lived cell that originates during early embryonic development. Not only does it contribute half of an embryo’s genome, but it also provides most of the proteins, lipids, mRNA, and nutrients required for developmental competence. Translation is a vital molecular player that supports developmental competence, yet it remains unclear if an oocyte’s translation abilities change with age. I have generated substantial preliminary evidence that suggest two key aspects of translation, (1) ribosome biogenesis and (2) protein synthesis, become perturbed with age in oocytes. My proposal will elucidate how translation becomes perturbed with age throughout oocyte development and maturation using a mouse model. Aim 1 will characterize how ribosome biogenesis changes with age by taking a ribosomal RNA (rRNA)-centric approach, as rRNA is the rate limiting factor of ribosome biogenesis. This aim will be addressed by examining rRNA production and the three key components of rRNA transcription regulation: rDNA methylation, rDNA transcription factor binding, and RNA Polymerase 1, in oocytes from reproductively young and old mice. Aim 2 will determine how translation activity and accuracy changes with age, with a combined in vivo and in vitro approach. Global translation activity, polysome and monosome distributions, and the occurrence of translation errors will be measured in oocytes from reproductively young and old mice. The completion of the proposed study will provide novel insight to age-dependent changes in a critical component of oocyte quality and could contribute to new therapeutic targets to improve reproductive longevity, and ultimately maternal and fetal health.
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