Photoperiod, melatonin, and reproductive aging

描述（由申请人提供）：本提案概述了申请人的职业发展计划，申请人是一名经过临床培训的妇产科医生，正在从临床医生过渡到基础生物医学研究人员。该奖项的候选人的目标是学习现代分子和细胞技术，应用于他对女性生殖衰老的研究，并促进最终过渡到成为一名独立的研究者。在知名研究人员和多学科咨询委员会的指导下，候选人将从事指导和研究计划，最大限度地提高他发展成为独立科学家的可能性。该研究旨在确定光周期和松果体褪黑激素如何影响女性生殖衰老。典型物种是西伯利亚仓鼠（Phodopus sungorus），这是一种易于维护的实验动物，其生殖生物学对白昼长度和褪黑激素非常敏感。在较短的日间光照周期内饲养雌性仓鼠可减缓生殖老化。在9个月大时，短日母鼠产仔成功率明显高于长日母鼠。妊娠失败只发生在长时间工作的女性中，在这一组中，分娩期间的母婴死亡与子宫功能障碍一致。成年短日雌性卵巢的原始卵泡数量是同龄长日雌性卵巢的两倍。提出了三个目的：1)确定光周期效应对卵巢原始卵泡数量的影响是由于卵泡闭锁减少和/或卵泡更新增加；2)确定光周期和褪黑激素对调节原始卵泡激活的激素和因子的影响；3)确定光周期和褪黑激素是否通过抑制细胞衰老、端粒缩短和雌激素受体的消耗来调节与年龄相关的子宫功能下降。这项工作有助于理解生殖衰老背后的细胞和分子机制，以及如何减缓这一过程。一旦这个奖项的目标已经实现，候选人将作为一个独立的研究者，并开展生殖衰老的研究，这是真正的综合。

DESCRIPTION (provided by applicant): This proposal outlines a career development plan for the applicant, a clinically trained obstetrician/gynecologist, who is making the transition from clinician to basic biomedical researcher. The candidate's goals for this award are to learn modern molecular and cellular techniques as applied to his research on female reproductive aging, and to facilitate the final transition to becoming an independent investigator. Under the mentorship of established investigators and a multidisciplinary advisory committee, the candidate will pursue a program of instruction and research that maximizes the likelihood of his developing into an independent scientist. The research proposed seeks to determine how photoperiod and the pineal gland hormone melatonin affect female reproductive aging. The model species is the Siberian hamster (Phodopus sungorus), an easily maintained laboratory animal whose reproductive biology is exquisitely sensitive to day length and melatonin. Rearing female hamsters in a short day photoperiod decelerates reproductive aging. Short day females had significantly greater litter success than age-matched long day females at 9 months of age. Pregnancy failures occurred only in long day females, and maternal and fetal deaths during parturition in this group are consistent with uterine dysfunction. Ovaries from adult short day females had twice as many primordial follicles as ovaries from age-matched long day females. Three aims are proposed: 1) to determine if the photoperiodic effect on ovarian primordial follicle number is due to a decrease in follicular atresia and/or an increase in follicular renewal; 2) to identify how the hormones and factors that modulate primordial follicle activation are affected by photoperiod and melatonin; and 3) to determine if photoperiod and melatonin modulate the age-associated decline in uterine function by inhibiting cellular senescence, telomere shortening, and attrition of estrogen receptors. The proposed work is relevant to understanding the cellular and molecular mechanisms underlying reproductive aging, and how that process may be decelerated. Once the objectives of this award have been met, the candidate will work as an independent investigator, and carry out research on reproductive aging that is truly integrative.