Photoperiod, melatonin, and reproductive aging

描述(由申请人提供)：本建议书概述了申请者的职业发展计划，该申请者是一名受过临床培训的产科/妇科医生，正在从临床医生过渡到基础生物医学研究人员。这位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人员。在现有研究人员和多学科咨询委员会的指导下，候选人将追求一项指导和研究计划，以最大限度地提高他成长为独立科学家的可能性。这项研究旨在确定光周期和松果体激素褪黑激素如何影响女性生殖衰老。模式物种是西伯利亚仓鼠，这是一种易于维护的实验动物，其繁殖生物学对日长和褪黑素非常敏感。在短短一天的光周期内饲养雌性仓鼠可以减缓生殖衰老。9个月龄时，短日龄母鱼的产仔成功率显著高于同龄的长日龄母鱼。妊娠失败只发生在长日龄女性，这一组产妇和胎儿在分娩期间死亡与子宫功能障碍相一致。成年短日龄雌性卵巢的原始卵泡数量是年龄匹配的长日龄雌性卵巢的两倍。有三个目的被提出：1)确定光周期对卵巢原始卵泡数量的影响是否由于卵泡闭锁的减少和/或卵泡更新的增加；2)确定调节原始卵泡激活的激素和因素如何受光周期和褪黑素的影响；以及3)确定光周期和褪黑素是否通过抑制细胞衰老、端粒缩短和雌激素受体的磨损来调节与年龄相关的子宫功能下降。这项拟议的工作与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有关。一旦达到该奖项的目标，候选人将作为独立研究员工作，并开展真正综合性的生殖衰老研究。

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.