Identify genetic mechanisms that regulate female sexual maturation

描述(申请人提供)：性成熟是生物体进化成功的关键。进化假说预测，较慢但功能齐全的女性生殖表明衰老较慢，并与延长寿命有关。在人类中，月经初潮年龄(AAM)与晚年的重大健康状况有关，至少有一半 AAM的变异是由尚未完全了解的遗传因素决定的。最近，我们对32个品系的小鼠性成熟年龄(FSM)进行了系统测量。FSM的年龄在这些菌株之间差异很大，延迟FSM与循环中胰岛素样生长因子1(IGF1)水平降低和寿命延长有关。但部分菌株的FSM延迟，但IGF1升高，说明循环中的IGF1依赖和独立的机制参与其中。为了确定潜在的遗传机制，我们从15个近交系中产生了7个小鼠杂交，这些杂交广泛地代表了小鼠家族中FSM的遗传多样性和年龄变异。我们收集了这些杂交组合中1,962个雌性的FSM年龄、血浆和DNA样本。利用遗传学和生物信息学的方法，我们确定了一个有希望的候选基因--枯草杆菌蛋白原转换酶/可信2(Pcsk2)。在这个项目中，我们建议确定女性性成熟的新的调控候选者。该项目将为今后对密克罗尼西亚联邦及其相关疾病S以及衰老过程本身的研究奠定坚实的基础。

DESCRIPTION (provided by applicant): Sexual maturation is key to the evolutionary success of an organism. Evolutionary hypotheses predict that slower but fully functional female reproduction indicates slower aging and associates with extended lifespan. In humans, the age at menarche (AAM) is associated with significant health conditions later in life, and at least half the variation in AAM is determined by genetic factors that are not yet fully understood. Recently, we systematically measured age of female sexual maturation (FSM) in 32 mouse strains. The age of FSM varied dramatically among these strains, and delayed FSM correlated with lower circulating insulin like growth factor 1 (IGF1) and extended longevity. Some strains, however, had delayed FSM but higher IGF1, showing that circulating IGF1 dependent and independent mechanisms are involved. To identify the underlying genetic mechanisms, we generated 7 mouse crosses from 15 inbred strains that broadly represent the genetic diversity and variation in age of FSM across the mouse family. We have collected the age of FSM, plasma and DNA samples for 1,962 females of these crosses. And using genetic and bioinformatic methods, we identified a promising candidate gene, proprotein convertase subtilisin/kexin type 2 (Pcsk2). In this project, we propose to identify novel regulatory candidates of female sexual maturation. This project will lay a solid foundation for future investigation of FSM and its related diseases, s well as the aging process itself.