The Role of Gonadotrope in Stress-Induced Reproductive Impairment

6.项目总结/摘要 在现代社会中，压力对生殖的影响可能导致不必要的周期中断， 不孕作为一个例子，功能性下丘脑性闭经（FHA）是一种混合性的无排卵状态， 起源于GnRH驱动力降低和脉冲性促性腺激素分泌减少。FHA已经 归因于压力，特别是心理社会压力，并与下丘脑-垂体-肾上腺轴有关 活化和增强的糖皮质激素分泌。糖皮质激素一直被认为是潜在的 应激诱导的卵巢周期性抑制的介质;然而，涉及的机制并不清楚 明白本提案的总体目标是检验以下统一假设： 糖皮质激素对压力的反应损害女性的生殖功能。这种抑制发生在 通过急性非基因组和慢性基因组机制。GR对于应力诱导的 生殖功能障碍，并通过垂体中的协调作用促进抑制 促性腺激素和GnRH神经元。提出了三个具体目标：1）测试假设， 皮质酮的慢性抑制作用通过促性腺激素基因的减少进行基因组转导 皮质酮的急性效应涉及非核GR作用，其介导改变的糖皮质激素受体。 促性腺激素细胞内的信号传导。2：研究应激诱导的促性腺激素抑制 体内卵巢周期性的合成、分泌和破坏：GR在促性腺细胞中的作用 3：检查压力对体内生殖神经内分泌活动的核心作用：卵巢的影响 类固醇和GR在GnRH神经元中的作用。通过多学科培训，候选人 为自己精心打造了一个科学利基市场通过她的研究生和早期博士后工作，她 确定糖皮质激素足以作为神经内分泌轴内的抑制中间体 也是应对某些压力时抑制生殖所必需的。有了这个项目的资金 途径独立奖，候选人将专门她的训练，以剖析 糖皮质激素在分子和遗传水平上调节促性腺激素功能的机制。的 加州圣地亚哥大学位于加州的拉霍亚，是研究合作的温床。 候选人组建了一支由来自两所著名机构的导师团队：加州大学、 圣地亚哥和索尔克生物研究所，这将提供在体内同化的专业知识， 和体外系统来理解分子机制。帕梅拉·梅隆博士位于大学 是体内和体外系统同化的先驱， 分子机制在索尔克研究所，凯瑟琳·里维尔博士将提供专业知识， 生殖神经内分泌功能障碍研究的应激范式和应激系统。为指导 这些导师，结合候选人以前在分子神经内分泌学方面的工作，将 为候选人发展独立的多学科研究计划提供坚实的基础 旨在了解生殖神经内分泌功能障碍的分子基础。这些宝贵 研究经验将跨越分子和细胞机制的研究，以整个动物体内 生理功能，使她在一个强大的地位，作为一个年轻的调查员武装与一系列的研究 如果没有过渡性K99/R 00资金，所有这些都是不可能的。

6. Project Summary/Abstract The impact of stress on reproduction in modern society can lead to unwanted cycle disruption and infertility. As an example, functional hypothalamic amenorrhea (FHA) is an anovulatory condition of mixed origin resulting from decreased GnRH drive and reduced pulsatile gonadotropin secretion. FHA has been attributed to stress, especially psychosocial stress, and is associated with hypothalamic-pituitary-adrenal axis activation and enhanced glucocorticoid secretion. Glucocorticoids have long been considered to be potential mediators of stress-induced suppression of ovarian cyclicity; however, the mechanisms involved are not well understood. The overall goal of this proposal is to test the unifying hypothesis that: Elevated circulating glucocorticoids, in response to stress, impair reproductive function in females. This inhibition occurs both by acute non-genomic and by chronic genomic mechanisms. GR is necessary for stress-induced reproductive dysfunction and contributes to suppression via coordinated actions in the pituitary gonadotrope and GnRH neuron. Three specific aims are proposed to: 1) Test the hypothesis that the chronic inhibitory effect of corticosterone is transduced genomically via a reduction in gonadotropin gene transcription, whereas the acute effect of corticosterone involves non-nuclear GR actions that mediate altered intracellular signaling within the gonadotrope. 2: Investigate stress-induced suppression of gonadotropin synthesis and secretion and disruption of ovarian cyclicity in vivo: role of GR action within the gonadotrope cell. 3: Examine the central actions of stress on reproductive neuroendocrine activity in vivo: influence of ovarian steroids and role of GR within the GnRH neuron. Through multidisciplinary training, the Candidate has carefully carved out a scientific niche for herself. Through her graduate and early postdoctoral work, she determined that glucocorticoids were sufficient to act as inhibitory intermediates within the neuroendocrine axis and necessary for reproductive suppression in response to certain types of stress. With the funding of this PATHWAY TO INDEPENDENCE AWARD, the Candidate will specialize her training to dissect the mechanisms of glucocorticoid regulation of gonadotrope function at the molecular and genetic levels. The University of California, San Diego, is located in La Jolla, California, and is a hotbed of research collaboration. The candidate has assembled a team of mentors from two distinguished institutions, University of California, San Diego and the Salk Institute for Biological Study, which will provide expertise in the assimilation of in vivo and in vitro systems for understanding molecular mechanisms. Dr. Pamela Mellon is located at the University of California, San Diego and is a pioneer in the assimilation of in vivo and in vitro systems for understanding molecular mechanisms. At the Salk Institute, Dr. Catherine Rivier will provide expertise in the integration of stress paradigms and stress systems for the study of reproductive neuroendocrine dysfunction. The guidance of these mentors, in conjunction with the candidate's previous work in molecular neuroendocrinology, will provide a solid foundation for the candidate to develop an independent multidisciplinary research program aimed at understanding the molecular basis reproductive neuroendocrine dysfunction. These valuable research experiences will span the study of molecular and cellular mechanisms to whole animal in vivo physiologic function, placing her in a powerful position as a young investigator armed with a host of research skills, techniques and training, all of which would not be possible without transitional K99/R00 funding.