The Role of Gonadotrope in Stress-Induced Reproductive Impairment

描述（由申请人提供）：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和不育。例如，功能性下丘脑性闭经（FHA）是一种由GnRH驱动减少和脉冲性促性腺激素分泌减少引起的混合性无排卵疾病。FHA归因于压力，特别是心理社会压力，并与下丘脑-垂体-肾上腺轴激活和糖皮质激素分泌增加有关。长期以来，糖皮质激素被认为是应激诱导的卵巢周期性抑制的潜在介质;然而，所涉及的机制尚不清楚。本提案的总体目标是检验以下统一假设：循环糖皮质激素升高，对压力的反应，损害女性的生殖功能。这种抑制通过急性非基因组机制和慢性基因组机制发生。GR是应激诱导的生殖功能障碍所必需的，并通过垂体促性腺激素和GnRH神经元的协调作用而有助于抑制。提出了三个具体的目标：1）测试的假设，皮质酮的慢性抑制作用是通过减少促性腺激素基因转录的基因组转导，而皮质酮的急性作用涉及非核GR的行动，介导改变细胞内信号在促性腺激素。2)研究体内应激诱导的促性腺激素合成和分泌的抑制以及卵巢周期性的破坏：GR在促性腺激素细胞中的作用。3)检查应激对体内生殖神经内分泌活动的中枢作用：卵巢类固醇的影响和GnRH神经元内GR的作用。通过多学科的培训，候选人精心为自己开辟了一个科学利基。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性中间体，并且是应对某些类型压力的生殖抑制所必需的。在独立之路奖的资助下，候选人将专注于她的培训，以在分子和遗传水平上剖析糖皮质激素调节促性腺激素功能的机制。加州大学圣地亚哥分校位于加州的拉霍亚，是研究合作的温床。候选人已经组建了一个来自两个著名机构的导师团队，加州大学圣地亚哥分校和索尔克生物研究所，这将提供体内和体外系统同化的专业知识，以了解分子机制。Pamela Mellon博士位于圣地亚哥的加州大学，是体内和体外系统同化以了解分子机制的先驱。在索尔克研究所，凯瑟琳·里维尔博士将为生殖神经内分泌功能障碍的研究提供压力范式和压力系统整合方面的专业知识。这些导师的指导，结合候选人以前在分子神经内分泌学方面的工作，将为候选人制定一个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。这些宝贵的研究经验将涵盖分子和细胞机制的研究，以整个动物体内生理功能，使她处于一个强大的位置，作为一个年轻的研究人员，拥有大量的研究技能，技术和培训，所有这些都是不可能没有过渡K99/R 00资金。 公共卫生相关性：压力越来越多地与卵巢功能破坏和无法怀孕有关。糖皮质激素的分泌增加是对应激的一种常见反应，其与介导应激诱导的生殖功能障碍有关。了解糖皮质激素干扰生殖功能的机制对妇女的健康以及周期紊乱和不孕症的管理非常重要。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Stress is increasingly associated with disruption in ovarian function and the inability to conceive. Enhanced secretion of glucocorticoids is one common response to stress that has been implicated in mediating stress-induced reproductive dysfunction. Understanding the mechanisms whereby glucocorticoids disrupt reproductive function is important to women's health and the management of cycle disorders and infertility.