The Role of Gonadotrope in Stress-Induced Reproductive Impairment

描述（由申请人提供）：在现代社会，压力对生殖的影响可能导致不必要的周期中断和不孕。例如，功能性下丘脑闭经（FHA）是一种来源混合的无排卵状况，由GnRH驱动减弱和搏动性促性腺激素分泌减少引起。FHA归因于压力，特别是社会心理压力，并与下丘脑-垂体-肾上腺轴激活和糖皮质激素分泌增强有关。糖皮质激素一直被认为是应激诱导的卵巢周期抑制的潜在介质；然而，所涉及的机制尚不清楚。这一提议的总体目标是测试一个统一的假设：在压力下，循环糖皮质激素升高会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对于应激性生殖功能障碍是必需的，并通过垂体促性腺激素和GnRH神经元的协同作用来抑制GR。提出了三个具体目的：1)验证皮质酮的慢性抑制作用是通过促性腺激素基因转录的减少在基因组上转导的假设，而皮质酮的急性作用涉及介导促性腺激素细胞内信号传导改变的非核GR作用。2)研究应激诱导的促性腺激素合成和分泌的抑制以及体内卵巢周期的破坏：GR在促性腺激素细胞中的作用。3)研究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GR在GnRH神经元中的作用。通过多学科的训练，候选人为自己精心开辟了一个科学的利基。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的抑制中间体，并且是应对某些类型压力的生殖抑制所必需的。在获得PATHWAY TO INDEPENDENCE AWARD的资助后，候选人将专攻糖皮质激素在分子和基因水平上调控促性腺激素功能的机制。加州大学圣地亚哥分校位于加州拉霍亚，是研究合作的温床。该候选人已经组建了一个由来自加州大学圣地亚哥分校和索尔克生物研究所这两个著名机构的导师组成的团队，他们将提供体内和体外系统同化方面的专业知识，以了解分子机制。Pamela Mellon博士位于加州大学圣地亚哥分校，是体内和体外系统同化的先驱，以理解分子机制。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，结合候选人之前在分子神经内分泌学方面的工作，将为候选人发展一个独立的多学科研究项目提供坚实的基础，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从分子和细胞机制到整个动物体内生理功能的研究，使她成为一名拥有大量研究技能、技术和培训的年轻研究者，这一切都是在没有K99/R00过渡资助的情况下不可能实现的。

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.