The Role of Gonadotrope in Stress-Induced Reproductive Impairment

描述(由申请者提供)：在现代社会，压力对生殖的影响可能会导致不必要的周期中断和不孕。例如，功能性下丘脑闭经(FHA)是一种混合原因的无排卵状态，原因是GnRH驱动力和脉动性促性腺激素分泌减少。FHA被认为是应激，尤其是心理社会应激，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，糖皮质激素一直被认为是应激诱导的卵巢周期抑制的潜在介质；然而，涉及的机制尚不清楚。这项提议的总体目标是检验统一的假设，即循环中的糖皮质激素水平升高，以应对压力，损害女性的生殖功能。这种抑制既有急性的非基因组机制，也有慢性的基因组机制。GR对于应激诱导的生殖功能障碍是必需的，并通过在脑垂体促性腺激素和GnRH神经元中的协调作用而促进抑制。提出了三个特定的目标：1)验证皮质酮的慢性抑制作用是通过降低促性腺激素基因转录而在基因组中转导的假设，而皮质酮的急性作用涉及非核GR作用，介导促性腺激素内细胞内信号的改变。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作用在促性腺激素细胞中的作用。3)研究应激在体内对生殖神经内分泌活动的中枢作用：卵巢类固醇激素的影响以及GR在GnRH神经元中的作用。通过多学科培训，这位候选人小心翼翼地为自己开辟了一个科学利基市场。通过她的研究生和博士后早期工作，她确定糖皮质激素足以作为神经内分泌轴中的抑制中间体，并在应对某些类型的压力时对生殖抑制是必要的。在独立之路奖的资助下，候选人将专门接受培训，在分子和遗传水平上剖析糖皮质激素对促性腺激素功能的调节机制。加州大学圣地亚哥分校位于加利福尼亚州拉霍亚，是研究合作的温床。这位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，这两个机构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。帕梅拉·梅隆博士位于加州大学圣地亚哥分校，是了解分子机制的体内和体外系统同化的先驱。在索尔克研究所，Catherine Rivier博士将为生殖神经内分泌功能障碍的研究提供压力范例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，将为候选人开发旨在了解生殖神经内分泌功能障碍的分子基础的独立多学科研究计划提供坚实的基础。这些宝贵的研究经验将横跨从分子和细胞机制到整个动物体内生理功能的研究，使她作为一名年轻的研究人员处于强大的地位，拥有大量的研究技能、技术和培训，如果没有过渡K99/R00的资助，所有这些都是不可能的。 公共卫生相关性：压力越来越多地与卵巢功能紊乱和无法怀孕联系在一起。糖皮质激素的分泌增加是一种常见的应激反应，它与应激诱导的生殖功能障碍有关。了解糖皮质激素破坏生殖功能的机制对于妇女的健康以及周期紊乱和不孕不育的管理非常重要。

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.