The Role of Gonadotrope in Stress-Induced Reproductive Impairment

促性腺激素在压力引起的生殖损伤中的作用

• 批准号: 7893551
• 负责人: KELLIE Breen Church
• 金额: $ 9.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-26 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893551
• 关键词: Acute; Adrenal Glands; Animal Model; Animals; Area; Assimilations; Award; Biological; California; Chronic; Collaborations; Corticosterone; Coupled; Disease; Female; Fertility; Foundations; Frequencies; Functional disorder; Funding; Genetic Transcription; Genomics; Glucocorticoid Receptor; Glucocorticoids; Goals; Gonadotrope Cell; Gonadotropins; Hydrocortisone; Hypothalamic structure; Impairment; In Vitro; Infertility; Institutes; Institution; Interdisciplinary Study; Lead; Literature; Mediating; Mediator of activation protein; Mentors; Messenger RNA; Molecular; Molecular Genetics; Nature; Neuroendocrinology; Neurons; Neurosecretory Systems; Nuclear; Ovarian; Ovarian Ablation; Pathway interactions; Periodicity; Physiologic pulse; Physiological; Pituitary Gland; Positioning Attribute; Psychosocial Stress; Reaction; Regulation; Reproduction; Research; Research Personnel; Role; Sheep; Signal Transduction; Societies; Solid; Steroids; Stimulus; Stress; System; Testing; Time; Training; Training Technics; Universities; Women' s Health; Work; acute stress; arm; base; experience; functional hypothalamic amenorrhea; hypothalamic-pituitary-adrenal axis; in vivo; interest; multidisciplinary; non-genomic; programs; public health relevance; reproductive; reproductive function; response; skills; stressor

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.

描述（由申请人提供）：现代社会的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) 是一种混合起源的无排卵病症，由 GnRH 驱动减少和脉动促性腺激素分泌减少引起。 FHA 归因于压力，尤其是社会心理压力，并且与下丘脑-垂体-肾上腺轴激活和糖皮质激素分泌增强有关。长期以来，糖皮质激素一直被认为是应激引起的卵巢周期抑制的潜在介质。然而，所涉及的机制尚不清楚。该提案的总体目标是检验以下统一假设：响应压力而升高的循环糖皮质激素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 对于应激引起的生殖功能障碍是必要的，并通过垂体促性腺激素和 GnRH 神经元的协调作用来抑制生殖功能障碍。提出了三个具体目标：1) 测试以下假设：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，而皮质酮的急性作用涉及介导促性腺激素内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抑制以及体内卵巢周期的破坏：促性腺激素细胞内 GR 作用的作用。 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。通过多学科培训，候选人精心为自己开辟了一个科学领域。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充当神经内分泌轴内的抑制中间体，并且是响应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，候选人将接受专门培训，在分子和基因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。该候选人组建了一支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。帕梅拉·梅隆博士位于加州大学圣地亚哥分校，是通过体内和体外系统同化来理解分子机制的先驱。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项目奠定坚实的基础。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，使她作为一名年轻的研究人员处于有利地位，拥有大量的研究技能、技术和培训，如果没有过渡性的 K99/R00 资助，所有这些都是不可能实现的。 公众健康相关性：压力与卵巢功能破坏和无法怀孕的关系日益密切。糖皮质激素分泌增强是对压力的一种常见反应，与介导压力引起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女性健康以及周期紊乱和不孕症的治疗非常重要。