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

基本信息

批准号：
8547860
负责人：
KELLIE Breen Church
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-26 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8547860
关键词：
Acute 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 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 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&apos s Health Work abstracting acute stress arm base experience functional hypothalamic amenorrhea hypothalamic-pituitary-adrenal axis in vivo interest multidisciplinary non-genomic programs reproductive reproductive function response skills stressor

项目摘要

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.

6. 项目总结/摘要现代社会的压力对生殖的影响可能会导致不必要的循环中断和不孕症。例如，功能性下丘脑闭经 (FHA) 是一种混合性无排卵病症。起源于 GnRH 驱动力下降和脉动促性腺激素分泌减少。联邦住房管理局已归因于压力，尤其是社会心理压力，并且与下丘脑-垂体-肾上腺轴有关激活并增强糖皮质激素的分泌。糖皮质激素长期以来被认为具有潜力应激引起的卵巢周期抑制的介质；但所涉及的机制并不完善明白了。该提案的总体目标是测试以下统一假设：糖皮质激素在应对压力时会损害女性的生殖功能。这种抑制现象发生通过急性非基因组机制和慢性基因组机制。 GR对于压力诱导是必要的生殖功能障碍并通过垂体的协调作用导致抑制促性腺激素和 GnRH 神经元。提出了三个具体目标： 1) 检验假设皮质酮的慢性抑制作用是通过促性腺激素基因的减少在基因组上转导的转录，而皮质酮的急性作用涉及非核 GR 作用，介导改变促性腺激素内的细胞内信号传导。 2：研究压力引起的促性腺激素抑制体内卵巢周期性的合成、分泌和破坏：促性腺细胞内 GR 作用的作用。 3：考察应激对体内生殖神经内分泌活动的中枢作用：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，候选人已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以及为应对某些类型的压力而抑制生殖所必需的。有了这笔资金的资助通往独立之路奖，候选人将专门接受培训来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。这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。候选人组建了一支由来自两所著名院校的导师组成的团队：加州大学、圣地亚哥和索尔克生物研究所将提供体内同化的专业知识以及用于理解分子机制的体外系统。帕梅拉梅隆博士位于大学加利福尼亚州圣地亚哥，是体内和体外系统同化以理解的先驱分子机制。在索尔克研究所，Catherine Rivier 博士将提供整合方面的专业知识用于研究生殖神经内分泌功能障碍的应激范式和应激系统。指导意见这些导师，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。这些有价值的研究经验将涵盖从分子和细胞机制到整个动物体内的研究生理功能，使她作为一名拥有大量研究成果的年轻调查员处于有利地位技能、技术和培训，如果没有 K99/R00 过渡资金，所有这些都是不可能实现的。