Integration of PR and FoxO Signaling in Pituitary Gonadotropes

描述（由申请人提供）： 这份导师研究科学家发展奖的申请概述了Varykina Thackray博士的培训和研究计划。她在LH和FSH的激素调节领域设计了一个综合和强化的培训计划。以高胰岛素血症和胰岛素抵抗为特征的代谢紊乱通常与女性生育力降低有关。由于垂体促性腺激素整合来自多种外部刺激的信号，她建议研究代谢和生育能力是否通过孕酮受体（PR）和叉头（FoxO）信号的整合在这个水平上连接。拟议的工作和独特的培训环境在加州大学圣地亚哥分校将允许博士.萨克雷实现她的长期目标，在生殖内分泌学领域的一个完全独立的研究生涯.培训和发展将需要Pamela Mellon博士和Karen Arden博士的指导，他们分别是神经内分泌学和FoxO调节和功能领域的著名专家。Thackray博士在UCSD生殖医学系和生殖科学与医学中心的参与将增强她的研究和职业发展。该提案的研究部分测试了PR与FoxO转录因子进行串扰以调节促性腺激素的转录程序（包括LH和FSH合成）的假设。在她的博士后工作中，Thackray博士已经表明PR调节垂体促性腺激素中的LH和FSH β基因表达，并且PR与肽激素信号通路中的转录因子中间体（如Smad和FoxO蛋白）相互作用。她的初步结果表明，FoxO蛋白在促性腺激素合成中起直接作用，并增强PR反应。在具体目标1，生化和组织细胞培养模型将被用来研究的FoxO1转录因子在调节促性腺激素的生产的作用。在特定目标2中，将使用条件性无效FoxO1小鼠的遗传分析来扩展对垂体促性腺激素中FoxO1功能的理解，以研究其体内功能，特定目标3将使用全基因组定位分析来确定共调节的PR和FoxO1靶基因，以解决促性腺激素中的PR和FoxO串扰。该提案的结果有可能回答有关PR和FoxO转录因子在促性腺激素产生中的作用的基本问题，深入了解激素控制生育的广泛机制，并允许候选人发展成为完全独立的主要研究者。潜在的应用可能会导致治疗一系列生理疾病的新方向，这些疾病可能是由促性腺激素产生功能障碍引起的，如闭经，性早熟，特发性性腺功能减退症，多囊卵巢综合征和不孕症。

DESCRIPTION (provided by applicant): This application for a Mentored Research Scientist Development Award outlines the training and research plans for Dr. Varykina Thackray. She has designed an integrated and intensive training program in the area of hormonal regulation of LH and FSH. Metabolic disorders characterized by hyperinsulinemia and insulin resistance are often associated with reduced fertility in women. Since the pituitary gonadotrope integrates signals from multiple external stimuli, she proposes to study whether metabolism and fertility are connected at this level by integration of progesterone receptor (PR) and forkhead (FoxO) signaling. The proposed work and unique training environment at the University of California, San Diego will allow Dr. Thackray to achieve her long-term goal of a fully independent research career in the field of reproductive endocrinology. Training and development will entail mentoring by Dr. Pamela Mellon and Dr. Karen Arden, noted experts in the fields of neuroendocrinology and FoxO regulation and function, respectively. Dr. Thackray's participation in UCSD's Department of Reproductive Medicine and the Center for Reproductive Science and Medicine will augment both her research and career development. The research component of the proposal tests the hypothesis that PR engages in cross-talk with FoxO transcription factors to modulate the transcriptional program of the gonadotrope including LH and FSH synthesis. In her post-doctoral work, Dr. Thackray has shown that PR modulates LH and FSH beta gene expression in the pituitary gonadotrope and that PR interacts with transcription factors intermediates in peptide hormone signaling pathways such as Smad and FoxO proteins. Her preliminary results indicate that FoxO proteins play a direct role in gonadotropin synthesis and enhance PR responsiveness. In Specific Aim 1, biochemical and tissue cell culture models will be used to study the role of the FoxO1 transcription factor in the regulation of gonadotropin production. In Specific Aim 2, comprehension of FoxO1 function in the pituitary gonadotrope will be expanded using genetic analysis of conditional null FoxO1 mice to study its function in vivo and Specific Aim 3 will address PR and FoxO cross-talk in the gonadotrope using genome wide location analysis to identify co-regulated PR and FoxO1 target genes. Results from this proposal have the potential to answer fundamental questions regarding the role of PR and FoxO transcription factors in gonadotropin production, provide insight into broad mechanisms of hormonal control of fertility, and allow the candidate to develop into an fully independent principal investigator. Potential applications could lead to new directions in treating a range of physiological disorders that can result from malfunction in gonadotropin production such as amenorrhea, precocious puberty, ideopathic hypogonadism, polycystic ovarian syndrome and infertility.