Integration of PR and FoxO Signaling in Pituitary Gonadotropes

描述(由申请人提供)： 这份申请导师研究科学家发展奖的申请书概述了Varyina Thackray博士的培训和研究计划。她在黄体生成素和卵泡刺激素的激素调节方面设计了一套完整的强化训练计划。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下降有关。由于垂体促性腺激素整合了来自多个外部刺激的信号，她建议研究新陈代谢和生育是否在这个水平上通过整合孕激素受体(PR)和叉头(FoxO)信号联系在一起。加州大学圣地亚哥分校拟议的工作和独特的培训环境将使萨克雷博士能够实现她在生殖内分泌学领域完全独立的研究生涯的长期目标。培训和发展将需要帕梅拉·梅隆博士和凯伦·阿登博士的指导，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。萨克雷博士加入了加州大学圣迭戈分校生殖医学系和生殖科学与医学中心，这将促进她的研究和职业发展。该提案的研究部分验证了这样的假设，即PR与FoxO转录因子相互作用，以调节促性腺激素的转录程序，包括黄体生成素和卵泡刺激素的合成。在她的博士后工作中，Thackray博士已经证明PR调节垂体促性腺激素中的LH和FSHβ基因的表达，并且PR与多肽激素信号通路中的转录因子相互作用，如Smad和FoxO蛋白。她的初步结果表明，FoxO蛋白在促性腺激素的合成和增强PR反应中起着直接作用。在具体目标1中，将使用生化和组织细胞培养模型来研究FoxO1转录因子在促性腺激素产生调节中的作用。在特定目标2中，将通过对条件缺失FoxO1小鼠的遗传分析来扩大对FoxO1在垂体促性腺激素中功能的理解，以研究其在体内的功能；特定目标3将利用全基因组定位分析来解决促性腺激素中PR和FoxO的相互作用，以确定共同调节的PR和FoxO1靶基因。这一建议的结果有可能回答关于PR和FoxO转录因子在促性腺激素产生中的作用的基本问题，提供对激素控制生育的广泛机制的洞察，并允许候选人发展成为完全独立的首席研究员。潜在的应用可能会为治疗一系列生理性疾病带来新的方向，这些疾病可能是由于促性腺激素产生故障而导致的，如闭经、性早熟、理想性性腺功能减退、多囊卵巢综合征和不孕不育。

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.