Estrogenic signaling upstream and downstream of mTOR

摘要 霍尔茨实验室的工作重点是雌激素信号和mTOR(机制靶点)之间的串扰 雷帕霉素)，这是调节细胞生长和增殖的两个基本途径。其中一个主要的 悬而未决的问题是雌激素的细胞质信号如何激活mTOR，以及下游是什么 MTOR效应器是雌激素的特异性靶点。这个问题代表了我们的一个重大差距 理解雌激素与mTOR信号之间的关系，并与正常细胞相关 许多雌激素依赖性疾病中的动态平衡和不适当的信号转导。两个相关项目 从我们公布的和初步的数据来看。首先，我们将研究雌激素是如何激活mTOR的，以及 发起下行蜂窝事件。为了实现这一目标，我们将使用定量蛋白质组学和 磷酸蛋白质组学用于信号通路的发现，随后是生化研究和细胞生物学- 基于对雌激素和mTOR调节蛋白的研究。第二，我们将研究蛋白质的控制 雌激素合成。虽然雌激素对转录的调控已经得到了很好的研究，但我们建议研究 雌激素在调节翻译控制中的未知作用。我们将使用多聚体分析耦合 使用RNA-SEQ来识别翻译调控的雌激素靶点。拟议的研究计划将 结合我们对雌激素信号和mTOR调节的翻译控制的兴趣，将使我们能够自由地 生成新数据并探索令人兴奋的方向。

Abstract Work in the Holz lab focuses on the crosstalk between estrogen signaling and mTOR (mechanistic target of rapamycin), two fundamental pathways that regulate growth and proliferation in the cell. One of the major unanswered questions is how cytoplasmic signaling by estrogen activates mTOR, and what downstream mTOR effectors are the specific targets of estrogen. This question represents a major gap in our understanding of the relationship between estrogen and mTOR signaling, with relevance to normal cell homeostasis and inappropriate signaling in many estrogen-dependent diseases. Two related projects stem from our published and preliminary data. First, we will examine how mTOR is activated by estrogen, and what downstream cellular events are initiated. To accomplish this goal, we will use quantitative proteomics and phosphoproteomics for signaling pathway discovery, followed by biochemical investigation and cell biology- based studies of estrogen- and mTOR-regulated proteins. Second, we will investigate the control of protein synthesis by estrogen. While regulation of transcription by estrogen is well studied, we propose to investigate an unexplored role for estrogen in mediating translational control. We will employ polysome profiling coupled with RNA-seq to identify translationally regulated estrogenic targets. The proposed research program will combine our interests in estrogen signaling and mTOR-regulated translational control, will allow us to freely generate new data and to explore exciting directions.