Estrogenic signaling upstream and downstream of mTOR

摘要 Holz实验室的工作重点是雌激素信号和mTOR（雌激素受体的机制靶点）之间的串扰。 雷帕霉素），这是调节细胞生长和增殖的两种基本途径。的一个主要 尚未回答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效应子是雌激素的特异性靶点。这个问题代表了我们的一个主要差距， 了解雌激素和mTOR信号之间的关系，与正常细胞的相关性 在许多雌激素依赖性疾病中的稳态和不适当的信号传导。两个相关项目干 从我们公布的和初步的数据。首先，我们将研究mTOR是如何被雌激素激活的， 启动下游细胞事件。为了实现这一目标，我们将使用定量蛋白质组学， 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- 基于雌激素和mTOR调节蛋白的研究。其次，我们将研究蛋白质的控制 由雌激素合成。虽然雌激素对转录的调节已经研究得很好，但我们建议研究 雌激素在介导翻译控制中的未探索作用。我们将采用多核糖体分析技术， 用RNA-seq来鉴定诱导调节的雌激素靶点。拟议的研究计划将 联合收割机结合我们对雌激素信号传导和mTOR调节的翻译控制的兴趣，将使我们能够自由地 产生新的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.