CAREER: Physiological Regulation of Estrogen Receptor Gene Expression by Estrogen

9514038雌激素是动物和人类体内最强大的荷尔蒙，它以低剂量长时间起作用，调节生殖和许多其他身体过程。丁博士提出的这项研究的目标是了解雌激素在分子水平上的作用。雌激素增强其作用的一种方式是通过增加它在组织内结合的蛋白质(“雌激素受体”)。对雌激素有反应的组织。通过它，她证明了雌激素增加了雌激素受体蛋白和雌激素受体信使RNA(MRNA)。然而，与目前对雌激素作用的看法相反，雌激素并不能提高雌激素受体基因合成雌激素受体基因的速率。由于蛋白质，就像雌激素受体一样，是由基因中编码的信息组成的(蛋白质是由基因组成的mRNAs组成的)，所以调节可能发生在mRNA而不是基因的水平上。因此，她的假设是雌激素可以减少雌激素受体mRNA的衰变，从而提高动物组织中雌激素受体蛋白的浓度和雌激素的反应。拟议中的实验将证明这一假设，然后确定它是如何在分子方面发生的。首先，对接受雌激素治疗的动物和对照动物的子宫组织进行培养和分析，以确定雌激素是否真的能稳定雌激素受体mRNA。下一步，将在突变的mRNAs中鉴定负责雌激素调节稳定性的雌激素受体mRNA的特定片段。最后，将描述在雌激素存在的情况下，结合并作用于雌激素受体mRNA以稳定它的调节蛋白的特征。这种对这种强大荷尔蒙的基本作用的洞察将导致在分子水平上更好地理解正常的生殖生理。***

9514038 Ing Estrogen is the most powerful hormone within animals and man which, in low doses that work over long times, regulates reproduction and many other body processes. The goal of the proposed research by Dr. Ing is to learn how estrogen acts at the molecular level. One way estrogen enhances its effects is by increasing the protein it binds ("estrogen receptor") within the tissues. The tissues that respond to estrogen. With it, she has demonstrated that estrogen increases estrogen receptor protein and estrogen receptor messenger RNA (mRNA). Contrary to current beliefs in estrogen action, however, estrogen did not enhance the rate of estrogen receptor mRNA synthesis from the estrogen receptor gene. Since proteins, like the estrogen receptor, are made with information encoded in genes (proteins are made from mRNAs which are made from genes), regulation may be occurring at the level of the mRNA instead of the gene. Therefore, her hypothesis is that estrogen decreases the decay of estrogen receptor mRNA to enhance concentrations of estrogen receptor protein in tissues and estrogen responses of animals. The proposed experiments will prove the hypothesis and then determine how it occurs in molecular terms. First, uterine tissues from estrogen-treated and control animals will be cultured and analyzed to determine if estrogen really does stabilize estrogen receptor mRNA. Next, the specific segment of the estrogen receptor mRNA responsible for estrogen-regulated stability will be identified in mutated mRNAs. Finally, the regulatory proteins that bind and act on the estrogen receptor mRNA to stabilize it in the presence of estrogen will be characterized. This insight into the basic action of this powerful hormone will lead to a better understanding of normal reproductive physiology on a molecular level. ***