CAREER: Physiological Regulation of Estrogen Receptor Gene Expression by Estrogen

小行星9514038 雌激素是动物和人类体内最强大的激素，在低剂量下长时间工作，调节生殖和许多其他身体过程。 Ing博士提出的研究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。 有了它，她已经证明，雌激素增加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，雌激素并没有提高雌激素受体基因合成雌激素受体mRNA的速率。 由于蛋白质，如雌激素受体，是由基因编码的信息制成的（蛋白质是由基因制成的mRNA制成的），调节可能发生在mRNA而不是基因水平。 因此，她的假设是，雌激素减少雌激素受体mRNA的衰变，以提高组织中雌激素受体蛋白的浓度和动物的雌激素反应。 拟议的实验将证明这一假设，然后确定它如何在分子方面发生。 首先，将培养和分析雌激素治疗和对照动物的子宫组织，以确定雌激素是否真的稳定雌激素受体mRNA。 接下来，将在突变的mRNA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，将表征结合并作用于雌激素受体mRNA以在雌激素存在下使其稳定的调节蛋白。 对这种强大激素的基本作用的这种洞察将导致在分子水平上更好地理解正常生殖生理学。 ***

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. ***