MECHANISM OF ESTROGEN RECEPTOR DOWN REGULATION

描述：(申请者描述)雌激素调节其作用于 生殖组织，如乳房和子宫，通过与 雌激素受体(ER)，一种核、配体依赖的转录因子。 因此，内质网含量是细胞能力的关键决定因素 对雌激素的反应：ER状态在预后中的应用 用于乳腺癌患者的内分泌治疗。申请人的长期利益 研究目标是研究ER蛋白的调控机制 表情和功能。为此，她发起了对 雌激素对内质网的调节作用及新的蛋白降解机制 参与垂体和乳房ER的自体下调 癌症模型。本项目的目标是：1)确定 延长ER半衰期的功能后果。这些研究考察了 大鼠雌激素受体反式激活和雌激素结合功能的变化 雌激素不对雌激素产生反应而降解的条件。2) 确定控制ER退化的参数。突变分析 将在内质网上进行，重点是磷酸化，DNA结合， 和核定位位点来绘制所需的编码序列 雌激素诱导的降解反应。这些研究的结果将 代表着未来对监管机构的调查的基础 雌激素受体状态与功能的联结机制。这一分析 利用她在生殖内分泌学方面的专业知识 她在类固醇受体生物化学和肿瘤生物学方面的训练。在 威斯康星大学麦迪逊分校生理学系 有机会将这项研究发展成一个独立的计划 致力于她作为校长取得成功的支持性环境 学术界的研究员。获得本专业的教员职位 该部门将是朝着她的目标迈出的关键一步 科学界既是研究人员，又是导师。

DESCRIPTION: (Applicant's Description) Estrogen mediates its actions on reproductive tissues, such as the breast and uterus, by binding to the estrogen receptor (ER), a nuclear, ligand-dependent transcription factor. The ER content, therefore, is a crucial determinant in the cell's ability to respond to estrogen as exemplified by the use of ER status in the prognosis for endocrine therapy in breast cancer patients. The applicant's long term research goal is to investigate the mechanisms governing ER protein expression and function. To this end, she has initiated studies into the regulation of ER by estrogen and identified a novel proteolytic mechanism involved in autologous down-regulation of the ER in pituitary and breast cancer models. The objectives of this project are to: 1) Determine the functional consequence of extending the ER half-life. These studies examine alterations in ER transactivation and estrogen-binding functions under conditions in which ER does not degrade in response to estrogen. 2) Identify the parameters controlling ER degradation. Mutational analysis will be performed on the ER with emphasis on phosphorylation, DNA binding, and nuclear localization sites to map the coding sequences required for the estrogen-induced degradation response. The results of these studies will represent the foundation for future investigations into the regulatory mechanisms coupling estrogen receptor status to function. This analysis takes advantage of her expertise in reproductive endocrinology and expands her training in steroid receptor biochemistry and tumor biology. In the Department of Physiology at the University of Wisconsin-Madison, she has the opportunity to develop this research into an independent program in a supportive environment that is committed to her success as a principal investigator in academia. The attainment of a faculty position within this department will be a critical step toward her goal to contribute to the scientific community as both a researcher and a mentor.