Role of Palmitolyation on Neuronal Estrogen and Androgen Receptor Function

棕榈酰化对神经元雌激素和雄激素受体功能的作用

• 批准号: 1146016
• 负责人: Paul Mermelstein
• 金额: $ 40万
• 依托单位: University of Minnesota-Twin Cities
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1146016&HistoricalAwards=false
• 关键词: Role; Palmitolyation; Neuronal; Estrogen; Androgen

Estrogen receptors were originally characterized as intracellular receptors, acting only in brain regions that regulate reproductive behaviors. Recent discoveries have identified that various neurons throughout the nervous system exhibit responses to estradiol through the activation of surface membrane receptors. These membrane estrogen receptors are now known to lead to alterations in learning and memory, sexual receptivity, motor control and pain. The nervous system is not unique in this regard, as membrane estrogen receptors affect the reproductive organs, the cardiovascular system and bone. The goal of this project is to determine how estrogen receptors are adapted to act as surface membrane signaling molecules. The project willl test the hypothesis that palmitoylation of the estrogen receptor is the essential regulatory step in converting intracellular receptors into membrane signaling proteins. There are 23 different enzymes known to palmitoylate proteins. The principal goal is to identify which of the 23 enzymes is responsible for estrogen receptor palmitoylation, and then to determine the physiological and behavioral impact of manipulating estrogen receptor palmitoylation within brain. Identifying the proteins that palmitoylate steroid receptors provides an innovative experimental system that will challenge dogma and train personnel to integrate various in vivo and in vitro model systems. State-of-the-art cellular/molecular methods will be integrated with established behavioral approaches. Using specific assessment tools, Dr. Mermelstein will monitor the technical, intellectual and instructional development of his trainees. Dr. Mermelstein and his students will also participate in multiple outreach activities, including the development of a Neuroscience Minor as part of the undergraduate curriculum at the University of Minnesota.

雌激素受体最初的特征是细胞内受体，只作用于调节生殖行为的大脑区域。最近的发现发现，神经系统中的各种神经元都通过激活表面膜受体对雌二醇产生反应。这些膜上的雌激素受体现在已知会导致学习和记忆、性接受能力、运动控制和疼痛的改变。神经系统在这方面并不是独一无二的，因为膜雌激素受体影响生殖器官、心血管系统和骨骼。这个项目的目标是确定雌激素受体是如何适应作为表膜信号分子的。该项目将检验这一假设，即雌激素受体的棕榈酰化是将细胞内受体转化为膜信号蛋白的关键调控步骤。已知棕榈酰化蛋白有23种不同的酶。主要目的是确定23种酶中的哪一种负责雌激素受体棕榈酰化，然后确定在脑内操纵雌激素受体棕榈酰化对生理和行为的影响。识别棕榈酰化类固醇受体的蛋白质提供了一个创新的实验系统，它将挑战教条，并培训人员整合各种体内和体外模型系统。最先进的细胞/分子方法将与既定的行为方法相结合。梅梅尔斯坦博士将使用特定的评估工具，监测受训者在技术、智力和教学方面的发展。梅梅尔斯坦博士和他的学生还将参加多项外展活动，包括将神经科学辅修课程作为明尼苏达大学本科课程的一部分。