ACTIVATION OF BRAIN ESTROGEN RECEPTORS

激活大脑雌激素受体

• 批准号: 2877691
• 负责人: Ede M Apostolakis
• 金额: $ 10万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2877691
• 关键词: epidermal growth factor; estrogen receptors; female; growth factor receptors; hypothalamus; laboratory mouse; laboratory rat; neuroendocrine system; receptor expression

Circulating ovarian steroid hormones, estrogen (E) and progesterone (P), have a profound modulatory in brain cells that ensure both the release of pituitary gonadotropins which trigger ovulation and the synchronous expression of behavioral receptivity. We have recently reported that both epidermal growth factor (EGF) and insulin growth factor-1 (IGF-1) exert influences on hypothalamic steroid receptors in the absence of E and/or P. At present, the molecular and cellular mechanisms and interneuronal interactions underlying ligand-independent regulation of steroid receptor-dependent function in the central nervous system (CNS) are undefined. Receptors for both EGF and IGF-1 are expressed in hypothalamic regions linked to reproduction. The goal of this project is to characterize critical signal transduction and phosphorylated molecules (the tyrosine src kinase, cAMP, CREB, STAT3, SRC-1, ERalpha, ERbeta, and OSCP) in the brain for an effect of E and EGF on downstream gene targets. By using a blend of present molecular technology (in vivo use of antisense oligonucleotides, mutant mice model, characterization of individual cell mRNA population and differential display) with powerful neuroanatomical tools (immunohistochemistry, in situ hybridization, patch clamp dialysis), the relationship between E and EGF will be examined in order to devise new, more effective treatment strategies for reproductive disorders associated with E. The proposed in vivo studies of ligand-independent activation of ER are at an early stage, but are absolutely required for understanding physiological responses at the molecular and cellular level within the CNS which mediate neuroendocrine control of ovulation and reproductive function.

循环卵巢类固醇激素，雌激素（E）和孕激素（P）， 在脑细胞中有一种深刻的调节作用， 垂体促性腺激素的分泌， 行为感受性的表达。 我们最近报道说， 表皮生长因子（EGF）和胰岛素生长因子-1（IGF-1） 在缺乏E的情况下对下丘脑类固醇受体产生影响 目前，分子和细胞机制， 神经元间的相互作用是配体非依赖性调节的基础 中枢神经系统（CNS）中的类固醇受体依赖性功能 是未定义的。 EGF和IGF-1的受体都表达于 与生殖有关的下丘脑区域。 这个项目的目标 是表征关键的信号转导和磷酸化 分子（酪氨酸src激酶，cAMP，CREB，STAT 3，SRC-1，ER α， ER β和OSCP）在大脑中的作用，E和EGF对下游的影响。 基因靶点 通过使用现有分子技术的混合物（体内 反义寡核苷酸的应用，突变小鼠模型，表征 单个细胞mRNA群体和差异显示）， 强大的神经解剖学工具（免疫组织化学，原位 杂交、膜片钳透析）、E与EGF的关系 将被研究以设计新的更有效的治疗方法 与E. 拟议 ER的配体非依赖性激活的体内研究处于早期阶段， 阶段，但绝对需要了解生理 中枢神经系统内分子和细胞水平的反应， 介导神经内分泌控制排卵和生殖功能。