Mechanisms and Neural Consequences of Estrogen Action

描述(由申请人提供)：本研究的总体目标是 为了确定雌激素对人体的作用机制和后果。 前脑，我们将在两个具体目标中解决这一问题。第一个目标是 确定雌激素介导的细胞改变的细胞后果 神经营养素受体比率。在成人的前脑中，雌激素增加了Trk 受体和降低p75，导致有利的trk/p75比率，而在 自相矛盾的是，生殖衰老的前脑，雌激素的替代， 导致不利的trk/p75比率。而两种神经营养素受体 刺激不同的和重叠的信号通路，trk通常 促进细胞存活，而p75可以刺激细胞存活或细胞 死亡。在这里，我们的体内模型将被用来评估雌激素是如何介导 Trk/p75比率的变化将影响下游神经营养因子信号转导， 因此，细胞命运，当受到挑战时，在体内，与神经营养因子 刺激或伤害。第二个目标是检验假设 雌激素受体(ER-α)的α形式的表达/激活是 对细胞健康有害。已经确定了两种雌激素受体， 尽管每个受体对神经功能的具体贡献不是 清楚地定义了。最近的观察表明，ER-α的高表达是 与雌激素反应性降低有关的措施，如 神经营养因子的表达与细胞存活。雌激素受体特异性配体， 结合体外和体外模型，将被用于确定 各雌激素受体对神经营养素表达、信号的影响 转导和细胞死亡。这些研究还将使用DNA微阵列 分析，最终目标是开发战略性基因阵列来 促进快速检测雌激素介导的细胞变化，并 区分受体特异性配体的作用。 鉴于最近关于雌激素使用的相互矛盾的证据和 阿尔茨海默病，了解雌激素的生物学作用更多 现在比以往任何时候都危急。此外，识别激素刺激的途径 启动细胞退化事件将对 靶标和受体特异性雌激素化合物的开发。

DESCRIPTION (provided by the applicant): The overall goal of this research is to define the mechanisms and consequences of estrogens actions on the forebrain, which we will address in two specific aims. The first aim is to determine the cellular consequences of estrogen-mediated alterations in the ratio of neurotrophin receptors. In the adult forebrain, estrogen increases trk receptors and decreases p75, resulting in a favorable trk/p75 ratio, while in the reproductively senescent forebrain, estrogen replacement, paradoxically, results in an unfavorable trk/p75 ratio. While both neurotrophin receptors stimulate distinct and overlapping signaling pathways, the trks typically promote cell survival, while p75 may stimulate either cell survival or cell death. Here, our in vivo models will be used to assess how estrogen mediated changes in trk/p75 ratios will affect down-stream neurotrophin signaling and, consequently, cell fate, when challenged, in vivo, with neurotrophin stimulation or injury. The second aim is to test the hypothesis that expression/activation of the alpha form of the estrogen receptor (ER-alpha) is detrimental to cell health. Two estrogen receptors have been identified, although the specific contribution of each receptor to neural function is not clearly defined. Recent observations indicate that high ER-alpha expression is associated with decreased estrogen responsiveness on measures such as neurotrophin expression and cell survival. Estrogen receptor specific ligands, in conjunction with ex vivo and in vitro models, will be used to determine the contribution of each estrogen receptor to neurotrophin expression, signal transduction and cell death. These studies will also employ DNA microarray analysis, with the eventual goal of developing strategic gene arrays to facilitate rapid detection of estrogen-mediated cellular changes and to discriminate between the actions of receptor specific ligands. In view of the recent conflicting evidence regarding estrogen use and Alzheimer's disease, understanding the biology of estrogens actions are more critical now than ever. Moreover, identifying hormone-stimulated pathways that initiate cell-degenerative events will be increasingly important to the development of target and receptor specific estrogenic compounds.