Neuroprotective effects of estrogens & SERMS

雌激素对哺乳动物大脑不同区域的靶神经元的存活和生长的影响是有据可查的。在成人和老年人的大脑中，雌激素可能对认知中重要的神经元群体(如基底前脑胆碱能系统)具有营养和/或保护作用。男性和女性的衰老都与雌激素和雄激素分泌的下降有关，这种下降可能与大脑神经元的衰老有关。这种类型的影响是否发生在人脑中尚不清楚，但有趣的报告表明，雌激素治疗改善了年轻和老年女性的状况，绝经后女性雌激素替代治疗中阿尔茨海默病的发病率比没有接受这种治疗的女性低得多。神经元的发育似乎在很大程度上依赖于神经营养因子的作用，例如通过酪氨酸激酶受体作用的神经生长，特别是trk A和p75。我们最近报道，雌激素和某些被称为选择性雌激素受体调节剂(SERM)的药物可以离散地激活某些下游信号转导通路，这些信号转导通路由生长因子如MAP-Kinase途径所使用。在目前的应用中，我们建议建立原代培养和人神经细胞模型，在其中进一步评估雌激素的神经保护作用及其与神经营养素和MAP激酶相关信号机制的相互作用。具体目的1：评价雌激素、SERM和ER-β选择性植物雌激素对原代培养神经元的神经保护作用。具体目的2.在原代培养的神经细胞中确定介导雌激素神经保护作用的信号转导事件。具体目的3.鉴定雌激素受体α和β的结构特征以及它们相互作用以在转基因细胞系统中介导神经保护的蛋白。具体目的4.探讨雌激素对人NT2N神经元诱导表达神经保护基因的作用。

Estrogens have well-documented effects on the survival and growth of target neurons in various regions of the mammalian brain. In the adult and aged brain, estrogen may be trophic to and/or protect from damage neuronal populations important in cognition such as the basal forebrain cholinergic system. Aging in both the male and female is associated with a decline in the secretion of estrogens and androgens and it is possible that this decline could have implications for aging of brain neurons. Whether effects of this type occur in the human brain are unknown, but interesting reports have suggested that estrogen treatment improves condition in young and elderly women and that the incidence of Alzheimer's disease in estrogen-replaced in postmenopausal women is much lower than in women not given this treatment. Neuronal development appears to be in large part dependent upon the actions of neurotrophins such as nerve growth acting through tyrosine kinase receptors, specifically trk A and p75. We have recently reported that estrogen and certain agents termed selective estrogen receptor modulators (SERMs) can discretely activate certain of the downstream signal transduction cascades used by growth factors such as the MAP-Kinase pathway. In the present application, we propose to develop primary cultures and human neuronal cell-line models in which to evaluate further the neuroprotective effects of estrogen and its interaction with neurotrophin and MAP kinase-related signaling mechanisms. Specific Aim 1: To assess the neuroprotective effects of estrogen, SERMs, and ER-beta selective phytoestrogens in primary neuronal cultures. Specific Aim 2. To identify the signal transduction events which mediate the neuroprotective effects of estrogens in primary neuronal cultures. Specific Aim 3. To identify structural features of the estrogen receptors alpha and beta and the proteins which they interact to mediate neuroprotection in transfected cell systems. Specific aim 4. To investigate the ability of estrogen to induce neuroprotective genes such as Bcl-2 in human NT2N neurons.