Neuroprotective and Neurogenic Actions of E2 and SERMs

描述（由申请人提供）：越来越多的证据表明，雌激素（E2）和SERMs可能对神经退行性疾病的中枢神经系统有有益的作用。本应用将进一步研究E2/SERM在脑缺血中神经保护的潜在机制，并将继续我们实验室令人兴奋的初步工作，即E2/SERM促进脑缺血后神经发生。在神经保护方面，我们的初步研究表明E2和SERM，他莫昔芬（TMX）抑制预期的前死亡因子（ROS, ERKs， INK, c-Jun）的激活，并增加促生存因子Akt的激活。为了证实这些初步发现并阐明潜在的机制，Aim 1将确定雌性动物脑缺血后ERK/JNK/Akt激活的时间模式和细胞类型（目前缺乏），确定E2/SERM对这些关键激酶的调节作用的开始和持续时间，并确定雌激素受体在调节作用中的作用。目的2将确定活性氧（ROS）是否作为脑缺血后ERKs/JNK的主要上游激活剂，并确定E2和TMX是否可以抑制ROS的产生作为抑制ERK/JNK激活的机制。ROS和ERK/JNK活化之间的因果关系将通过使用抗氧化剂SOD模拟化合物tempol（清除/减少ROS的产生）来确定。Aim 3将确定AP-1转录复合物和促凋亡的BH-3蛋白是否作用于ERKs/JNK下游诱导半影区凋亡，并确定E2和TMX是否抑制AP-1激活和诱导BH-3蛋白作为神经保护手段。目的4将表征E2/SERM对神经发生影响的时间模式，并表征脑缺血后新生成细胞向脑损伤区域的迁移、分化和长期存活。与功能性神经预后的相关性也将被确定。综上所述，本研究将显著促进我们对E2和SERMs在损伤脑中的神经保护和神经原性作用的理解。

DESCRIPTION (provided by applicant): There is growing evidence that estrogen (E2) and SERMs may have beneficial effects upon the CNS in neurodegenerative diseases. This application would study the potential mechanisms of E2/SERM neuroprotection in cerebral ischemia, and would follow up on exciting preliminary work by our lab which suggests that E2/SERMs enhance neurogenesis following cerebral ischemia. With regards to neuroprotection, our preliminary studies suggest that E2 and the SERM, tamoxifen (TMX) inhibit activation of putative prodeath factors (ROS, ERKs, INK, c-Jun), with an increase in activation of the prosurvival factor, Akt. To confirm these preliminary findings and clarify the underlying mechanisms, Aim 1 would determine the temporal pattern and cell type of ERK/JNK/Akt activation following cerebral ischemia in female animals (which is currently lacking), establish the onset and duration of E2/SERM regulatory effects upon these key kinases, and determine the role of estrogen receptors in the regulatory effects. Aim 2 would determine whether reactive oxygen species (ROS) function as the major upstream activator of ERKs/JNK following cerebral ischemia, and establish whether E2 and TMX can suppress ROS production as a mechanism for suppression of ERK/JNK activation. Causation between ROS and ERK/JNK activation would be determined through the use of the antioxidant SOD mimetic compound, tempol (which scavenges/reduces ROS production). Aim 3 would determine whether AP-1 transcription complex and proapoptotic BH-3 proteins act downstream of ERKs/JNK to induce apoptosis in the penumbra region, and establish whether E2 and TMX suppress AP-1 activation and induction of BH-3 proteins as a means of neuroprotection. Aim 4 would characterize the temporal pattern of E2/SERM effects on neurogenesis, and characterize the migration, differentiation and long-term survival of newly generated cells into the injured regions of the brain following cerebral ischemia. Correlation to functional neurological outcomes will also be determined. As a whole, the proposed studies would significantly advance our understanding of the neuroprotective and neurogenic actions of E2 and SERMs in the injured brain.