Neuroprotective and Neurogenic Actions of E2 and SERMs

E2 和 SERM 的神经保护和神经源作用

• 批准号: 6988755
• 负责人: DARRELL W BRANN
• 金额: $ 33.07万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-24 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988755
• 关键词: JUN kinase; cell differentiation; cell migration; cell proliferation; cerebral ischemia /hypoxia; estrogen receptors; estrogens; free radical oxygen; immunocytochemistry; laboratory mouse; laboratory rat; mitogen activated protein kinase; neuroendocrine system; neurogenesis; neuroprotectants; selective estrogen receptor modulators; superoxide dismutase; tamoxifen; transcription factor; western blottings

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.

描述(申请人提供)：越来越多的证据表明，雌激素(E2)和SERM可能对神经退行性疾病的中枢神经系统有有益的影响。这一应用将研究E2/SERM在脑缺血中的潜在神经保护机制，并将继续我们实验室令人兴奋的前期工作，该工作表明E2/SERM促进脑缺血后的神经发生。在神经保护方面，我们的初步研究表明，E2和SERM，Tamoxifen(TMX)抑制了可能的促死亡因子(ROS，ERKs，INK，c-jun)的激活，而增加了促存活因子Akt的激活。为了证实这些初步发现并阐明潜在的机制，目标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，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确定脑缺血后活性氧(ROS)是否作为ERKs/JNK的主要上游激活剂，以及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活性之间的因果关系将通过使用抗氧化剂SOD模拟化合物tempoll(清除/减少ROS产生)来确定。目的3确定AP-1转录复合体和促凋亡的BH-3蛋白是否作用于ERKs/JNK下游以诱导半影区的细胞凋亡，以及E2和TMX是否抑制AP-1的激活和BH-3蛋白的诱导作为一种神经保护手段。目的4刻画E2/SERM对神经发生影响的时间模式，并刻画脑缺血后新生细胞向损伤脑区的迁移、分化和长期存活。还将确定与功能神经结局的相关性。总体而言，拟议的研究将极大地促进我们对E2和SERM在受损大脑中的神经保护和神经生成作用的理解。