Mechanisms of Estrogen Signaling and Neuroprotection

雌激素信号传导和神经保护机制

• 批准号: 8457121
• 负责人: DARRELL W BRANN
• 金额: $ 30.47万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457121
• 关键词: Acetylation; Alzheimer' s Disease; Animal Model; Antioxidants; Antisense Oligonucleotides; Area; Aromatase; Aromatase Inhibitors; Attenuated; Binding; Biological; Brain; Breast Cancer Cell; Cardiovascular system; Cell Nucleus; Cells; Cerebral Ischemia; Chromatin; Cloning; Complex; Cytoplasm; DNA Methylation; Data; Deacetylase; Dose; Effectiveness; Epigenetic Process; Estradiol; Estrogen Receptor Status; Estrogen Receptors; Estrogens; Exons; Gene Silencing; Genomics; Glutamic Acid; Knock-out; Knockout Mice; Laboratories; Leucine; Light; Link; Mediating; Menopause; Methylation; Methyltransferase; Modeling; Modification; Mus; Neurodegenerative Disorders; Nuclear Receptors; PXXP Motif; Parkinson Disease; Phosphorylation; Phosphotransferases; Physiological; Physiological Processes; Play; Post-Translational Protein Processing; Production; Proline; Promoter Regions; Prosencephalon; Proteins; Regulation; Research; Role; SH3 Domains; Severities; Signal Transduction; Stroke; Testing; Translations; Wild Type Mouse; Women' s Health; Work; attenuation; base; chromatin immunoprecipitation; deprivation; inhibitor/antagonist; innovation; mouse model; neuroprotection; non-genomic; novel; promoter; public health relevance; receptor expression; relating to nervous system

DESCRIPTION (provided by applicant): 172-Estradiol (E2) has been implicated to exert neuroprotection in a variety of neurodegenerative disorders, including stroke; however, the mechanisms underlying its nongenomic and genomic signaling in the brain, and its neuroprotective effects remains unclear. Work by our group may shed light on this issue via our cloning of a novel ER coregulator, called PELP1, which we propose is the critical "missing link" that explains E2 ability to induce both nongenomic and genomic signaling in the brain and neuroprotection. To test our hypothesis, Aim 1 would use a PELP1 forebrain-specific KO (PELP1 FB KO) mouse model to determine the role of PELP1 in E2 nongenomic and genomic signaling, antioxidant actions, and neuroprotective effects in the brain following cerebral ischemia. Since little is known about the regulation of PELP1 in the brain, Aim 2 would characterize PELP1 expression, phosphorylation and signalsome formation in the brain following cerebral ischemia, determine the regulatory role of E2, and identify kinases responsible for the phosphorylation of PELP1. Preliminary data suggest that PELP1 may also play an important role in regulating local E2 production in the brain by regulating activation of the brain aromatase promoter. Thus, Aim 3 would examine the effect of PELP1 knockout on basal and E2-induced aromatase expression and activity in the brain through use of PELP1 FB KO mice, and identify the specific brain aromatase promoter regulated by PELP1. Recruitment of PELP1 to the brain aromatase promoter would also be assessed by ChIP, and the potential role of local E2 production in amplifying neuroprotection by low physiological levels of E2 would also be examined. Finally, Aim 4 would test the hypothesis that loss of E2 neuroprotective ability after a period of long-term E2 deprivation (such as occurs after menopause) is due to a brain-specific epigenetic gene silencing of PELP1 and/or ER1, and would determine whether the gene silencing is reversible and whether E2 sensitivity can be reinstated in the brain. The proposed studies have the potential to significantly advance our understanding of how E2 exerts its signaling and neuroprotective effects in the brain, and may provide a mechanistic understanding of why E2 failed to exert beneficial cardiovascular and neural effects in the WHI study, where E2 replacement was begun long after the onset of menopause.

描述(申请人提供)：172-雌二醇(E2)被认为在包括中风在内的各种神经退行性疾病中发挥神经保护作用；然而，其在大脑中的非基因组和基因组信号的潜在机制以及其神经保护作用尚不清楚。我们团队的工作可能会通过我们克隆一种名为PELP1的新型ER辅助调节因子来揭示这个问题，我们认为这是解释E2能够在大脑中诱导非基因组和基因组信号以及神经保护的关键“缺失环节”。为了验证我们的假设，目标1将使用PELP1前脑特异性KO(PELP1 FB KO)小鼠模型来确定PELP1在脑缺血后E2非基因组和基因组信号、抗氧化作用和神经保护效应中的作用。由于对PELP1在脑中的调节知之甚少，AIM 2将研究脑缺血后PELP1的表达、磷酸化和信号体的形成，确定E2的调节作用，并确定与PELP1磷酸化有关的激酶。初步数据表明，PELP1还可能通过调节大脑芳香化酶启动子的激活，在调节脑内局部E2的产生方面发挥重要作用。因此，目的3将通过使用PELP1 FB KO小鼠来检测PELP1基因敲除对基础和E2诱导的脑内芳香化酶表达和活性的影响，并鉴定受PELP1调控的特异性脑芳香酶启动子。脑芳香酶启动子的PELP1招募也将通过芯片进行评估，并将研究局部产生的E2在通过低生理水平的E2放大神经保护方面的潜在作用。最后，Aim 4将测试一种假设，即长期剥夺E2(如绝经后)后，E2神经保护能力的丧失是由于大脑特有的PELP1和/或ER1的表观遗传基因沉默所致，并将确定这种基因沉默是否可逆，以及大脑是否可以恢复对E2的敏感性。拟议中的研究有可能极大地提高我们对E2如何在大脑中发挥其信号和神经保护作用的理解，并可能提供一种机制上的理解，为什么在WHI研究中，E2未能发挥有益的心血管和神经影响，在WHI研究中，E2的替代是在绝经开始很久之后开始的。