Mechanisms of Estrogen Signaling and Neuroprotection

雌激素信号传导和神经保护机制

• 批准号: 8011984
• 负责人: DARRELL W BRANN
• 金额: $ 31.58万
• 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/8011984
• 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; Principal Investigator; 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; programs; 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. PUBLIC HEALTH RELEVANCE: Estrogen (E2) has been implicated to exert neuroprotection in a variety of neurodegenerative disorders, including stroke. This proposal would elucidate the mechanisms underlying E2 neuroprotection in the brain and potentially provide a mechanistic explanation as to why the Women's' Health Initiative (WHI) studies failed to observe beneficial effect of E2.

描述（由申请人提供）：172-雌二醇（E2）在多种神经退行性疾病（包括中风）中发挥神经保护作用;然而，其在脑中的非基因组和基因组信号传导机制及其神经保护作用仍不清楚。我们小组的工作可能会通过我们克隆一种新的ER辅助调节因子PELP 1来阐明这个问题，我们认为PELP 1是解释E2在大脑中诱导非基因组和基因组信号传导和神经保护的关键“缺失环节”。为了验证我们的假设，目的1将使用PELP 1前脑特异性KO（PELP 1 FB KO）小鼠模型来确定PELP 1在脑缺血后E2非基因组和基因组信号传导、抗氧化作用和神经保护作用中的作用。由于对PELP 1在脑中的调节知之甚少，Aim 2将表征脑缺血后脑中PELP 1的表达、磷酸化和信号体形成，确定E2的调节作用，并鉴定负责PELP 1磷酸化的激酶。初步数据表明，PELP 1也可能通过调节脑芳香化酶启动子的激活在调节脑中局部E2产生中发挥重要作用。因此，目的3将通过使用PELP 1 FB KO小鼠来检查PELP 1敲除对脑中基础和E2诱导的芳香酶表达和活性的影响，并鉴定由PELP 1调节的特异性脑芳香酶启动子。还将通过ChIP评估PELP 1向脑芳香化酶启动子的募集，并且还将检查局部E2产生在通过低生理水平的E2放大神经保护中的潜在作用。最后，目标4将测试这样的假设：长期E2剥夺（例如绝经后发生）后E2神经保护能力的丧失是由于PELP 1和/或ER 1的脑特异性表观遗传基因沉默造成的，并将确定基因沉默是否是可逆的以及是否可以在大脑中恢复E2敏感性。拟议的研究有可能显着推进我们对E2如何在大脑中发挥其信号传导和神经保护作用的理解，并可能提供为什么E2在WHI研究中未能发挥有益的心血管和神经作用的机制理解，其中E2替代在绝经后很久才开始。 公共卫生相关性：雌激素（E2）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。这一提议将阐明E2在大脑中神经保护的潜在机制，并可能为为什么妇女健康倡议（WHI）研究未能观察到E2的有益作用提供机械解释。