Ligand-independent signaling of estrogen receptor beta and the aging brain

描述(由申请人提供)：更年期是一种生殖衰老状态，同时血液中雌激素水平急剧下降。最近，妇女健康倡议(WHI)进行了一项大规模的临床研究，旨在评估雌激素替代疗法对绝经后妇女的神经学好处。这项研究的结果，与其他使用动物模型的研究相结合，引发了一场关于雌激素对正常大脑功能是有益还是有害的激烈辩论。大脑中的雌激素信号是由两个高特异性受体--雌激素受体α和β(ER1，ER2)传递的。我们实验室的数据集中在两个神经元特异性基因ER2的生物学功能上：促性腺激素释放激素(GnRH)和精氨酸加压素(AVP)。这两个基因是雌激素反应的，随着年龄的增长而发生显著变化。GnRH是生殖的主要中枢调节因子，AVP是情绪、昼夜节律和应激反应等过程的关键调节因子。我们的数据表明，在雌激素存在和不存在的情况下，ER2对这些基因进行了不同的调节，这导致了我们的中心假设，即ER2在大脑中的基本功能在衰老过程中发生了变化。了解ER2信号变化的分子基础和相关潜在后果对于评估外源性激素治疗的有效性和必要性至关重要。雌激素结合ER2的活性可以通过不同的机制来调节，包括受体的翻译后修饰，共调控蛋白在转录复合体中的募集，或者与靶基因上独特的顺式作用启动子元件的结合。目前尚不清楚ER2对AVP和GnRH的雌激素非依赖性激活是通过这些机制中的一种还是全部来实现的。这项提案中概述的具体目标将在神经细胞中使用各种分子生物学技术来研究每一种可能性。预期的结果将通过阐明驱动雌激素非依赖性调控ER2靶基因的精确分子机制，进一步加深我们对绝经后大脑中ER2信号的理解。与公共健康相关：在正常衰老期间，循环中的雌激素水平急剧下降。近年来，雌激素替代疗法对老年人大脑的积极健康益处引起了人们的极大兴趣；然而，我们对神经元中雌激素信号调节的分子机制的了解有限。这项提案将调查神经元中雌激素非依赖性基因调控的后果，了解这一点是必要的，以便批判性地评估外源性激素治疗的有效性和必要性。

DESCRIPTION (provided by applicant): Menopause is characterized as a state of reproductive senescence coincident with sharply decreased circulating estrogen levels. Recently, the women's health initiative (WHI) conducted a large-scale clinical study designed to evaluate the neurological benefits of estrogen replacement therapy for post-menopausal women. The results of that study, combined with other studies using animal models, have sparked a fervent debate about whether estrogen is beneficial or detrimental to normal brain function. Estrogen signaling in the brain is conveyed by two high specificity receptors, estrogen receptors alpha and beta (ER1, ER2). Data from our laboratory have focused on the biological function of ER2 for two neuronal-specific genes that are estrogen-responsive and dramatically altered as a direct result of the aging process: gonadotropin-releasing hormone (GnRH) and arginine vasopressin (AVP). GnRH is the primary central regulator of reproduction and AVP is a critical regulator of several processes including mood, circadian rhythms, and the stress response. Our data demonstrate that ER2 differentially regulates these genes in the presence and absence of estrogen, leading to our central hypothesis that the basic function of ER2 in the brain changes during the aging process. Understanding the molecular basis and the associated underlying consequences of changes in ER2 signaling is critical for evaluating the efficacy and necessity of exogenous hormone therapies. The activity of estrogen-bound ER2 can be modulated by different mechanisms, including posttranslational modifications of the receptor, recruitment of coregulatory proteins into the transcription complex, or binding to unique cis-acting promoter elements on the target genes. Whether the estrogen-independent activation of AVP and GnRH by ER2 is mediated by one or all of these mechanisms is unknown. The specific aims outlined in this proposal will investigate each of these possibilities using a variety of molecular biology techniques in neuronal cells. The expected results will further our understanding of ER2 signaling in the post-menopausal brain by elucidating the precise molecular mechanisms that drive estrogen-independent regulation of ER2 target genes. PUBLIC HEALTH RELEVANCE: During normal aging, there is a sharp decline in circulating estrogen levels. The positive health benefits of estrogen replacement therapy in the aged brain have gained considerable interest in recent years; however, our understanding of the molecular mechanisms regulating estrogen signaling in neurons is limited. This proposal will investigate the consequences of estrogen-independent gene regulation in neurons, which is imperative to understand in order to critically evaluate the efficacy and necessity of exogenous hormone therapies.