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

描述（由申请人提供）：更年期的特征是生殖衰老状态，与循环雌激素水平急剧下降相一致。最近，妇女健康倡议（WHI）进行了一项大规模的临床研究，旨在评估绝经后妇女雌激素替代疗法对神经系统的益处。这项研究的结果，加上其他使用动物模型的研究，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。雌激素信号在大脑中由两个高特异性受体传递，雌激素受体α和β (ER1, ER2)。我们实验室的数据集中在ER2对两种神经元特异性基因的生物学功能上，这两种基因对雌激素有反应，并作为衰老过程的直接结果发生显著改变：促性腺激素释放激素（GnRH）和精氨酸加压素（AVP）。GnRH是生殖的主要中枢调节因子，AVP是包括情绪、昼夜节律和应激反应在内的几个过程的关键调节因子。我们的数据表明，ER2在雌激素存在和不存在的情况下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进行调节，包括受体的翻译后修饰，将协调节蛋白募集到转录复合体中，或与靶基因上独特的顺式作用启动子元件结合。ER2对AVP和GnRH的雌激素非依赖性激活是否由一种或所有这些机制介导尚不清楚。本提案中概述的具体目标将使用各种分子生物学技术在神经元细胞中研究这些可能性。预期的结果将通过阐明驱动ER2靶基因不依赖雌激素调控的精确分子机制，进一步加深我们对绝经后大脑中ER2信号传导的理解。公共卫生相关性：在正常衰老过程中，循环雌激素水平急剧下降。近年来，雌激素替代疗法对老年大脑的积极健康益处已引起相当大的兴趣；然而，我们对神经元中调节雌激素信号的分子机制的理解是有限的。本研究将研究神经元中雌激素非依赖性基因调控的后果，这对于批判性地评估外源性激素治疗的有效性和必要性至关重要。

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.