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

雌激素受体β的配体独立信号传导和大脑老化

基本信息

  • 批准号:
    8305522
  • 负责人:
  • 金额:
    $ 29.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-08-01 至 2014-07-31
  • 项目状态:
    已结题

项目摘要

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.
描述(由申请人提供):更年期的特征是生殖衰老状态,同时循环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益处。该研究的结果与其他使用动物模型的研究相结合,引发了关于雌激素对正常大脑功能是否有益或有害的激烈争论。大脑中的雌激素信号由两种高特异性受体——雌激素受体α和β(ER1、ER2)传递。我们实验室的数据重点关注 ER2 对两种神经元特异性基因的生物学功能,这两种基因具有雌激素反应性,并因衰老过程的直接结果而发生显着改变: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剂,AVP 是情绪、昼夜节律和压力反应等多个过程的关键调节剂。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差异性调节,从而得出我们的中心假设:大脑中 ER2 的基本功能在衰老过程中发生变化。了解 ER2 信号变化的分子基础和相关的潜在后果对于评估外源激素疗法的有效性和必要性至关重要。雌激素结合的 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、将共调节蛋白招募到转录复合物中,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 的非雌激素依赖性激活是否是由这些机制中的一种或全部介导尚不清楚。该提案中概述的具体目标将在神经元细胞中使用各种分子生物学技术来研究每种可能性。预期结果将通过阐明驱动 ER2 靶基因的雌激素独立调节的精确分子机制,进一步加深我们对绝经后大脑中 ER2 信号传导的理解。公共健康相关性: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引起了人们极大的兴趣。然而,我们对调节神经元雌激素信号传导的分子机制的理解是有限的。该提案将研究神经元中雌激素独立基因调控的后果,为了批判性地评估外源激素疗法的功效和必要性,必须了解这一点。

项目成果

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Toni R. Pak其他文献

Adolescent Binge Alcohol Exposure Affects Cardiovascular Function
  • DOI:
    10.1016/j.bpj.2018.11.662
  • 发表时间:
    2019-02-15
  • 期刊:
  • 影响因子:
  • 作者:
    Lizhuo Ai;Edith Perez;Quan Cao;Maxime Heroux;Andrei Zlobin;AnnaDorothea Asimes;Toni R. Pak;Jonathan A. Kirk
  • 通讯作者:
    Jonathan A. Kirk

Toni R. Pak的其他文献

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{{ truncateString('Toni R. Pak', 18)}}的其他基金

Sex-specific regulation of microRNAs in Alzheimer Disease
阿尔茨海默病中 microRNA 的性别特异性调控
  • 批准号:
    10667123
  • 财政年份:
    2023
  • 资助金额:
    $ 29.16万
  • 项目类别:
NeuroMolecular consequences of adolescent binge drinking
青少年酗酒的神经分子后果
  • 批准号:
    8500967
  • 财政年份:
    2013
  • 资助金额:
    $ 29.16万
  • 项目类别:
Neuromolecular consequences of adolescent binge drinking
青少年酗酒的神经分子后果
  • 批准号:
    10706623
  • 财政年份:
    2013
  • 资助金额:
    $ 29.16万
  • 项目类别:
Ligand-independent signaling of estrogen receptor beta and the aging brain
雌激素受体β的配体独立信号传导和大脑老化
  • 批准号:
    7738857
  • 财政年份:
    2009
  • 资助金额:
    $ 29.16万
  • 项目类别:
Ligand-independent signaling of estrogen receptor beta and the aging brain
雌激素受体β的配体独立信号传导和大脑老化
  • 批准号:
    7898821
  • 财政年份:
    2009
  • 资助金额:
    $ 29.16万
  • 项目类别:
Ligand-independent signaling of estrogen receptor beta and the aging brain
雌激素受体β的配体独立信号传导和大脑老化
  • 批准号:
    8115816
  • 财政年份:
    2009
  • 资助金额:
    $ 29.16万
  • 项目类别:
Ligand-independent signaling of estrogen receptor beta and the aging brain
雌激素受体β的配体独立信号传导和大脑老化
  • 批准号:
    8712747
  • 财政年份:
    2009
  • 资助金额:
    $ 29.16万
  • 项目类别:
Ligand-independent signaling of estrogen receptor beta and the aging brain
雌激素受体β的配体独立信号传导和大脑老化
  • 批准号:
    8509558
  • 财政年份:
    2009
  • 资助金额:
    $ 29.16万
  • 项目类别:
Ligand-independent signaling of estrogen receptor beta and the aging brain
雌激素受体β的配体独立信号传导和大脑老化
  • 批准号:
    9401430
  • 财政年份:
    2009
  • 资助金额:
    $ 29.16万
  • 项目类别:
Interactive effects of ethanol and estrogen on brain vasopressin during puberty
青春期乙醇和雌激素对脑加压素的相互作用
  • 批准号:
    7934536
  • 财政年份:
    2009
  • 资助金额:
    $ 29.16万
  • 项目类别:

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