Estrogen Regulation of Channels Involved in the Control of Energy Homeostatis

参与能量动态平衡的神经元回路正在被广泛研究；然而，内在的 调控这些神经元的潜在机制才刚刚开始被阐明，并将是至关重要的 了解与能量平衡相关的疾病(如肥胖、厌食症、恶病质等)。这些 神经元回路受许多不同外周激素的调节，其中包括17-雌二醇(17β-estadiol，E2)。E2，哪一个 在月经周期中变化，是厌食，导致食物摄入量和体重减少。雌二醇可以改变 激活ERα和新型G蛋白偶联膜雌激素受体的动态平衡功能 改变控制神经元兴奋性的阳离子通道的表达和活性。因此，一个 在过去的十年里，神经内分泌学中新兴和重要的领域是 膜启动的类固醇信号和生理效应。雌二醇利用的膜启动事件 包括激活一系列控制神经元兴奋性、基因表达和细胞内的已知通路 功能。一种新的转基因小鼠品系(ERαKi/Ko)在ERα上缺乏功能性DNA结合域 蛋白质，因此没有雌激素反应元件介导的转录。使用这些小鼠和 野生型和完全ERαKO，我们可以确定ERE依赖和ERE非依赖的作用 转录和细胞信号对能量稳态的影响。此外，越来越多的证据表明，这两个 这些类型的信号事件是环境雌激素(双酚A(BPA)、 烷基酚、植物雌激素等)。因此，环境雌激素具有多种潜在靶点。 在下丘脑以外改变正常的生殖能力，包括其他下丘脑功能 受内源性雌激素控制。本申请概述的实验将检查多个受体介导的 雌激素(和环境雌激素)影响能量动态平衡和其他的途径 下丘脑在下丘脑中的功能。在第一个目标，K99/R00的具体目标3中，我们将阐明 ERE依赖和ERE非依赖的E2信号(ER、α和/或GQ-mer)在能量控制中的作用 动态平衡和下丘脑基因表达与母亲是否暴露于环境雌激素功能 通过类似的机制。第二个目标，K99/R00的特定目标4)将检查电生理 环境雌激素暴露对POMC和NPY神经元活性及阳离子通道的影响 在体内和切片制剂中均有表达。环境雌激素的电生理效应 对下丘脑神经元活动的影响以前没有被研究过。因为最近的证据表明 在发育过程中暴露于双酚A和成人肥胖之间，这项研究的目标是解决基本的 这些化合物的神经学效应，并进一步提高我们对环境影响的认识 使用新的方法(转基因小鼠模型和电生理)雌激素对人类健康的影响 技术)，并与整个动物研究相结合。

The neuronal circuits involved in energy homeostasis are being extensively explored; however, the intrinsic mechanisms underlying the regulation of these neurons are just beginning to be elucidated and will be critical for understanding disorders associated with energy homeostasis (i.e., obesity, anorexia, cachexia, etc.). These neuronal circuits are modulated by many different peripheral hormones including 17β-estradiol (E2). E2, which varies during the menstrual cycle, is anorectic leading to decreased food intake and body weight. E2 can alter homeostatic functions by activating ERα and novel G-protein coupled membrane estrogen receptors (GqmER) to alter the expression and activity of cation channels that control neuronal excitability. Hence, an emerging and significant field in neuroendocrinology within the past decade has been the convergence of membrane-initiated steroid signaling and physiological effects. The membrane-initiated events utilized by E2 involve activation of a host of known pathways that control neuronal excitability, gene expression and cellular functions. A novel transgenic strain of mice (ERα Ki/Ko) lack a functional DNA binding domain on the ERα protein and, thus exhibit no Estrogen Response Element-mediated transcription. Using these mice along with wild type and full ERα KO, we can determine the actions of ERE-dependent and ERE-independent transcription and cell signaling on energy homeostasis. Furthermore, there is growing evidence that both of these types of signaling events are potential targets for environmental estrogens (bisphenol A (BPA), alkylphenols, phytoestrogens, etc.). Therefore, environmental estrogens have a multiplicity of potential targets in the hypothalamus outside of altering normal reproductive capacity including other hypothalamic functions controlled by endogenous estrogen. Experiments outlined this application will examine the multiple receptormediated pathways that E2 (and environmental estrogens) impact energy homoeostasis and other hypothalamic functions in the hypothalamus. In the first aim, Specific Aim 3 of K99/R00, we will elucidate the effects of ERE-dependent and ERE-independent E2 signaling (ERα and/or Gq-mER) in the control of energy homeostasis and hypothalamic gene expression and if maternal exposure to environmental estrogens function through similar mechanisms. The second aim, Specific Aim 4 of K99/R00) will examine the electrophysiological effects of exposures to environmental estrogens on POMC and NPY neuronal activity and cation channel expression both in vivo and in slice preparations. The electrophysiological effects of environmental estrogens on hypothalamic neuronal activity has not been examine previously. Since recent evidence suggests a link between developmental exposure to BPA and adult obesity, the goals of this research will address basic neurological effects of these compounds and further enhance our knowledge of the impacts environmental estrogens have on human health using novel approaches (transgenic mouse models and electrophysiological techniques) and integration with whole animal studies.