Estrogen regulation of channels involved in the control of energy homeostasis

本申请的长期目标是了解雌激素和 环境雌激素影响下丘脑功能，例如能量稳态。有一种肥胖症 流行病在美国和了解病因的任何和所有因素，有助于表达 肥胖对于治疗这种疾病是至关重要的。因此，指导项目的目标是了解 雌二醇如何通过多种膜启动机制影响能量稳态， 通过雌二醇反应性膜GPCR（mER）控制神经元兴奋性和基因调控 通过ER α和mER介导的机制在弓状神经元中表达。众所周知， 通过ER α和mER控制能量稳态，因为STX，mER的选择性配体， 卵巢切除术后体重增加。雌二醇也改变POMC弓状神经元的兴奋性 通过急诊室。雌二醇作用的一个潜在的mER介导机制是调节细胞内的 调节POMC兴奋性的非失活、亚阈值K+电流（M电流）。确定是否 雌二醇对M电流的调节在这些效应中起作用，我将首先测量表达， 在POMC和NPY神经元中的KCNQ/M电流的活性，来自油和雌二醇处理的雌性， 合并单细胞中的qRT-PCR和电生理学。其次，我将测量急性（通过mER）的影响 雌二醇处理对POMC和NPY神经元M电流电生理特性的影响 全细胞贴片记录。独立阶段将建立在 指导阶段，并检查膜启动和雌激素非依赖性信号传导的作用， 下丘脑功能，并确定环境雌激素是否激活这些相同的途径， 他们的影响。第一个目标将确定在能量控制中不依赖于ERE的信号传导的作用 使用野生型、aERKO和 ER α KI/KO小鼠模型。最终的目的是确定双酚A的电生理效应， 弓形POMC和NPY神经元控制能量稳态。

The long range goal of this application is to understand the mechanisms by which estrogen and environmental estrogens affect hypothalamic functions such as energy homeostasis. There is an obesity epidemic in the US and understanding the etiology of any and all factors that contribute to expression of obesity is critical for treatment of this disorder. Therefore, the goal of the mentored projects is to understand how estradiol affects energy homeostasis through multiple membrane-initiated mechanisms that include the control of neuronal excitability through an estradiol-responsive membrane GPCR (mER) and control of gene expression in arcuate neurons through both ERa- and mER-mediated mechanisms. Estradiol is known to control energy homeostasis through ERa and mER because STX, a selective ligand for the mER, attenuates body weight gain post-ovariectomy. Estradiol also alters neuronal excitability of POMC arcuate neurons through the mER. One potential mER-mediated mechanism for the effects of estradiol is modulation of a non-inactivating, sub-threshold K+ current that tempers the excitability of POMC (M-current). To detennine if modulation of the M-current by estradiol plays a role in these effects, I will first measure the expression and activity of the KCNQ/M-current in POMC and NPY neurons from oil- and estradiol-treated females using qRT-PCR in pooled single cells and electrophysiology. Second, I will measure the effects of acute (via mER) estradiol treatment on the electrophysiological properties of the M-current in POMC and NPY neurons using whole cell patch recordings. The independent phase will build on the techniques learned during the mentored phase and examine the role of membrane-initiated and ERE-independent estrogen signaling in hypothalamic functions and determine whether environmental estrogens activate these same pathways in their effects. The first aim will determine the role of ERE-independent signaling in the control of energy homeostasis and hypothalamic gene regulation by estradiol and bisphenol A using wild-type, aERKO and ERalpha KI/KO mice models. The final aim will detennine the electrophysiological effects of bisphenol A on arcuate POMC and NPY neurons that control energy homeostasis.