Estrogen regulation of channels involved in the control of energy homeostasis

雌激素对参与能量稳态控制的通道的调节

• 批准号: 8465757
• 负责人: Troy Adam Roepke
• 金额: $ 22.34万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465757
• 关键词: Acute; Address; Adult; Affect; Agonist; Animals; Attenuated; Cations; Cell physiology; Cells; Coupled; Development; Disease; Electrophysiology (science); Endocrinology; Environmental Estrogen; Epidemic; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Etiology; Event; Exposure to; Female; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; Gene Expression; Gene Expression Regulation; Goals; Health; Homeostasis; Hormone replacement therapy; Human; Hypothalamic structure; Instruction; Knowledge; Lead; Learning; Ligands; Link; Measures; Mediating; Membrane; Membrane Potentials; Mentors; Mouse Strains; Neurologic; Neurons; Neurosciences; Obesity; Oils; Ovariectomy; Patch-Clamp Techniques; Pathway interactions; Phase; Physiological; Play; Polychlorinated Biphenyls; Postmenopause; Property; Regulation; Research; Role; Signal Transduction; Steroids; Techniques; Time; Transgenic Mice; Transgenic Organisms; Weight Gain; Wild Type Mouse; Woman; Women' s Health; bisphenol A; cell type; mouse model; neuronal excitability; novel; novel strategies; reproductive

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.

该应用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。有一种肥胖现象 流行病在美国并了解导致表达的所有因素的病因学 肥胖对于治疗这种疾病至关重要。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，包括 通过雌二醇反应膜 GPCR (mER) 控制神经元兴奋性和基因控制 通过 ERa 和 mER 介导的机制在弓形神经元中表达。已知雌二醇 通过 ERa 和 mER 控制能量稳态，因为 STX（mER 的选择性配体）会减弱 卵巢切除术后体重增加。雌二醇还改变 POMC 弓状神经元的神经元兴奋性 通过梅尔。雌二醇作用的一种潜在的 mER 介导机制是调节 非失活的亚阈值 K+ 电流，可调节 POMC 的兴奋性（M 电流）。判断是否 雌二醇对 M 电流的调节在这些效应中发挥了作用，我将首先测量表达和 使用油和雌二醇处理的雌性的 POMC 和 NPY 神经元中 KCNQ/M 电流的活性 混合单细胞中的 qRT-PCR 和电生理学。其次，我将测量急性的影响（通过 mER） 雌二醇治疗对 POMC 和 NPY 神经元 M 电流电生理特性的影响 全细胞贴片记录。独立阶段将建立在学习期间学到的技术的基础上 指导阶段并检查膜启动和 ERE 独立的雌激素信号传导的作用 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。第一个目标是确定独立于 ERE 的信号在能量控制中的作用 使用野生型、aERKO 和雌二醇和双酚 A 调节体内平衡和下丘脑基因 ERalpha KI/KO 小鼠模型。最终目标是确定双酚 A 对电生理的影响。 控制能量稳态的弓形 POMC 和 NPY 神经元。