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Estrogen Regulation of the Hypothalamic-Pituitary-Adrenal Axis

雌激素对下丘脑-垂体-肾上腺轴的调节

基本信息

批准号：
10017956
负责人：
Brent Philip Myers
金额：
$ 30.06万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-05 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017956
关键词：
Adrenal Glands Adult Agonist Androgens Animals Area Behavior Binding Body Weight Changes Body Weight decreased Brain Cells Chronic Corticosterone Corticotropin Corticotropin-Releasing Hormone Data Disease Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens FOS gene Feeding behaviors Female Gap Junctions Genes Glucocorticoids Glycols Goals Gonadal Hormones Gonadal Steroid Hormones Homeostasis Hormonal Hypothalamic structure In Vitro Individual Differences Knowledge Label Mammals Mediating Metabolic Metabolism Molecular Monitor Mus Neurologic Deficit Neurons Neuropeptides Neurosecretory Systems Output Oxytocin Oxytocin Receptor Pathway interactions Pattern Phenotype Physiological Pituitary Gland Pituitary-Adrenal System Play Population Regulation Rodent Role Sex Differences Site Stanolone Stress Tamoxifen Technology Testing Tracer Transgenic Mice Vasopressins Viral Weight Gain acute stress base biological adaptation to stress designer receptors exclusively activated by designer drugs energy balance feeding genetic manipulation hypothalamic-pituitary-adrenal axis insight knock-down male mouse Cre recombinase mouse model multimodality nano-string neural circuit neurobiological mechanism new therapeutic target novel paraventricular nucleus prevent promoter reproductive response restraint sex stressor

项目摘要

ABSTRACT: The long-term goal of this project is to determine the neurobiological mechanisms that underlie the effects of estrogens on the adult hypothalamo-pituitary-adrenal (HPA) axis. HPA axis activation in mammals is a basic response to environmental perturbations that threaten homeostasis and such responses, although beneficial in the short-term, have deleterious consequences under chronic conditions. Prolonged elevations of adrenal glucocorticoids (GCs) are neuroendangering and alter feeding and autonomic functions. Moreover, a dysregulation of the HPA activity accompanies these disorders. In rodents, females show a more robust HPA axis response to stress than do males, partly because of sex-differences in circulating estradiol (E2) levels. Thus, the overarching postulate of this application is that individual differences in adult stress-responses arise from differential E2 actions on the stress-circuitry. Our studies focus predominantly on estrogen receptor beta (ERβ). Rodent studies show that the alpha form of ER (ERα) increases adrenal corticosterone (CORT) and the pituitary adrenocorticotropic hormone (ACTH) response to stressors whereas activation of ERβ inhibits HPA activity. Importantly, ERβ is highly expressed in neurons of the PVN of both male and female mice to allow integration of gonadal hormone levels with stress-related inputs. Using novel transgenic mouse models, we will identify stress responsive ERβ-ergic neural circuitry of the mouse hypothalamus and determine how activation of PVN ERβ reduces HPA drive and energy balance. Specific aim 1 will determine if OT is required for ERβ regulation of PVN function using a novel Oxytocin:cre recombinase mouse line and an ERβ-cre mouse line to genetically manipulate OT and ERβ neurons. Aim 2 will assess the function of ERβ neurons that are incorporated into the stress circuitry of the mouse brain following multimodal stress and chronic unpredictable mild stressors. Aim 3 will elucidate molecular changes and sex differences that occur in PVN ERβ neurons in response to MMS and to glucocorticoids. In all cases we are highly cognizant of the presence of sex differences in these physiological pathways and will explore the role that estradiol or 5α-androstan 3β,17β diol (3β diol), a metabolite of the androgen, dihydrotestosterone that binds and activates ERβ, have on HPA axis activation and feeding behaviors. The results of these studies will provide novel insight into the role played by PVN ERβ neurons in controlling hypophysiotrophic function and metabolism with hopes of identifying novel targets for therapeutic approaches to treating stress and associated neurological deficits.

摘要：该项目的长期目标是确定神经生物学机制，这些机制是雌激素对成人下丘脑-垂体-肾上腺（HPA）轴的影响。哺乳动物HPA轴的激活是一种基本的对威胁体内平衡的环境扰动的反应，以及这种反应，尽管在短期的，在慢性条件下具有有害的后果。肾上腺长时间升高糖皮质激素（GC）具有神经危害性，并改变进食和自主神经功能。而且 HPA活性的失调伴随着这些疾病。在啮齿类动物中，雌性显示出更强的HPA 轴反应的压力比男性，部分原因是性别差异，循环雌二醇（E2）水平。因此，这个应用程序的首要假设是，成年人的压力反应出现个体差异压力电路上的微分E2作用。我们的研究主要集中在雌激素受体β (ERβ）。啮齿动物研究表明，ER α（ER α）增加肾上腺皮质酮（CORT），垂体促肾上腺皮质激素（ACTH）对应激的反应，而ER β的激活抑制 HPA活性。重要的是，ER β在雄性和雌性小鼠的PVN神经元中高度表达，使性腺激素水平与压力相关的输入整合。使用新的转基因小鼠模型，我们将确定小鼠下丘脑的应激反应性ER β能神经回路，并确定如何 PVN ER β的活化降低HPA驱动和能量平衡。具体目标1将确定是否需要加班使用新型催产素：cre重组酶小鼠系和ER β-cre小鼠，线遗传操纵OT和ER β神经元。目的2将评估ER β神经元的功能，在多模式应激和慢性不可预测的应激后，轻度压力源目的3将阐明PVN ER β神经元中发生的分子变化和性别差异，对MMS和糖皮质激素的反应。在所有情况下，我们都高度认识到性的存在，这些生理途径的差异，并将探讨雌二醇或5 α-雄甾烷3 β，17 β二醇的作用，（3 β二醇）是雄激素双氢睾酮的代谢产物，结合并激活ER β，激活和摄食行为。这些研究的结果将提供新的见解所发挥的作用 PVN ER β神经元在控制垂体营养功能和代谢中的作用治疗压力和相关神经缺陷的治疗方法的目标。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity.

DOI：
10.1080/10253890.2017.1369523
发表时间：
2017-09
期刊：
Stress (Amsterdam, Netherlands)
影响因子：
0
作者：
Oyola MG;Handa RJ
通讯作者：
Handa RJ

Dietary Isoflavone-Dependent and Estradiol Replacement Effects on Body Weight in the Ovariectomized (OVX) Rat.

DOI：
10.1055/s-0043-108250
发表时间：
2017-06
期刊：
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
影响因子：
0
作者：
Russell AL;Grimes JM;Cruthirds DF;Westerfield J;Wooten L;Keil M;Weiser MJ;Landauer MR;Handa RJ;Wu TJ;Larco DO
通讯作者：
Larco DO

Estrogen Receptors Modulation of Anxiety-Like Behavior.