TRH Regulation/Biosynthesis and Paraventricular Nucleus

TRH 调节/生物合成和室旁核

• 批准号: 7997902
• 负责人: RONALD Michael LECHAN
• 金额: $ 6.73万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-21 至 2010-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7997902
• 关键词: 5' -AMP-activated protein kinase; Agonist; Anabolism; Attention; Axon; Axonal Transport; CREB1 gene; Cannabinoids; Cell Nucleus; Cells; Chronic Disease; Circadian Rhythms; Complex; Corticotropin-Releasing Hormone; Critical Illness; Cyclic AMP; Cyclic AMP Response Element; Diet; Disease; Endocannabinoids; Endotoxins; Fasting; Feedback; Figs - dietary; Glutamates; Homeostasis; Hyperthyroidism; Hypothalamic structure; Infection; Iodothyronine Deiodinase; Leptin; Maintenance; Medial Dorsal Nucleus; Mediating; Mediator of activation protein; Metabolic; Nature; Neurons; Obesity; Pathway interactions; Periodicity; Phosphorylation; Physiologic pulse; Pituitary Gland; Play; Presynaptic Terminals; Regulation; Role; Signal Pathway; Signal Transduction; Structure of dorsomedial hypothalamic nucleus; Structure of nucleus infundibularis hypothalami; Syndrome; System; Testing; Third ventricle structure; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyrotropin-Releasing Hormone; Tissues; Transgenic Mice; Up-Regulation; Vimentin; cannabinoid receptor; hormone regulation; insight; median eminence; nerve supply; novel; paraventricular nucleus; pituitary thyroid axis; receptor; recombinase; research study; selective expression

DESCRIPTION (provided by applicant): Thyrotropin-releasing hormone (TRH) produced by neurons in the hypothalamic paraventricular nucleus (PVN) has an important role in the regulation of energy homeostasis by establishing circulating levels of thyroid hormone under normal conditions and during special circumstances when metabolic adaptation is necessary such as fasting, infection and chronic illnesses. Mechanisms whereby metabolic signals regulate TRH neurons in the PVN will be explored, facilitated by the use of the Cre/loxP recombinase system in transgenic mice in which Cre-recombinase is expressed selectively in TRH cells. Attention will be given to the importance of direct vs indirect leptin signaling during fasting and in association with diet-induced obesity, the role of AGRP as an inverse agonist at MC-4 receptors, participation of CREB, ERK and AMPK signaling pathways as mediators of leptin's diverse actions on hypophysiotropic TRH neurons, and cannabinoid/glutamate interactions as a novel mechanism involved in fasting-induced suppression the HPT axis. The importance of the hypothalamic dorsomedial nucleus (DMN) as a relay station between the arcuate nucleus and TRH neurons in the PVN will be explored and the hypothesis tested that the DMN integrates signals from leptin- responsive arcuate nucleus neurons and the subparaventricular zone to give rise to the circadian periodicity of the HPT axis. Mechanisms by which endotoxin suppress hypophysiotropic TRH neurons will also be studied, focusing on effects mediated by cAMP-response element modulator (CREM), inducible cAMP early repressor (ICER), corticotropin-releasing hormone (CRH) and the role of increased T3 levels in the mediobasal hypothalamus as a result of endotoxin-induced increased type 2 iodothyronine deiodinase levels in tanycytes. Thyrotropin-releasing hormone (TRH) plays a major role in energy homeostasis by establishing circulating levels of thyroid hormone under normal conditions and during special circumstances such as fasting and critical illness when changes in thyroid status are required for adaptation. The proposed studies will elucidate how this specialized group of neurons in the hypothalamic paraventricular nucleus is regulated by metabolic signals and the neuroanatomical pathways and modulators involved, providing insight into disorders commonly referred to as the nonthyroidal illness syndrome.

描述（由申请人提供）：由下丘脑室旁核（PVN）神经元产生的促甲状腺激素释放激素（TRH）在正常条件下以及在需要代谢适应的特殊情况下（如禁食、感染和慢性疾病），通过建立甲状腺激素循环水平来调节能量稳态方面具有重要作用。代谢信号调节TRH神经元的PVN的机制将进行探讨，促进使用的Cre/loxP重组酶系统在转基因小鼠中Cre重组酶选择性表达TRH细胞。注意力将给予直接与间接瘦素信号在禁食期间的重要性，并与饮食诱导的肥胖，AGRP作为MC-4受体的反向激动剂的作用，CREB，ERK和AMPK信号通路的参与，作为中介体的瘦素的不同行动促垂体TRH神经元，大麻素/谷氨酸相互作用作为一种新的机制参与禁食诱导的抑制HPT轴。下丘脑背内侧核（DMN）作为PVN中弓状核和TRH神经元之间的中继站的重要性将被探索，并且假设DMN整合来自瘦素反应性弓状核神经元和室旁下区的信号以引起HPT轴的昼夜周期性。还将研究内毒素抑制促垂体TRH神经元的机制，重点关注cAMP反应元件调节剂（CREM）、诱导型cAMP早期阻遏物（ICER）、促肾上腺皮质激素释放激素（CRH）介导的效应，以及内毒素诱导的延长细胞中2型碘甲腺原氨酸脱碘酶水平升高导致的中基底下丘脑T3水平升高的作用。促甲状腺激素释放激素（TRH）通过在正常条件下以及在特殊情况下（如禁食和危重病）建立甲状腺激素的循环水平，在能量稳态中发挥重要作用，此时需要甲状腺状态的变化来适应。拟议的研究将阐明下丘脑室旁核中的这一专门的神经元群是如何受代谢信号和神经解剖学通路和相关调节剂的调节的，从而为通常被称为非甲状腺疾病综合征的疾病提供了深入了解。

项目成果

Glucocorticoids inhibit stress-induced phosphorylation of CREB in corticotropin-releasing hormone neurons of the hypothalamic paraventricular nucleus.

• DOI: 10.1159/000127224
• 发表时间: 1997-07
• 期刊: Neuroendocrinology
• 影响因子: 4.1
• 作者: G. Légrádi;D. Holzer;L. Kapcala;R. Lechan

Parallel regulation of thyroid hormone transporters OATP1c1 and MCT8 during and after endotoxemia at the blood-brain barrier of male rodents.

• DOI: 10.1210/en.2014-1830
• 发表时间: 2015-01
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: G. Wittmann;Judit Szabon;P. Mohácsik;Shira S Nouriel;B. Gereben;C. Fekete;R. Lechan

Isoform-specific retinoid-X receptor (RXR) antibodies detect differential expression of RXR proteins in the pituitary gland.

亚型特异性视黄酸-X 受体 (RXR) 抗体可检测垂体中 RXR 蛋白的差异表达。

• DOI: 10.1210/endo.136.4.7895689
• 发表时间: 1995
• 期刊: Endocrinology.
• 作者: Sugawara,A;Yen,PM;Qi,Y;Lechan,RM;Chin,WW
• 通讯作者: Chin,WW

Regulation of cocaine- and amphetamine-regulated transcript-synthesising neurons of the hypothalamic paraventricular nucleus by endotoxin; implications for lipopolysaccharide-induced regulation of energy homeostasis.

内毒素对下丘脑室旁核可卡因和安非他明调节的转录合成神经元的调节；

• DOI: 10.1111/j.1365-2826.2008.01758.x
• 发表时间: 2008
• 期刊: Journal of neuroendocrinology
• 影响因子: 3.2
• 作者: Füzesi,T;Sánchez,E;Wittmann,G;Singru,PS;Fekete,C;Lechan,RM
• 通讯作者: Lechan,RM

Distinct glutamatergic and GABAergic subsets of hypothalamic pro-opiomelanocortin neurons revealed by in situ hybridization in male rats and mice.

• DOI: 10.1002/cne.23350
• 发表时间: 2013-10-01
• 期刊: JOURNAL OF COMPARATIVE NEUROLOGY
• 影响因子: 2.5
• 作者: Wittmann, Gabor;Hrabovszky, Erik;Lechan, Ronald M.
• 通讯作者: Lechan, Ronald M.