TRH Regulation/Biosynthesis and Paraventricular Nucleus

TRH 调节/生物合成和室旁核

基本信息

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
项目类别：
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&apos -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

项目摘要

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）通过在正常条件下和特殊情况下建立甲状腺激素的循环水平，在调节能量稳态方面发挥着重要作用。代谢适应是必要的，例如禁食、感染和慢性疾病。将探索代谢信号调节 PVN 中 TRH 神经元的机制，通过在转基因小鼠中使用 Cre/loxP 重组酶系统来促进，其中 Cre 重组酶在 TRH 细胞中选择性表达。将关注禁食期间直接瘦素信号转导与间接瘦素信号转导的重要性以及与饮食诱导的肥胖相关的重要性、AGRP 作为 MC-4 受体反向激动剂的作用、CREB、ERK 和 AMPK 信号转导通路作为调节因子的参与瘦素对促垂体 TRH 神经元的多种作用，以及大麻素/谷氨酸相互作用作为参与禁食诱导的 HPT 轴抑制的新机制。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，并检验 DMN 整合来自瘦素反应性弓状核神经元和室旁区的信号以产生信号的假设HPT 轴的昼夜节律周期。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) 介导的作用以及 T3 水平升高在内毒素诱导的单细胞中 2 型碘甲状腺原氨酸脱碘酶水平升高导致中基底层下丘脑的异常。促甲状腺激素释放激素（TRH）在正常情况下和特殊情况下（例如禁食和危重疾病时需要改变甲状腺状态以适应）建立甲状腺激素的循环水平，从而在能量稳态中发挥重要作用。拟议的研究将阐明下丘脑室旁核中的这一特殊神经元群如何受到代谢信号以及所涉及的神经解剖学途径和调节剂的调节，从而深入了解通常被称为非甲状腺疾病综合征的疾病。

项目成果

期刊论文数量（77）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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.
影响因子：
0
作者：
Sugawara,A;Yen,PM;Qi,Y;Lechan,RM;Chin,WW
通讯作者：
Chin,WW

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
通讯作者：
G. Wittmann;Judit Szabon;P. Mohácsik;Shira S Nouriel;B. Gereben;C. Fekete;R. Lechan

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