TRH Regulation/Biosynthesis and Paraventricular Nucleus

描述（由申请人提供）：下丘脑室旁核（PVN）的神经元产生促甲状腺素释放激素（TRH），在正常情况下和在需要代谢适应的特殊情况下（如禁食、感染和慢性疾病），通过建立循环甲状腺激素水平，在调节能量稳态中起重要作用。通过在转基因小鼠中使用Cre/loxP重组酶系统，其中Cre-重组酶在TRH细胞中选择性表达，将探索代谢信号调节PVN中TRH神经元的机制。将关注空腹期间直接和间接瘦素信号传导的重要性以及与饮食诱导的肥胖的关系，AGRP作为MC-4受体的逆激动剂的作用，CREB， ERK和AMPK信号通路作为瘦素对垂体性TRH神经元的多种作用的介质的参与，以及大麻素/谷氨酸相互作用作为空腹诱导的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讨，并验证DMN整合来自瘦素反应弓状核神经元和室旁带的信号以引起HPT轴的昼夜周期性的假设。内毒素抑制垂体性TRH神经元的机制也将被研究，重点关注cAMP反应元件调节剂（CREM）、诱导性cAMP早期抑制因子（ICER）、促肾上腺皮质激素释放激素（CRH）介导的作用，以及内毒素诱导的tanycytes中2型碘甲状腺原氨酸脱碘酶水平升高导致下丘脑中基底区T3水平升高的作用。促甲状腺激素释放激素（TRH）在能量稳态中起着重要作用，在正常情况下以及在禁食和危重疾病等特殊情况下，当甲状腺状态需要改变以适应时，TRH可以建立甲状腺激素的循环水平。本研究将阐明下丘脑室旁核的这一特殊神经元群是如何受到代谢信号和相关神经解剖学通路和调节剂的调节的，从而为通常被称为非甲状腺疾病综合征的疾病提供见解。

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.