Negative regulation by thyroid hormone

描述（由申请人提供）：甲状腺激素（TH）是人体代谢稳态的关键调节因子。它还在人类发展中发挥着重要作用。因此，一个优雅的反馈系统已经发展到严格控制循环TH水平在一个狭窄的范围内。这种控制的核心是TH对下丘脑室旁核（PVH）促甲状腺素释放激素（TRH）基因表达的负调节。除TH外，TRH还受瘦素和黑皮质素信号通路调节，使得禁食抑制TRH表达。然而，TH和禁食对TRH负调节的分子机制尚不清楚。在正调控基因上，TH与TH反应元件（TRes）上的甲状腺激素受体亚型（TRs）相互作用，以最初解除由未配体受体募集辅阻遏物复合物的能力引起的阻遏。除了解除阻遏，TH还通过允许TR募集一系列作为组蛋白修饰酶并增强转录的共激活因子来进一步激活基因表达。虽然辅抑制因子和辅激活因子被认为在负调节中发挥作用，但尚未开发出体内模型系统来测试其作用。此外，真阴性TREs的鉴定仍然是难以捉摸的。因此，了解TRH基因表达的调控提供了一个理想的模型，以辨别由TH负调控的机制。此外，在TH神经元中瘦素和TH信号之间必须存在的串扰中将获得新的见解。在这个建议中，我们将使用一些新的遗传模型，使我们能够确定TRH基因表达调控的分子机制。目的1将采用新的小鼠模型，以确定在TH的TRH负调节的协同调节的作用。目的2利用一种新型转基因小鼠，该小鼠含有靶向PVN并受TH调节的TRH BAG。对该BAG的操作将允许首次识别阴性TRE。目标3将集中在TRH神经元内瘦素和TH通路之间的串扰，并了解瘦素和/或下游通路调节TRH表达的确切机制。这些目标的完成将为代谢途径如何靶向基因表达以保持代谢稳态提供新的线索。这将有助于更好地理解对疾病的生理适应。

DESCRIPTION (provided by applicant): Thyroid hormone (TH) is a key regulator of metabolic homeostasis in humans. It also plays a fundamental role in human development. Thus, an elegant feedback system has developed to tightly control circulating TH levels within a tight range. Central to this control is the negative regulation of thyrotropin-releasing hormone (TRH) gene expression in the paraventricular nucleus of the hypothalamus (PVH) by TH. In addition to TH, TRH is also regulated by leptin and melanocortin signaling pathways such that fasting represses TRH expression. However, the molecular mechanism by which TRH is negatively regulated by both TH and fasting is not known. On positively regulated genes TH interacts with thyroid hormone receptor isoforms (TRs) on TH response elements (TREs) to initially relieve repression caused by the unliganded receptor's ability to recruit a corepressor complex. In addition to relieving repression, TH further activates gene expression by allowing the TR to recruit a cast of coactivators which act as histone-modifying enzymes and enhance transcription. While corepressors and coactivators are presumed to play a role in negative regulation no in vivo model system has been developed to test there role. Furthermore, the identification of true negative TREs has remained elusive. Thus, understanding the regulation of TRH gene expression provides an ideal model to discern the mechanisms governing negative regulation by TH. In addition, new insight will be garnered in the cross-talk that must exist between leptin and TH signaling in the TH neuron. In this proposal we will use a number of new genetic models to allow us to determine the molecular mechanism governing the regulation of TRH gene expression. Aim 1 will employ novel mouse models to discern the role of coregulators in negative regulation of TRH by TH. Aim 2 will utilize a novel transgenic mouse which contains a TRH BAG that the targets the PVN and is regulated by TH. Manipulation of this BAG will allow for the identification for the first time of a negative TRE. Aim 3 will focus on both cross-talk between the leptin and TH pathways within the TRH neuron and also understanding the exact mechanism by which leptin and/or downstream pathways regulate TRH expression. Completion of these Aims will shed new light on how metabolic pathwys target gene expression to preserve metabolic homeostasis. This should allow for a better understanding of physiologic adaptation to disease.