Negative regulation by thyroid hormone

描述(申请人提供)：甲状腺激素(TH)是人体代谢稳态的关键调节剂。它在人类发展中也发挥着基础性作用。因此，开发了一种优雅的反馈系统，将循环TH水平严格控制在较小的范围内。这种调控的核心是TH对下丘脑室旁核(PVH)促甲状腺激素释放激素(TRH)基因表达的负调控。除TH外，TRH还受瘦素和黑素皮质素信号通路的调节，禁食可抑制TRH的表达。然而，TRH同时受TH和禁食负调控的分子机制尚不清楚。在正调节基因上，TH与TH反应元件(TRES)上的甲状腺激素受体亚型(TRs)相互作用，最初解除未连接受体招募辅阻遏物复合体的能力所造成的抑制。除了解除抑制外，TH还通过允许tr招募作为组蛋白修饰酶并增强转录的辅活化子来进一步激活基因表达。虽然协同抑制因子和协同激活因子被认为在负调控中发挥作用，但目前还没有体内模型系统来测试它们的作用。此外，对真正的负面TRES的识别仍然难以捉摸。因此，了解TRH基因表达的调控为阐明TH负调控机制提供了一个理想的模型。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。在这项提案中，我们将使用一些新的遗传模型来确定控制TRH基因表达调控的分子机制。目的1将利用新的小鼠模型来辨别TH对TRH的负调控中的协同调节作用。目的2将利用一种新的转基因小鼠，该小鼠含有针对PVN的TRH袋子，并受TH调节。对这个袋子的操作将允许第一次识别阴性的TrE。目标3将重点放在TRH神经元内瘦素和TH通路之间的串扰，以及了解瘦素和/或下游通路调节TRH表达的确切机制。这些目标的完成将为新陈代谢途径如何通过靶向基因表达来维持代谢动态平衡提供新的线索。这应该允许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.