New Targets of Thyroid Hormone Action

描述（由申请人提供）：甲状腺激素（TH）是人体代谢和体重的关键调节剂。事实上，TH已被证明可以调节能量消耗、脂质水平和胰岛素敏感性，以改善代谢结果。由于这些有益的作用，TH或其类似物之一是用于多种代谢疾病的潜在治疗剂。然而，如果过量使用TH，则会产生显著的副作用，特别是对心脏和骨骼。值得注意的是，人类的TH作用几乎完全由促甲状腺激素（TSH）测定法确定，该测定法仅依赖于下丘脑和垂体水平的TH作用。因此，迫切需要改进的生物标志物，其将允许定制TH疗法以改善代谢健康并允许增强的安全性。为了开始实现这一点，我们已经使用代谢组学分析和小鼠遗传模型来开始表征体内TH敏感途径。我们的初步工作已经确定了独特的代谢物，由TH调节，既作为生物标志物，也作为甲状腺激素作用的介质。在第一个目标的这个建议中，我们将扩展我们对TH以组织特异性和TH受体特异性方式调节代谢产物谱的分析，并首次将我们的分析扩展到人类。在第二个目标中，我们将确定TH调节甲硫氨酸代谢的机制，这可能对TH控制基因表达和调节脂肪酸氧化等程序的能力至关重要。在第三个目标中，我们将使用新的遗传小鼠模型来确定TH如何控制胆固醇代谢，进一步了解TH调控的关键途径。总之，这些目标的完成将为理解和定义TH在体内的作用提供一个新的平台。

DESCRIPTION (provided by applicant): Thyroid hormone (TH) is a critical regulator of metabolism and body weight in humans. Indeed, TH has been shown to regulate energy expenditure, lipid levels and insulin sensitivity to improve metabolic outcome. Because of these beneficial effects, TH or one of its analogs is a potential therapeutic for a wide variety of metabolic diseases. However, if excessively dosed TH has significant side effects especially on the heart and bone. Remarkably, TH action in humans is determined almost exclusively by the use of the thyrotropin (TSH) assay which depends only upon TH action at the level of the hypothalamus and pituitary. Thus, there is a critical need for improved biomarkers that would allow for tailoring of TH therapy to improve metabolic health and allow for enhanced safety. To begin to accomplish this we have used metabolomic profiling and mouse genetic models to begin to characterize TH sensitive pathways in vivo. Our preliminary work has identified unique metabolites that are regulated by TH that serve both as biomarkers and also as mediators of thyroid hormone action. In this proposal in the first aim we will extend our analysis of the regulation of metabolite profiles by TH in a tissue-specific and TH receptor specific fashion and extend our analysis into humans for the first time. In the second Aim we will determine the mechanism by which TH regulates methionine metabolism which is likely critical to TH ability to control gene expression and regulate programs such as fatty acid oxidation. In the third Aim we will use novel genetic mouse models to determine how TH controls cholesterol metabolism gaining further insight into a key pathway regulated by TH. Together, completion of these Aims will provide for a new platform for both understanding and defining TH action in vivo.