Identification of pathways associated with thyroid hormones and their molecular regulators by integrated OMICs analyses of cross-sectional and longitudinal studies in the general population and selected patients

甲状腺激素（THs）在细胞生长、发育和代谢中起着关键作用。甲状腺疾病引起的甲状腺功能改变一般会影响许多组织和代谢。促甲状腺素是甲状腺功能最重要的标志物，是循环甲状腺激素的重要调控因子。近年来，甲状腺素胺（thyronamines, tam）作为一类新的调节因子出现，可能对抗甲状腺素的作用。它们是甲状腺激素的代谢物，其分子结构与甲状腺前激素不同。所有的研究都显示了与经典三通相反的生理效应，包括施用TAMs后的快速和深度低体温和心动过缓。然而，到目前为止，人们对这两种药物的确切作用机制和调控机制知之甚少。已经发表的数据表明，遗传对TH水平有很大影响；很大一部分的遗传性被认为是受多基因控制的，但是负责的基因和受影响的途径大多是未知的。在优先计划“THYROID TRANS ACT”（SPP 1629）的框架内，我们现在建议对横断面和纵向人口研究（波美拉尼亚健康研究- SHIP和SHIP- trend）和选定的患者队列进行综合多组学分析，以揭示THs和TAMs作用的新方面。作为初步工作，我们向该联盟提供了全基因组个体基因分型数据（N= 4105个SHIP- trend先证体和998个SHIP- trend先证体）、全基因组全血表达数据（N=998个SHIP- trend先证体）和代谢组数据（N=1000个SHIP- trend样本，N=7400个SHIP-0/1样本）。利用这些数据以及项目中生成的miRNA、代谢组和蛋白质组数据集，我们将在SHIP和SHIP- trend中讨论这些复杂数据如何与TH (T3, T4)-和TAM （T1AM,）水平的变化相关。这些来自流行病学分析的新发现将通过对明显甲状腺功能亢进或甲状腺功能减退患者（N=400）的体外研究来跟进。在这里，我们将研究三萜类和tam对基因表达模式、代谢活性和选定的候选蛋白的调节作用，以验证我们在显性甲状腺功能亢进和甲状腺功能减退患者队列中基于人群的研究结果，并探索治疗对甲状腺功能正常化的影响。一个具体的重点将是TH和TAM相关的变化的区别。生成的数据也将成为优先项目的其他小组验证特定项目中生成的假设的资源。

Thyroid hormones (THs) play a key role in cellular growth, development and metabolism. Changes in thyroid function caused by thyroid disorders affect many tissues and metabolism in general. Circulating thyroid hormones are tightly regulated by thyrotropin, which is the most important marker for thyroid function. Recently, thyronamines (TAMs) emerged as a new class of regulators probably antagonizing the effects of TH. They constitute metabolites of the THs and their molecular structure differs from the thyroid pro-hormones. All studies revealed physiological effects opposite to those of classical THs, including a rapid and profound hypothermia and bradycardia upon administration of TAMs. However, up to now, the precise mechanisms of action and regulation of THs and TAMs are poorly understood.Already published data indicate a strong genetic influence on TH levels; a large portion of heritability is supposed to be under polygenic control, but the genes responsible and affected pathways are mostly unknown. Within the framework of the Priority Programme “THYROID TRANS ACT” (SPP 1629) we now propose an integrated multi-OMICs analysis of a combination of a cross sectional and longitudinal population based study (Study of Health in Pomerania – SHIP and SHIP-TREND) and selected patient cohorts to reveal new facets of the action of THs and TAMs.As preliminary work we provide to the consortium genome-wide individual genotyping data (N= 4105 probands of SHIP and 998 probands of SHIP-TREND), genome-wide whole blood expression data (N=998 probands SHIP-TREND) and metabolome data (N=1000 SHIP-TREND, N=7400 SHIP-0/1 samples). Using these data and miRNA, metabolome and proteome data sets generated within the project we will address in SHIP and SHIP-TREND how these complex data correlate to variations in TH (T3, T4)- and TAM (T1AM,)-levels. These new findings from the epidemiological analyses will be followed-up by studies of patients with overt hyper- or hypothyroidism (N=400) ex vivo. Here, we will investigate the regulatory impact of THs and TAMs on the gene expression pattern, metabolom activity and selected protein candidates to validate our findings of the population based study in a cohort of patients with overt hyper- and hypothyroidism and to explore the impact of normalisation of thyroid function by therapy. A specific focus will be the distinction of TH and TAM related alterations. The generated data will also be a resource for other groups of the priority program to validate hypotheses generated in the specific projects.