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

通过对一般人群和选定患者的横断面和纵向研究进行综合 OMIC 分析，鉴定与甲状腺激素及其分子调节剂相关的途径

• 批准号: 221200942
• 负责人: Professor Dr. Uwe Völker, since 11/2013
• 金额: --
• 依托单位: Institut für Klinische Chemie und Laboratoriumsmedizin
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/221200942?language=en
• 关键词: Identification; pathways; associated; thyroid; hormones

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.

甲状腺激素（TH）在细胞生长、发育和代谢中起关键作用。甲状腺疾病引起的甲状腺功能变化一般会影响许多组织和代谢。循环中的甲状腺激素受促甲状腺激素的严格调节，促甲状腺激素是甲状腺功能最重要的标志物。最近，甲状腺素胺（TAMs）作为一类新的调节剂出现，可能拮抗TH的作用。它们构成TH的代谢物，其分子结构不同于甲状腺激素原。所有研究均显示了与经典TH相反的生理效应，包括TAM给药后快速且深度的体温过低和心动过缓。然而，到目前为止，TH和TAMs的确切作用和调节机制知之甚少，已经发表的数据表明TH水平有很强的遗传影响;很大一部分遗传可能是受多基因控制的，但负责和影响途径的基因大多是未知的。在优先方案“甲状腺移植法”的框架内（SPP 1629）我们现在提出了一个综合的多OMIC分析，结合了基于横断面和纵向人群的研究（波美拉尼亚健康研究- SHIP和SHIP-TREND）和选定的患者队列，以揭示TH和TAM作用的新方面。（N= 4105例SHIP先证者和998例SHIP-TREND先证者）、全基因组全血表达数据（N=998例SHIP-TREND先证者）和代谢组数据（N=1000例SHIP-TREND，N=7400例SHIP-0/1样本）。使用这些数据和项目中生成的miRNA、代谢组和蛋白质组数据集，我们将在SHIP和SHIP-TREND中解决这些复杂数据如何与TH（T3，T4）和TAM（T1 AM）水平的变化相关。流行病学分析的这些新发现将通过对明显甲状腺功能亢进或减退患者（N=400）的体外研究进行随访。在这里，我们将研究TH和TAM对基因表达模式、代谢组活性和选定蛋白候选物的调节影响，以验证我们在一组明显甲状腺功能亢进和甲状腺功能减退患者中进行的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相关的改变的区别。所产生的数据也将成为优先项目其他小组的资源，以验证特定项目中产生的假设。