Integrated-OMICs analyses to identify pathways associated with thyroid hormones and their molecular regulators: Screening for new markers to assess thyroid hormone action

甲状腺激素对正常发育和几乎所有组织的功能都是必不可少的。在临床实践中，促甲状腺素（TSH）和游离甲状腺素（fT4）具有可靠、敏感和可重复的关系，是诊断甲状腺功能障碍和评估甲状腺疾病治疗质量的金标准。在特殊的临床情况下，额外的标记物如测量游离3,3,5-三碘- 1 -甲状腺原氨酸（fT3）浓度和/或标准化的fT4:fT3比率或逆转T3的支持作用被建议，但似乎并不普遍适用。此外，在各种临床情况下，如中枢性甲状腺功能减退症，TSH和fT4的关系会失效，需要其他生化指标来判断甲状腺激素状态。目前，还没有关于甲状腺功能其他血浆标志物潜在应用的系统数据。特别是，只有少数研究试图通过无偏倚的方法来寻找新的甲状腺激素依赖标记物来捕捉外周甲状腺激素的作用。为了解决这一困境，在拟议项目的框架内，我们的目标是使用集成的多组学方法（基因组，转录组，代谢组和蛋白质组）来确定由经典甲状腺激素和甲状腺胺（TAM），特别是3-碘甲状腺胺（3-T1AM）和可能具有临床相关性的新候选物调节的相关途径。我们计划调查代表甲状腺激素相关疾病不同阶段的四种不同设置：1)最初有明显内源性未经治疗的甲状腺功能亢进或甲状腺功能减退的患者接受甲状腺激素替代治疗；2)接受过甲状腺功能减退治疗的患者暂时停止替代治疗7天，随后会发展为急性轻度甲状腺功能减退；3)健康志愿者接受单剂量fT4的介入研究，以评估对甲状腺功能亢进的急性适应性。4)一项介入研究，健康志愿者每天暴露于fT4剂量8周，以评估对甲状腺毒症的中期适应。通过将这些数据与波美拉尼亚健康研究（SHIP）基于人群的环境中已有的多组学数据以及动物模型的数据相结合，该项目将提供一个全面的时间分辨率图像，显示甲状腺激素变化对血浆/尿液的代谢物和蛋白质组成的影响，以及从急性适应到显性疾病的全血表达模式。此外，我们将首次提供TAM水平与组学模式的关联印象。总之，这些研究将旨在识别潜在的分子特征，这些特征可以指示甲状腺激素代谢的变化，并可用于改善甲状腺疾病的诊断和治疗管理。

Thyroid hormones are essential for normal development and for the function of virtually all tissues. In clinical praxis thyrotropin (TSH) and free thyroxine (fT4), linked by a robust, sensitive, and reproducible relation, represent the gold standard for the diagnosis of thyroid dysfunction and the assessment of the quality of treatment for thyroid disorders. The supportive role of additional markers such as the measurement of free 3,3,5-triiodo-l-thyronine (fT3) concentrations and/or a normalized fT4:fT3 ratio or reverse T3 is suggested in special clinical situations but appears not to be generally applicable. Furthermore, in a variety of clinical situations e.g. central hypothyroidism, the relation of TSH and fT4 will fail and other biochemical markers will be needed to judge thyroid hormone status. Currently, there are no systematic data available on the potential application of other plasma markers of thyroid function. In particular, only few studies attempted to capture peripheral thyroid hormone effects by an unbiased approach to find new thyroid hormone dependent markers. To solve this dilemma, within the framework of the proposed project we aim to use an integrated multi-OMICS approach (genome, transcriptome, metabolome, and proteome) to identify relevant pathways regulated by classical thyroid hormones and thyronamines (TAM) in particular 3-iodothyronamines (3-T1AM) and new candidates that might turn out to be of clinical relevance. We plan to investigate four different settings that represent different phases of thyroid hormone associated disease: 1) patients with initially overt endogenous untreated hyperthyroidism or hypothyroidism who will receive thyroid hormone replacement therapy, 2) treated patients with hypothyroidism in whom replacement therapy will be temporally paused for 7 days and who will consequently develope acute mild hypothyroidism, 3) an interventional study with healthy volunteers exposed to a single dose of fT4 to evaluate the acute adaptation to hyperthyrotoxicosis, and 4) an interventional study with healthy volunteers exposed to a daily dose of fT4 for 8 weeks to evaluate the mid-time adaptation to thyrotoxicosis. By integrating these data with already available multi-OMICS data in the population-based setting of the Study of Health in Pomerania (SHIP) and from animal models the project will provide a comprehensive time-resolved picture of the influence of variations of thyroid hormones on the metabolite and protein composition of plasma/ urine and whole-blood expression patterns from acute adaptation to overt disease. Moreover for the first time, we will provide an impression of the association of TAM levels with OMICS patterns. Together, these studies will aim at the identification of potential molecular signatures that can indicate changes in thyroid hormone metabolism and can be used to improve diagnosis and therapy management of thyroid disease.