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，促甲状腺激素（TSH）和游离甲状腺素（fT 4），通过一个强大的，敏感的，可重复的关系，代表了诊断甲状腺功能障碍和甲状腺疾病的治疗质量评估的金标准。在特殊的临床情况下，建议使用其他标志物的支持作用，例如游离3，3，5-三碘-1-甲状腺原氨酸（fT 3）浓度和/或标准化fT 4：fT 3比值或反向T3，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fT 4的关系将失败，需要其他生化标志物来判断甲状腺激素状态。目前，没有关于甲状腺功能其他血浆标志物的潜在应用的系统数据。特别是，只有少数研究试图捕捉外周甲状腺激素的影响，通过一个公正的方法，找到新的甲状腺激素依赖性标志物。为了解决这一难题，在拟议项目的框架内，我们的目标是使用一个集成的多OMICS方法（基因组，转录组，代谢组和蛋白质组），以确定相关的途径调节的经典甲状腺激素和甲状腺素（TAM），特别是3-碘甲状腺素（3-T1 AM）和新的候选人，可能会变成临床相关性。我们计划研究四种不同的环境，代表甲状腺激素相关疾病的不同阶段：1）最初明显的内源性未治疗的甲状腺功能亢进症或甲状腺功能减退症患者，他们将接受甲状腺激素替代治疗，2）治疗的甲状腺功能减退症患者，其中替代治疗将暂时停止7天，并因此发展为急性轻度甲状腺功能减退症，3）一项干预性研究，健康志愿者暴露于单剂量的fT 4，以评估对甲亢的急性适应; 4）一项干预性研究，健康志愿者暴露于每日剂量的fT 4，持续8周，以评估对甲亢的中期适应。通过将这些数据与波美拉尼亚健康研究（SHIP）人群环境中已有的多OMICS数据和动物模型相结合，该项目将提供甲状腺激素变化对血浆/尿液代谢物和蛋白质组成的影响以及从急性适应到明显疾病的全血表达模式的全面时间分辨图片。此外，第一次，我们将提供一个TAM水平与OMICS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，这些分子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.