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

综合组学分析以确定与甲状腺激素及其分子调节剂相关的途径：筛选新标记物以评估甲状腺激素作用

• 批准号: 280201336
• 负责人: Professor Dr. Georg Brabant
• 金额: --
• 依托单位: Medizinische Klinik I
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280201336?language=en
• 关键词: Integrated; OMICs; analyses; identify; pathways

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.

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(FT4)之间存在着强大、灵敏和可重复性的联系，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。附加标记物的辅助作用，如测量游离3，3，5-三碘-L-甲状腺原氨酸(FT3)浓度和/或归一化FT4/FT3比值或逆转T3，在特殊临床情况下被认为是支持作用，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，TSH和FT4的关系将失效，需要其他生化标志物来判断甲状腺激素状态。目前，还没有关于其他甲状腺功能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一种无偏见的方法来捕捉外周甲状腺激素的影响，以寻找新的甲状腺激素依赖标记物。为了解决这一困境，在拟议的项目框架内，我们的目标是使用集成的多OMICS方法(基因组、转录组、代谢组和蛋白质组)来识别受经典甲状腺激素和甲状腺原氨酸()特别是3-碘甲状腺原胺(3-T1AM)调节的相关通路，以及可能被证明具有临床意义的新的候选通路。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环境：1)最初明确的内源性甲亢或甲减患者将接受甲状腺激素替代治疗，2)甲减患者替代治疗将暂时暂停7天，因此将发展为急性轻度甲状腺功能减退，3)对暴露于单剂量FT4的健康志愿者进行干预性研究，以评估对甲亢的急性适应，4)对健康志愿者进行干预性研究，以评估每日暴露于FT4剂量8周的健康志愿者对甲亢的中期适应。通过将这些数据与波美拉尼亚健康研究(SHIP)人群环境和动物模型中现有的多OMICS数据相结合，该项目将提供一幅全面的时间分辨图像，展示甲状腺激素变化对血浆/尿液代谢物和蛋白质组成的影响，以及从急性适应到临床疾病的全血表达模式。此外，我们将第一次提供能级与OMICS模式之间的联系的印象。总之，这些研究将旨在确定潜在的分子标记，这些标记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。