Unraveling the molecular basis for successful thyroid hormone replacement therapy

揭示成功甲状腺激素替代疗法的分子基础

• 批准号: 280020722
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280020722?language=en
• 关键词: Unraveling; molecular; basis; successful; thyroid

Clinical symptoms and signs are frequently misleading to diagnose thyroid dysfunction or to monitor thyroid hormone replacement therapy. Currently, the measurement of serum TSH concentrations is regarded the best single, robust, sensitive, and reproducible test for determining systemic thyroid status whereas free or total thyroid hormone concentrations appear to be too insensitive to draw firm conclusions from small alterations. However, TSH fails as a marker in an increasing number of clinically difficult situations such as in central hypothyroidism where immunoactive TSH may be measurable despite a loss of its bioactivity or in the differential diagnosis of inadequately elevated TSH due to a mutation of the T3 receptor beta. Particularly under these conditions, other biochemical markers, generally representing organ-specific markers for thyroid hormone action, have been tested, but only the determination of sex-hormone binding globulin is of some clinical impact. The recent characterization of mutations of the thyroid hormone receptor alpha highlight that classical diagnostic approaches based on TSH and free thyroxine determination fail to diagnose the condition and new markers are urgently required. Using an unsupervised proteomic and metabolomics approach we obtained during the first period of the priority program first, very promising data in humans on a large number of new thyroid hormone dependent markers. In the present proposal we aim to identify a biochemical fingerprint indicative of thyroid hormone economy in the mouse because the mouse model allows us to relate changes in proteome and metabolome to organ-specific alterations and to test the impact of thyroid hormone receptor specific mutations. Comparison to the human model allows us to validate which molecular markers for thyroid hormone metabolism in wildtype and genetically modified mice of defined pathology are suitable for a transfer to the human condition. Furthermore, we will characterize the molecular changes occurring with the classical thyroxine monotherapy for replacement in different target-tissues compared to the wildtype situation. Comparison to plasma proteome and metabolome analysis will help to further characterize these markers and determine their potential to serve for fine-tuning of the replacement therapy. We expect that these systematic studies will allow us to identify important new markers to monitor thyroid function and to relate marker changes to the underlying pathology.

临床症状和体征经常误导诊断甲状腺功能障碍或监测甲状腺激素替代治疗。目前，血清TSH浓度的测量被认为是确定全身甲状腺状况的最好的单一、可靠、灵敏和可重复性的测试，而游离或总甲状腺激素浓度似乎太不敏感，无法从微小的变化中得出确切的结论。然而，在越来越多的临床困难情况下，TSH不能作为一种标志物，例如在中枢性甲状腺功能减退症中，尽管失去了生物活性，免疫活性TSH仍可被检测到，或者在鉴别诊断由于T3受体β突变而导致的TSH不足升高。特别是在这种情况下，已经检测了其他生化标记物，通常代表甲状腺激素作用的器官特异性标记物，但只有性激素结合球蛋白的测定具有一定的临床影响。最近对甲状腺激素受体α突变的研究表明，基于TSH和游离甲状腺激素测定的经典诊断方法无法诊断这种情况，迫切需要新的标记物。使用非监督蛋白质组学和代谢组学方法，我们在优先计划的第一阶段首先在人类中获得了关于大量新的甲状腺激素依赖标记的非常有希望的数据。在目前的提案中，我们的目标是识别指示小鼠甲状腺激素经济性的生化指纹，因为小鼠模型允许我们将蛋白质组和代谢组的变化与器官特异性变化联系起来，并测试甲状腺激素受体特异性突变的影响。通过与人类模型的比较，我们可以验证野生型和转基因小鼠中哪些甲状腺激素代谢的分子标志物适合转移到人类状态。此外，我们将描述与野生型情况相比，在不同的靶组织中使用经典的甲状腺激素单一疗法进行替代时发生的分子变化。与血浆蛋白质组和代谢组分析进行比较将有助于进一步确定这些标记物的特征，并确定它们为替代疗法的微调服务的潜力。我们期望这些系统性研究将使我们能够确定重要的新标志物来监测甲状腺功能，并将标志物的变化与潜在的病理联系起来。