Unraveling the molecular basis for successful thyroid hormone replacement therapy

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态的最佳单一，稳健，灵敏和可重复的测试，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明确的结论。然而，在越来越多的临床困难情况下，TSH不能作为标记物，例如在中枢性甲状腺功能减退症中，尽管其生物活性丧失，但免疫活性TSH可以测量，或者在T3受体β突变导致的TSH不充分升高的鉴别诊断中。特别是在这些条件下，其他生化标志物，通常代表甲状腺激素作用的器官特异性标志物，已被测试，但只有性激素结合球蛋白的测定具有一定的临床影响。甲状腺激素受体α突变的最新特征突出表明，基于TSH和游离甲状腺素测定的经典诊断方法无法诊断该疾病，迫切需要新的标志物。使用无监督的蛋白质组学和代谢组学方法，我们在优先计划的第一阶段获得了大量新的甲状腺激素依赖性标志物的非常有希望的人类数据。在本提案中，我们的目标是确定一个生化指纹指示甲状腺激素经济的小鼠，因为小鼠模型使我们能够将蛋白质组和代谢组的变化与器官特异性改变联系起来，并测试甲状腺激素受体特异性突变的影响。与人类模型的比较使我们能够验证在定义病理学的野生型和遗传修饰小鼠中甲状腺激素代谢的哪些分子标志物适合转移到人类条件。此外，我们将描述与野生型情况相比，经典甲状腺素单一疗法在不同靶组织中发生的分子变化。与血浆蛋白质组和代谢组分析的比较将有助于进一步表征这些标记物，并确定其用于替代治疗微调的潜力。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，并将标志物变化与潜在的病理学联系起来。

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.