Unraveling the molecular basis for successful thyroid hormone replacement therapy

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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.