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

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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.