Local control of thyroid hormone action

Circulating concentrations of thyroid hormones (TH) and thyroid stimulating hormone (TSH) are routinely used for diagnosis of thyroid disorders in patients. However, the recent  discoveries of patients with mutations in TH transporters or TH receptors have demonstrated that circulating hormone levels can be insufficient to correctly assess thyroid state in the body. More importantly, further studies have shown that tissues or cells can be in a hyper- or  hypothyroid state discordant to serum TH concentrations due to several cellular layers  controlling TH action in tissues. These include i) TH transport across the cell membrane regulating hormone import and export, ii) intracellular TH metabolism through different deiodinases and iii) canonical signaling via nuclear receptors (TRs), and noncanonical signaling via cytosolic TRs. Taken together, these findings have challenged the importance of systemic TH and have shifted the focus to regulation of TH action at the organ or cell level. It is, however, still poorly understood, how these local control mechanisms are organized under physiological and pathophysiological conditions. Moreover, there is accumulating evidence, that a restoration or modulation of TH action in a specific tissue can be highly beneficial in certain pathologies such as non-alcoholic steatohepatitis, myocardial infarction,
or stroke. With our proposed CRC/TR “Local control of TH action” (LocoTact) we will address these current challenges in the field of TH research. Using a worldwide unique and comprehensive
collection of mouse models for all key components of local TH action, defined disease models for prevalent disorders, a human organoid platform, as well as relevant and wellcharacterized
patient cohorts we aim to carefully dissect the local control of TH action in physiology and pathophysiology. We will focus on brain, heart and liver as the most prominent targets of TH and will characterize the role of altered local TH action for disease progression at the organ and cell level. Furthermore, we will evaluate possible therapeutic TH benefits, employing pharmacological tools such as hormone conjugates, genetic model systems and targeted viral gene delivery. As a truly interdisciplinary research consortium comprising basic and clinical researchers from endocrinology, neurobiology, neurology, cardiology, cardiogenetics, hepatology, pharmacology, stem cell biology and biochemistry, LocoTact is well equipped to meet the challenge of defining local control of TH action and to develop translational strategies tailored to cells and tissues with the perspective to capitalize on the power of the hormone to treat rare or prevalent diseases.

Antragstellerin

Universitätsklinikum Essen: Prof. Dr. Dagmar Füher-Sakel
Klinik für Endokrinologie, Diabetologie und Stoffwechsel

Förderlinie: Strategiefonds
Fördermittel: 42.765,00 Euro
Laufzeit: 01.09.2019 – 30.03.2020

Ansprechpartnerin

Prof. Dr. Dagmar Führer
Universitätsklinikum Essen
Klinik für Endokrinologie, Diabetologie, Stoffwechsel
Hufelandstr. 55
45127 Essen

E-Mail: sekretariat.endokrinologie@uk-essen.de