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 signalling via nuclear receptors (TRs), and noncanonical signalling 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 CRC/TR “Local control of TH action” (LocoTact) we will address these current challenges in the field of TH research. Using a globally unique and comprehensive collection of mouse models for all key components of local TH action, defined disease models for rare and prevalent disorders, a human organoid platform, as well as relevant and well-characterised 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 characterise 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, translational and clinical researchers from endocrinology, biochemistry, neurobiology, neurology, stroke and cardiovascular medicine, hepatology, genetics, pharmacology, immunology, stem cell biology and biotechnology 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 capitalise on the power of the hormone to treat rare or prevalent diseases.
- LOCOTACT Lectures – Alexandra Dumitrescu 09 September 2023
- ETA Project Research Grant for LOCOTACT PostDoc Leonardo de Assis 08 August 2023
- 1st International LOCOTACT Conference 2023 06 June 2023
- LOCOTACT at 66th annual meeting of the Germany Society for Endocrinology (DGE) 06 June 2023
- Cardiac defect in rare genetic disease unraveled - new LOCOTACT publication 06 June 2023