CRC/TRR 296 LocoTact: Local control of TH action

Circulating concentrations of thyroid hormones (TH) and thyroid stimulating hormone (TSH) are routinely used for diagnosis of thyroid disorders. Recent discoveries of patients with TH transporter or receptor mutations have demonstrated that using circulating hormone levels for assessing thyroid state is fallible, due to several cellular layers controlling TH action. There is accumulating evidence that modulation of TH action in specific tissues can be highly beneficial in pathologies such as non-alcoholic steatohepatitis, myocardial infarction and stroke.
Taken together, these findings have challenged the importance of systemic TH and have shifted the focus onto regulation of TH action at the organ or cell level. With our proposed CRC/TR “Local control of TH action” we will address these challenges in an interdisciplinary manner. Using a globally unique 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 well-characterised patient cohorts, we aim to carefully dissect mechanisms of local control of TH action in physiology and pathophysiology in the most prominent targets, brain, heart and liver. Furthermore, we will evaluate possible therapeutic TH benefits, employing pharmacological tools such as hormone conjugates, genetic model systems and targeted viral gene delivery, aiming to develop cell- and tissue-specific translational strategies.