TRR 296:  Local control of TH action (LocoTact)

• Subject Area: Medicine
• Term: since 2020
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 424957847

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. Furthermore, there is accumulating evidence that modulation of TH action in specific tissues can be highly beneficial in pathologies such as fatty liver disease, myocardial infarction and stroke. Taken together, these findings have challenged the importance of systemic thyroid status and have shifted the focus onto regulation of TH action at the organ or cell level. With our CRC/TR “Local control of TH action” that started in July 2020, we 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 genetic and prevalent acquired disorders, a human iPSC/organoid platform, as well as well-characterized patient cohorts, we aim to carefully dissect mechanisms of local control of TH action in physiology and pathophysiology in brain, cardiovascular system/heart and liver. Furthermore, we strive to exploit therapeutic TH benefits, by employing pharmacological tools such as hormone conjugates, analogues and targeted viral gene delivery, to develop cell- and tissue-specific translational strategies. With many exciting novel discoveries in the first funding period, our consortium will now proceed towards a higher spatiotemporal resolution of local TH action in organ function and for developmental aspects relevant to ultimately target and improve outcome in patients with common and rare diseases.

• DFG Programme: CRC/Transregios

Current projects

• P01 - TH transporters at brain barriers (Project Heads Heuer, Heike ;  Schwaninger, Markus )
• P02 - Impact of TH on tanycyte functions and the relevance on central regulation of the liver and hormone uptake (Project Head Müller-Fielitz, Helge )
• P04 - Thyroid hormone action in hiPSC-derived cerebral organoids (Project Heads Kühnen, Peter ;  Opitz, Robert )
• P05 - Novel pharmacotherapies for the treatment of central hypothyroidism associated with Mct8/Oatp1c1 deficiency (Project Heads Müller, Timo ;  Pfluger, Paul )
• P07 - A brain imaging approach to TH function in consequence to mutations in genes encoding the TH receptors (Project Heads Cirkel, Anna ;  Münte, Thomas F. ;  Prasuhn, Jannik )
• P08 - Local TH transport and action in ischaemic brain injury (Project Heads Führer-Sakel, Dagmar ;  Kleinschnitz, Christoph ;  Langhauser, Friederike )
• P09 - TH transporters in myelin formation and regeneration (Project Heads Engel, Daniel Robert ;  Heuer, Heike )
• P10 - Local TH action in acute and chronic ischaemic heart disease (Project Heads Führer-Sakel, Dagmar ;  Lorenz, Kristina ;  Möller, Lars )
• P11 - Role of the enigmatic TR2 isoform in regulating cardiac TH function (Project Heads Kaiser, Frank ;  Köster, Johannes )
• P12 - TH receptor α1 at the crossroad of autonomic and cardiac functions in mice (Project Head Mittag, Jens )
• P13 - TH receptor-clock interaction in NAFLD development (Project Head Oster, Henrik )
• P14 - Control of cellular TH metabolism in human and mouse NASH (Project Heads Kirchner, Henriette ;  Mittag, Jens ;  Spielmann, Malte )
• P15 - Impact of liver-specific TH activity on modulation of NAFLD and NASH (Project Heads Mai, Knut ;  Püngel, Tobias ;  Spranger, Joachim ;  Tacke, Ph.D., Frank ;  Wirth, Eva K. )
• P17 - Control of deiodinase type 1 (DIO1) expression and its protective function in human hepatocytes (Project Head Schomburg, Lutz )
• P18 - Hepatic TH signalling in acute and chronic liver injury (Project Heads Lange, Christian ;  Möller, Lars ;  Zwanziger, Denise )
• P19 - Role of local TH action in epilepsy (Project Head Mayerl, Steffen )
• Z01 - Establishment and provision of human pluripotent stem cell (hiPSC)-derived 2D and 3D cellular models of brain, liver and heart and technologies for their analysis (Project Heads Obermayer-Wasserscheid, Benedikt ;  Stachelscheid, Harald )
• Z02 - Integrated Research Training Group (iRTG) (Project Heads Heuer, Heike ;  Kühnen, Peter ;  Müller-Fielitz, Helge ;  Opitz, Robert )
• Z03 - Visual data analysis platform for predesigned workflows - Research data management (INF) (Project Heads Engel, Daniel Robert ;  Führer-Sakel, Dagmar ;  Köster, Johannes ;  Mittag, Jens ;  Opitz, Robert ;  Rehwald, Stephanie )
• Z04 - Central administration of the collaborative research centre (ADM) (Project Head Führer-Sakel, Dagmar )

Completed projects

• P03 - Transporter expression and TH action in the brain (Project Heads Bechmann, Ingo ;  Biebermann, Heike )
• P06 - THRA deficiency and Allan-Herndon-Dudley-Syndrome: Defects of local TH function during human brain development (Project Heads Krude, Heiko ;  Schülke-Gerstenfeld, Markus )
• P16 - Strategies to increase local T3 availability in liver (Project Heads Köhrle, Josef ;  Wirth, Eva K. )

• Applicant Institution: Universität Duisburg-Essen
• Co-Applicant Institution: Charité - Universitätsmedizin Berlin; Universität zu Lübeck
• Participating University: Ludwig-Maximilians-Universität München
• Participating Institution: Helmholtz Zentrum München; Deutsches Forschungszentrum für Gesundheit und Umwelt; Leibniz-Institut für Analytische Wissenschaften -ISAS- e.V.
• Spokesperson: Professorin Dr. Dagmar Führer-Sakel