Generation and characterization of murine models to study the molecular mechanisms of G protein signaling in the thyroid and their role in thyroid diseases

• Applicant: Dr. Holger Jäschke
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2015 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 275486634

Constitutively activating mutations of the thyroid stimulating hormone receptor (TSHR) lead to nonautoimmune hyperthyroidism (NAH) in humans through a permanent activation of the G protein Gs resulting in an uncontrolled release of thyroid hormones. In rare cases some TSHR variants also activate Gq/11. The detailed functional outcome of this G protein activation in the course of NAH remains unclear. Constitutively activating mutations of the TSHR are the major molecular cause for nonautoimmune hyperthyroidism and were detected in patients with toxic thyroid nodules (TTNs), in sporadic nonautoimmune hyperthyroidism (SCNAH) and familiar nonautoimmune hyperthyroidism (FNAH) Functional identification of TSHR mutations as the molecular cause for this disease is exclusively carried out by in vitro experiments in heterologous cell systems, which hampers the physiological and molecular genetic investigation of NAH under in vivo conditions. Studying an activating TSHR mutation in vivo would show the impact for the development and manifestation of NAH and would allow a comparison to findings obtained by in vitro approaches. Therefore, we generated a mouse model with activating TSHR mutation D633H, which activates both signaling cascades (Gs and Gq/11) independently from the natural ligand thyrotropin. This model will enable the investigation of the contribution of different signaling pathways in thyroid function, the determination of changes in genetic expression profiles, the impact of different G proteins in cancerogenesis, the impact of iodine supply and the investigation of extra-thyroidal TSHR expression. Further, it represents an in vivo model to investigate the potential of newly identified small molecular ligands for the TSHR with inverse agonistic properties over currently used anti-thyroid drugs for the treatment of NAH.

• DFG Programme: Research Fellowships
• International Connection: Finland
• Host: Professor Matti Poutanen, Ph.D.