Mount Sinai Center for Translational Medicine and Pharmacology

The research program is undertaking several studies to learn more about the TSH receptor, how it works, and how to help patients with thyroid disorders. These include:

TSH Signaling and Small Molecules

The TSHR is key to regulating thyroid growth and function; when it doesn’t work properly, it can lead to an overactive thyroid (Graves’ disease). When the receptor becomes activated, it leads to thyroid hormone synthesis and secretion, cell proliferation, and cell survival. This research program has identified agonists and antagonists, molecules that encourage or prevent TSHR activation. These findings may lead to new treatments for thyroid disease.

Antibodies to the TSH Receptor

The research program has studied TSH receptor neutral antibodies, which have no effect on TSH action, but can influence cells in the thyroid gland that produce and secrete hormones (called thryocytes). Current efforts look at such TSHR-autoantibodies to identify their biological functions and signal transduction pathways. Gaining this information will enable development of new therapeutic strategies.

Using Embryonic Stem Cell Model Systems to Study Thyroid Differentiation

The program is studying how embryonic stem cells in mice can be induced to change in vitro to form three-dimensional structures called embryoid bodies. Using this insight, the program is developing patient-specific induced pluripotent stem cells to explore options for cell replacement therapy for patients with underactive or absent thyroids following surgery. We are also using these cells to explore the molecular and epigenetic regulation of thyroid development.

Relationship Between TSH and Bone Modeling

Using mice that do not have TSH receptors, the program has been working with members of the Mount Sinai Bone Program to explore the role of TSH outside the thyroid. We have shown that TSH regulators can “turn on” (express) cells responsible for resorbing aging bone (osteoclasts) and those that form new bone (osteoblasts). In addition, the program is studying the role of a novel TSH splice-variant that has been discovered in the macrophage to understand a role for TSH in immune and bone cell interactions. This understanding should ultimately lead to novel approaches to dietary and medical treatments for thyroid and bone conditions.

Research Publications

The Thyroid Research Program has made a number of important contributions to the research literature. Recent contributions include:

• Developing the first complete in silico model of the TSH receptor.
• Suggesting, through structural modeling, that there is a water channel located inside of TSHRs. The program is exploring whether that could play a role in activating the TSHR, especially at the blood-brain barrier.
• Investigating a TSHR stimulating antibody; rather than shut something down, as most antibodies do, this antibody encourages thyroid overactivity, which can produce an inflammatory response in the eyes. The program is researching ways to keep the IGF-1R from interacting with the TSHR, as a way to treat this eye condition.