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Susanne Neumann, Ph.D.

Photo of Susanne Neumann
Scientific Focus Areas: Cell Biology, Molecular Biology and Biochemistry, Molecular Pharmacology

Professional Experience

  • Staff Scientist, Laboratory of Endocrinology and Receptor Biology, NIDDK, NIH, 2006–Present
  • Postdoctoral Fellow, Clinical Endocrinology Branch, NIDDK, NIH, 2002–2006
  • Postdoctoral Fellow, University of Leipzig, III. Medical Department/Endocrinology and Diabetes Branch, 2000–2001
  • Ph.D., University of Leipzig, III. Medical Department/Endocrinology and Diabetes Branch, 2000

Research Goal

We work on the development of an orally available thyrotropin receptor (TSHR) agonist for the diagnosis and treatment of thyroid cancer. Furthermore, we focus on the development of TSHR antagonists that might have potential for the treatment of Grave's disease, an autoimmune disease, and associated Grave's orbitopathy.

Current Research

TSH activates TSH receptors (TSHR), thereby stimulating the function of thyroid follicular cells (thyrocytes). This leads to the biosynthesis and secretion of thyroid hormones. Several thyroid pathologies are associated with TSHR, providing a strong argument for the design of small molecule ligands (SML). Our focus is the development of SMLs that agonize or antagonize the TSHR.

rhTSH (Thyrogen®, Genzyme) has been used in the follow-up of patients with thyroid cancer to increase the sensitivity for detection of recurrent or metastatic disease. rhTSH, which is a heterodimeric 30 kilodalton glycoprotein, is difficult to produce and must be administered by injection. A small molecule TSHR agonist could produce the same beneficial effects as rhTSH but with greater ease of production and of oral administration. We developed a SML that is a full agonist at TSHR and has clinical potential. We are working on the further development of this agonist and its test in preclinical studies. Moreover, we use this agonist as a probe of the molecular mechanism of TSHR activation and to study TSHR function in cells in culture and in animal models.

Graves’ disease (GD) is caused by persistent, unregulated stimulation of thyroid cells by thyroid-stimulating antibodies (TSAbs) that activate the TSHR. A small molecule antagonist that directly targets the TSHR could have therapeutic potential for GD patients. We identified the first small molecule TSHR antagonists and demonstrated their effects in primary cultures of human thyrocytes and in an animal model. Another possible clinical application of an antagonist beyond treatment of the hyperthyroidism of GD could be to alleviate the symptoms of Graves’ orbitopathy (GO). Therefore, we extended our studies to primary cultures of human Graves’ orbital fibroblasts. Our recent findings suggest that drug-like TSHR antagonists may have a role in treatment of GO, and might allow to treat patients with GD and GO with the same drugWe are working on the further development of our TSHR antagonist lead compound to be able to conduct studies in animal models of GO with the goal of subsequent preclinical tests.

Applying our Research

Patients with thyroid cancer could benefit from the development of a drug-like small molecule TSHR agonist. An orally available small molecule TSHR agonist will be available to a much larger patient population worldwide than human recombinant TSH that needs to be injected. Patients with GD and GO could benefit from the development of a small molecule TSHR antagonist.

Need for Further Study

Our results provide proof-of-principle for effectiveness of small molecule agonists and antagonists for TSHR. Chemical optimization of these small molecule ligands needs to be performed in an effort to produce more potent molecules for testing in animal models and for future clinical development.

Furthermore, these molecules can now be used as probes to study TSHR physiology and pathophysiology in cell culture and in animal models.

Select Publications

Evidence That Graves' Ophthalmopathy Immunoglobulins Do Not Directly Activate IGF-1 Receptors.
Marcus-Samuels B, Krieger CC, Boutin A, Kahaly GJ, Neumann S, Gershengorn MC.
Thyroid (2018 May) 28:650-655. Abstract/Full Text
Discovery of a Positive Allosteric Modulator of the Thyrotropin Receptor: Potentiation of Thyrotropin-Mediated Preosteoblast Differentiation In Vitro.
Neumann S, Eliseeva E, Boutin A, Barnaeva E, Ferrer M, Southall N, Kim D, Hu X, Morgan SJ, Marugan JJ, Gershengorn MC.
J Pharmacol Exp Ther (2018 Jan) 364:38-45. Abstract/Full Text
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Research in Plain Language

The thyroid is a butterfly-shaped gland in the neck. The TSH receptor (TSHR) is expressed in the thyroid and stimulated by the hormone TSH. The TSHR stimulates the function of thyroid follicular cells, the thyrocytes. This leads to biosynthesis (the production of chemical compounds) and the secretion of thyroid hormones.

Several thyroid pathogens (infectious agents that cause disease) are associated with TSHR. This provides a strong argument for the design of drug-like organic small molecule ligands (SMLs) that will influence TSHR action. Our focus is the development of SMLs that agonize (stimulate) or antagonize (inhibit) TSHR action.

A TSHR agonist will be useful for patients with thyroid cancer. Iodide uptake by thyroid cells is the first step in thyroid hormone synthesis and is very important for the sensitivity of the diagnosis of thyroid cancer. A TSHR agonist stimulates uptake of iodide by thyroid cancer cells and, therefore, can help to diagnose residual cancer tissue.

On the other hand, there are patients with an autoimmune disease, Graves’ disease (GD). Antibodies in the serum of these patients permanently stimulate the TSHR, leading to an unregulated stimulation of thyroid cells. A small molecule antagonist that inhibits the continuous stimulation of the TSHR by antibodies could be useful in the therapy of GD and Graves’ ophthalmopathy (GO), a disease associated with GD in the eye.

We have provided proof-of-principle for the effectiveness of small molecule agonists and antagonists for TSHR and are now focusing on the further development of these molecules. We are preparing them for testing in animal models and for future clinical development.

Related Links

Marvin C. Gershengorn Laboratory of Endocrinology and Receptor Biology

Research Images