U.S. Department of Health and Human Services
Susanne Neumann
 

 Contact Info

 
Tel: 301-451-6307
Email: susannen@intra.niddk.nih.gov
 

 Select Experience

 
  • Staff ScientistLaboratory of Endocrinology and Receptor Biology, NIDDK, NIH2006–Present
  • Postdoctoral FellowClinical Endocrinology Branch, NIDDK, NIH2002–2006
  • Postdoctoral FellowUniversity of Leipzig, III. Medical Department/Endocrinology and Diabetes Branch2000–2001
  • Ph.D.University of Leipzig, III. Medical Department/Endocrinology and Diabetes Branch2000
 

 Related Links

 
Specialties
  • Cell Biology/Cell Signaling
  • Molecular Biology/Biochemistry
  • Molecular Pharmacology/Toxicology
Research Summary/In Plain Language

Research Summary

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 GD, an autoimmune disease, and GO. 

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 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. Another possible clinical application of an antagonist beyond treatment of the hyperthyroidism of GD could be to alleviate the symptoms of Graves’ ophthalmopathy (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. We are working on the further development of antagonist lead compounds to be able to conduct studies in animal models, 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.