Hyperthyroid Graves'disease (GD) and Graves'Orbitopathy are associated with the development of autoantibodies to the TSH receptor (TSHR-Ab) which act as TSH agonists and activate TSHR signal transduction. The purpose of this application is: 1: To develop our lead small molecule agonists to the TSHR. To do this we will use a chemical modification strategy and examine the signaling pathways of the higher affinity analogs both in vitro (thyroid cells) and in vivo (mice). 2. We will use both a virtual and computational screening strategy and a high throughput assay to identify and characterize additional small molecules stimulating or blocking the TSHR 3. We will continue our studies of neutral TSHR monoclonal antibodies as TSHR modulators by using them in vivo in mice to characterize their influence on thyroid function and thyroid cell apoptosis.. 4. We will characterize human neutral antibodies to the TSHR in patients with Graves'disease and their role in the induction of thyroid cell apoptosis in vitro with a view to their potential as regulators of thyroid function in this disorder. The insight gained from these studies will have tremendous potential in furthering our understanding of the role of the TSHR in Graves'disease and of developing useful receptor regulators with therapeutic potential.

Public Health Relevance

Graves'disease is a leading cause of hyperthyroidism in the US and worldwide. Anti-thyroid drugs have many side effects and new therapeutics are needed. This work is designed to address these clinical deficiencies.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK069713-09
Application #
8709839
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Spain, Lisa M
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
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Baliram, R; Latif, R; Morshed, S A et al. (2016) T3 Regulates a Human Macrophage-Derived TSH-β Splice Variant: Implications for Human Bone Biology. Endocrinology 157:3658-67
Latif, Rauf; Ali, M Rejwan; Mezei, Mihaly et al. (2015) Transmembrane domains of attraction on the TSH receptor. Endocrinology 156:488-98
Ma, Risheng; Latif, Rauf; Davies, Terry F (2015) Human embryonic stem cells form functional thyroid follicles. Thyroid 25:455-61
Mezei, Mihaly (2015) Use of circular variance to quantify the deviation of a macromolecule from the spherical shape. J Math Chem 53:2184-2190
Ali, M Rejwan; Latif, Rauf; Davies, Terry F et al. (2015) Monte Carlo loop refinement and virtual screening of the thyroid-stimulating hormone receptor transmembrane domain. J Biomol Struct Dyn 33:1140-52
Davies, Terry F; Latif, Rauf (2015) Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies. Expert Opin Ther Targets 19:835-47
Morshed, S A; Davies, T F (2015) Graves' Disease Mechanisms: The Role of Stimulating, Blocking, and Cleavage Region TSH Receptor Antibodies. Horm Metab Res 47:727-34
Latif, Rauf; Ali, M Rejwan; Ma, Risheng et al. (2015) New small molecule agonists to the thyrotropin receptor. Thyroid 25:51-62
Yin, Xiaoming; Sachidanandam, Ravi; Morshed, Syed et al. (2014) mRNA-Seq reveals novel molecular mechanisms and a robust fingerprint in Graves' disease. J Clin Endocrinol Metab 99:E2076-83

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