Graves' hyperthyroidism is caused by autoantibodies which stimulate the thyroid by binding to and activating the thyroid stimulating hormone receptor (TSH-R). This phenomenon has been difficult to study due to the extreme scarcity of the receptor protein. Recently, Dr. Cone's laboratory has isolated a full length cDNA encoding a functional human TSH receptor. With this new reagent, he plans to determine the molecular mechanism by which TSH and Graves' autoantibodies bind to and activate the TSH receptor. A rare class of autoantibodies, which act as competitive antagonists of TSH, will also be studied. Normally a negative feedback of thyroid function results from thyroid hormone repression of TSH secretion and TSH beta chain gene expression. In Graves' disease TSH, levels are depressed; however, the levels of stimulatory autoantibodies remain constant resulting in continuous overstimulation of thyroid activity. While most receptors are downregulated by exposure to antagonists, this does not appear to be the case in Graves' disease. In addition to determining the structural mechanisms by which Graves' autoantibodies activate the TSH-R, the investigator would like also to understand the biological mechanism by which the autoantibodies persistently stimulate thyroid activity without apparent desensitization. Towards this end, he will examine the regulation of receptor mRNA and protein by TSH, Graves' autoantibodies, cAMP and thyroid hormone. The internationalization and recycling of the TSH-R protein at the plasma membrane will also be examined. Additional autoimmune phenomena occur in a small percentage of Graves' patients, resulting in an ophthalmopathy or dermopathy. Both of these conditions are characterized by lymphocytic infiltration and metabolic stimulation of resident fibroblasts or adipocytes. The TSH-R is expressed in some adipocytes, and this has led numerous investigators to propose that an autoimmune reaction against the TSH-R, expressed in retro-orbital muscle or the skin, leads to Graves' ophthalmopathy or dermopathy. To address these problems, the investigator proposes the following Specific Aims: 1) to develop a detailed structure/function model for binding and activation of the receptor by TSH and Graves' autoantibodies; 2) to study the expression and regulation of the receptor, and its role in stimulating thyroid growth and metabolism in normal thyroid, Graves' disease, and other abnormal thyroid growth states; and 3) to characterize the extrathyroidal sites of TSH receptor expression and test the hypothesis that extrathyroidal TSH receptor expression, or expression of antigenically related molecules, plays an etiological role in Graves' ophthalmopathy and dermopathy.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Endocrinology Study Section (END)
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Oregon Health and Science University
Other Domestic Higher Education
United States
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