This lab has further defined structure-function relationships of the thyrotropin receptor (TSHR) with respect to the following: TSH binding; signal transduction; cell cycle-coordinated, transcriptional regulation of thyroid growth and differentiation; relationships to gonadotropin receptor structure, function, and gonadal hyperfunction in precocious puberty; the action of autoantibodies causing autoimmune thyroid disease; the basis for the development of TSHR autoantibodies; and the link of thyroid autoimmunity to other autoimmune diseases. Epitopes for thyroid stimulating, thyroid blocking, and TSH binding inhibiting autoantibodies have been defined and related to the immunodominant peptide of the receptor. Factors and elements on the minimal TSHR promoter which are important for regulation of growth and function have been identified, characterized, and cloned, including unusual single-strand binding trans factors. These factors have been shown to coregulate TSHR and major histocompatibility (MHC) gene expression, class I and class II, as a function of the cell cycle. Autoimmune thyroid disease is postulated to result from loss of the coordinated negative regulation of TSHR, MHC class I, and MHC class II; too much negative regulation is linked to tumor development. A drug, methimizole (MMI), useful for Graves' disease, has been shown to be effective in experimental lupus and blepharitis; its sites of action on MHC class I and class II defined; and methods to develop better immunosuppressive drugs in this class, therefore, established. A new assay system using TSHR chimeric receptors has been developed which appears to prospectively identify Graves' patients sensitive to remission by MMI therapy alone.
