This lab has defined structure-function relationships of the thyrotropin receptor (TSHR) and transcriptional regulation of the TSHR with respect to their influence on thyroid growth vs differentiation, signal transduction, gonadotropin receptor regulation of growth vs differentiation, and the action of autoantibodies causing autoimmune thyroid disease. Epitopes for thyroid stimulating and blocking autoantibodies have been defined and related to the immunodominant peptide of the receptor. Cytoplasmic loop links to G-protein interactions and signal transduction mechanisms have been characterized. A minimal TSHR promoter having key properties of the native promoter, i.e. thyroid-specific expression, cAMP autoregulation, and insulin- dependent expression, has been defined and specific elements characterized. Unusual single-strand binding sites and their trans factors have been uncovered and linked to coregulation of TSHR and major histocompatibility (MHC) gene expression, class I and class II. The ability of mutant receptors and TSH crosstalk with gonadotropin receptors to cause gonadal hyperfunction has been described in vitro and in vivo. Sites on the 5'-flanking region of the MHC class I gene, which control its expression by hormones and methimazole (MMI) as well as the influence of interferon on them, have been uncovered and related to the development of thyroid as well as other organ-specific autoimmune diseases, including systemic lupus erythematosus and diabetes. Relationships between transcription factors regulating TSHR and MHC class I promoters have been uncovered and have been shown to be potentially useful to define MMI- derivatives better able to prevent autoimmune disease sequelae and develop donor cells for transplantation or gene therapy.
