This laboratory is studying the structure-function relationships of the thyrotropin (TSH) receptor, the involvement of this receptor in autoimmune thyroid disease, as well as the relationship between thyroid autoimmune diseases and other organ-specific autoimmune diseases, i.e. Lupus or diabetes. We compare structure/function of the TSH receptor to other glycoprotein hormone receptors and evaluate the interdependent regulation of thyroid function and growth by the TSH receptor and receptors for other ligands: gonadotropins, adrenergic, cholinergic, insulin, insulin-like growth factors (I and II), fibroblast growth factors, hydrocortisone, thyroid hormones, purinergic, bacterial toxins (cholera, pertussis, tetanus), interferon, and cytokines. Particular attention is given to identifying determinants on the receptors important for TSH and receptor autoantibody binding and signal transduction, as well as the transcriptional and post-transcriptional mechanisms by which TSH and the other receptors affect gene expression in thyroid cells. The relationship between oncogene transformation (thyroid tumors and adenomas), the development of autoimmunity, and the loss of normal regulation of thyroid function and growth is investigated. The role of different signal transduction mechanisms - CAMP, Ca/phosphoinositide and arachidonate - in thyroid cell growth and differentiated function is studied. We evaluate the role of membrane lipids in regulation of TSH receptor expression, LDL receptor expression, and cholesterol biosynthesis. We study the role of major histocompatibility antigens in the development of autoimmune thyroid diseases and organ specific immune diseases. Under development are human thyroid and islet cells which can grow in continuous culture, act as models of endocrine and thyroid disorders, and serve as donor cells for transplantation or gene therapy situations. These studies combine a molecular biology, cell biology and monoclonal antibody approach.
