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 interleukins. 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 posttranscriptional mechanisms by which TSH and the other receptors affect thyroid gene expression. The relationship between oncogene transformation, the development of autoimmunity, and the loss of normal regulation of thyroid function and growth is applied to understanding why thyroid tumors and adenomas develop. We relate the role of different signal transduction mechanisms - cAMP, Ca/phosphoinositide and arachidonate - to thyroid cell growth and differentiation, including thyroid hormone formation. 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. These studies combine a molecular biology, cell biology and monoclonal antibody approach. A long-term continuing project involves the development of thyroid cells which can grow in continuous culture in vitro and act as models of endocrine and thyroid disorders.
