Evaluation of structure-function relationships between glycoprotein hormones (thyrotropin), autoantibodies, oncogenes, alpha 1-adrenergic agents, insulin, insulin-like growth factors (I and II), bacterial toxins (cholera and pertussis, for example), interferon, and interleukins - alone and in combination. Studies of the mechanisms, both transcriptional and posttranscriptional, by which they interact with and transmit their message through the cell membrane to affect cell function and pathology. Studies using monoclonal antibodies and the idiotype antiidiotype theory explore the structure of the receptors for these ligands and the importance of these relationships to the expression of thyroid hyperfunction in Graves' disease; to organ specific autoimmunity (Graves' disease, Hashimoto's disease, Lupus, diabetes); to fluid losses in intestinal diarrheic states; to thyroid storm and the sympathetic overactivity syndrome of tetanus; to the ability of hormones to modulate the oncogenic state; and to the mechanism by which toxins subvert normal mechanisms to impose their pathological effects. Studies continue to evaluate the role of different signal transduction mechanisms - cAMP, Ca/phosphoinositide and arachidonate - for growth and differentiation for example, thyroglobulin biosynthesis, lipid/cholesterol biosynthesis, thyroglobulin biodegradation to T3 and T4, and the transport of T3, T4, monoiodotyrosine, diiodotyrosine, or other amino acids from the lysosome. The role of phosphate and carbohydrate moieties in thyroglobulin structure and post-translational processing is being studied. Studies explore lipid regulation of receptor expression, with special emphasis on thyroid cell growth and development, lipid metabolism, LDL receptor expression, and cholesterol biosynthesis. Studies to clone the TSH receptor and other autoantigens important to developing or expressing autoimmune Graves' and exophthalmos, as well as to define their structure and regulatory control at a gene level, are in progress as are studies to define the mechanisms by which TSH, insulin, IGF-I and other ligands regulate gene expression.
