This laboratory is studying the structure-function relationships of (a) the thyrotropin (TSH) receptor, (b) receptors for other glycoprotein hormones and (c) receptors on the thyroid which also regulate thyroid function and growth and function, i.e. receptors for alpha 1-adrenergic agents, cholinergic agents, and insulin or insulin-like growth factors.
The aim i s to identify (a) receptor determinants important for ligand interactions, receptor cross-talk, and signal transduction, (b) transcriptional and posttranscriptional mechanisms by which TSH and these other ligands affect gene expression and cell function, and (c) receptor determinants important for the expression and development of thyroid autoimmune disease, its complications, i.e. exophthalmos or pretibial myxedema, organ-specific autoimmunity (Lupus, diabetes), and thyroid tumors. This year, the rat and human TSH receptors have been cloned. Epitopes on the receptor recognized by autoantibodies in immune thyroid disease have been distinguished; regulation of receptor gene expression has been defined; and the role of the signal peptide in processing but not TSH binding, resolved. A heat shock 70 protein as well as gamma-actin have been recognized to be related to TSH receptor structure- function; and a new Graves' nuclear autoantigen has been characterized which binds TSH and DNA, whose MRNA and antigenic expression correlates with thyroid cell growth, goiter, as well as oncogene tumorigenicity in the thyroid, and which is identical to the Ku autoantigen of lupus. Related studies have resolved the role of different signal transduction mechanisms in thyroid cell growth; the transport thyroid hormones from the lysosome; and the role of membrane lipids in regulation of TSH receptor expression, LDL receptor expression, and cholesterol biosynthesis. For example, the induction of the cyclooxygenase and prostaglandin pathway has been shown to require TSH, insulin/IFG-I and serum and correlated with the time course and hormonal requirements of thyroid cell growth. PGE(2) is both a critical signal for DNA synthesis, a negative feedback regulator of cAMP mediated thyroid function, and an altered modulator in """"""""aging"""""""" cells.
