The general goal of this project is to understand the structure, function and physiology of the human glycoprotein hormones, thyroid-stimulating hormone (TSH), choriogonadotropin (hCG), luteinizing hormone (LH), and follicle-stimulating hormone (FHS), and thereby to develop diagnostic and therapeutic clinical applications. Recent research advances in the current period include the following: First, several betaFSH domains involved in FSH action were identified by using a novel technique for assessing the signal transducing activity of FSH mutants produced by site- directed mutagenesis. The data show that both of the betaFSH glycosylation sites have a role in FSH signal transduction; at the first site oligosaccharide is the critical moiety for efficient signalling, while at the second site the amino acid sequence is crucial for hormone activity, independent of the oligosaccharide. Second, the ability of human TSH to interact with and activate the human FSH receptor was established. This provides a novel pathophysiologic mechanism for the syndrome of precocious puberty and juvenile hypothyroidism. Third, for the first time direct demonstration of the ability of hCG to stimulate thyroid hormone secretion from human thyrocytes has been accomplished, thereby resolving a longstanding controversy. Fourth, the ability of GnRH antagonist to ameliorate murine lupus was shown, setting on the horizon a possible role for this agent in the treatment of human autoimmune diseases with this type of agent. Fifth, the presence of IGF-I and IGF-II receptors on GnRH-producing neurons has been demonstrated, suggesting a possible role of growth factors in the regulation of gonadotropin secretion. Future directions of the project will emphasize study of the structure-function characteristics of human FSH and the human FSH receptor through site-directed mutagenesis of their respective genes, and investigation of the signal transduction mechanisms in human thyrocytes in vitro with analogs of hCG.
