To provide insight into the normal pathway of androgen action during embryonic and postembryonic life and into the various ways that impairment of androgen action can result in disease states, a variety of experiments are planned. Anti-idiotypic antibodies to the androgen receptor will be made for the purpose of characterizing more precisely mutations that impair the androgen receptor, and studies of the individual steps in androgen action will be made in normal and mutant fibroblast strains, including investigation of the transformation of the dihydrotestosterone-androgen receptor complex (DHR-R) to the DNA-binding state, the interaction of DHT-R with the nuclear matrix, and the post receptor events in androgen action. Phenotypic differentiation of the male urogenital tract will be studied with the specific goal of determining whether the wolffian ducts virilize directly as a result of androgen action or indirectly as the result of some effect of the hormone on the testis itself. The molecular biology of 5Alpha-reductase deficiency will be investigated by attempting to develop a potent antibody to the 5Alpha-reductase enzyme, by investigating the effect of 5Alpha-reductase inhibition on the development of the male urogenital tract, and by studying how androgens act to promote spermatogenesis. Embryonic differentiation of the gonads as endocrine organs will be studied in organ culture preparations of rat and opossum gonads and in mice carrying either a single X chromosome or the sex reversal mutation. The genetic control of the aromatase reaction in peripheral tissue will be studied utilizing the henny feathering mutation in chickens as a model system for investigating normal ovarian development and extraglandular estrogen formation. Finally, we will explore androgen action at the post-receptor level, studying the nature of thyroxine and DHT interaction in the mouse submandibular gland, the unique resistance to androgen action in kidneys of certain wild-derived mouse strains, and the regulation of androgen-dependent genes in mouse L cells.
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