Our broad objectives are: 1) to investigate the molecular basis of thyroid hormone action with the specific purpose of gaining a better understanding of the role of this hormone in health and disease and, 2) to explore the potential therapeutic usefulness of thyroid hormone analogs inthe treatment of hyperlipidemia and perhaps other nonthroidal diseases. We plan further to purify and characterize the T3 nuclear receptor, to elucidate the structural and functional relationship of the receptor to chromatin, and to clarify the role of the recently described T3 receptor-containing fragment. We shall attempt to define, insofar as possible, the domain of thyroid hormone in the biochemical actions of individual tissues. In particular, we shall examine the effect of thyroid hormone on early covalent modification of specific nuclear proteins, alterations which may provide a clue with respect to the important postreceptor events in thyroid hormone action. Special attention will be directed to the interrelationship between thyroid hormone action and the induction of lipogenic enzymes as a potential model for other thyroid hormone actions at the cellular level. Other specific functions of the thyroid hormone in the adult liver will also be examined, including the role of thyroid hormones in the generation of the labile protein pool as well as the relationship between thyroid hormone status and the tissue concentration of ferritin. The effect of thyroid hormone on specific mRNA sequences will be investigated both in the developing and the adult rat brain. The effect of thyroid hormone on the generation of specific products from fibroblasts will be examined in cultured fibroblasts from patients with thyroid hormone resistance. Clinical field studies will be undertaken to assess the relative therapeutic effectiveness of the dextro and levo enantiomers of thyroxine in lowering serum lipid concentrations in patients with hyperlipidemia. We shall also attempt to define the molecular basis for differential thyroid hormone action of analogs. Additional studies will be undertaken to determine the nature and physiological impact of an inhibitor of tissue and plasma protein binding iodothyronines in patients with nonthyroidal disease.
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