Thyroid hormone (TH) is essential for normal growth and development as well as maintenance of metabolic activity in the adult. TM action is mediated by intranuclear thyroid hormone receptors (TRs) which regulate the transcription of hormone responsive genes. Coregulators are nuclear proteins which interact with liganded or unliganded nuclear receptors to further modulate the transcription of TR targeted genes. The coregulators may either be corepressors, which inhibit transcription in the absence of TH, or coactivators which stimulate transcriptional activation of the liganded TR. There are at least 3 TR isoforms and several different corepressors and coactivators that have been identified. The hypothesis guiding the proposed studies is that defects in cofactors involved in the mediation of TH action are responsible for the manifestation of resistance to TH (RTH) in a subgroup of human subjects without mutations in the TRB gene. Mice with deletions of one of the 3 coactivators will be evaluated for the physiologic and molecular consequences in a variety of tissues. It has been shown that TRB knockout mice are resistant to the action of thyroid hormone (TH) and new results presented in the Preliminary Studies section of this current application show that mice with deletion of the TRa gene are hypersensitive to TH. Since coactivators are important in TR mediated TH action in vitro, we ask the question whether coactivators differently modulate the function of TRalpha and TRB and if so, how does this effect influence TH action in different tissues in vivo. Our published and preliminary results demonstrate that elimination of each of the 3 coactivators results in different degrees of perturbation of TH action. Therefore, characterization of the phenotypes of these mice will have a dual effect: (1) it may identify defects in genes, other than TRB, that may cause RTH; (2) identify phenotypic differences in RTH caused by defects in cofactors and cofactor/TR interaction as compared to those of isolated TRB gene mutations that cannot be easily identified in humans; and (3) provide information on the physiologic outcome of specific gene interactions in terms of specificity and redundancy. Such information would generate important leads in understanding the specific mechanistic aspects of TH action.
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