Thyroid Hormone Receptor Isoforms &Coactivators In Vivo

Project: Research project

Project Details

Description

DESCRIPTION: (Scanned from the applicant's abstract) 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.
StatusFinished
Effective start/end date5/15/013/31/07

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $257,965.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $261,209.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $258,046.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $258,579.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $257,600.00

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