The mechanism of transcriptional repression by thyroid hormone receptor (TR) will be studied by creating a yeast model of TR action. Thyroid hormone is critical for intellectual and physical development in humans, and has effects on diverse organ systems ranging from bone to the cardiovascular system. Recent studies have shown that TR mediates repression by recruiting a histone deacetylase complex. However, the details of this interaction are unclear. Studies in mammalian cells have been complicated by the ubiquitous expression of other nuclear hormone receptors and comodulatory proteins that can interact with TR and affect TR action. Because histone deacetylases are fundamental chromatin remodeling proteins that are widely conserved, it is possible to model TR action by reconstituting TR-mediated gene regulation in a lower eukaryote, such as yeast. Yeast will be stably transformed with TR, along with a reporter gene and critical proteins involved in transcriptional repression, including nuclear receptor corepressor (N-CoR) and the corepressor protein mSin3A. This will result in a powerful model for generating and testing hypotheses of TR repression mechanisms. Initial studies will include testing the effects of different thyroid-hormone response elements (TREs) on repression, determining whether RXR is required for repression, and evaluating the role of local chromatin structure on TR-mediated repression. The generated data will have implications for gene regulation by all members of the nuclear receptor superfamily. It is hoped that a better understanding of the mechanisms of TR action will eventually lead to the development of novel ways in which the expression of thyroid hormone target genes can be modulated to affect the outcome of certain disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK010044-01
Application #
6070088
Study Section
Endocrinology Study Section (END)
Program Officer
Hyde, James F
Project Start
2000-07-01
Project End
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$42,628
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109