Thyroid hormone influences a variety of processes including development, metabolism and growth. Thyroid hormone action is mediated by nuclear receptors which interact with regulatory regions of genes stimulated or inhibited by thyroid hormone. There are 2 thyroid hormone receptor (TR) genes, alpha and beta, with a number of isoforms products from each gene. The relative abundance of these receptors varies in development and in different tissues in the body. A disorder in humans, Resistance to Thyroid Hormone (RTH), is associated with defects in these nuclear receptors. A variety of phenotypes are seen in RTH-affected individuals, ranging from growth delay and mental retardation to attention deficit disorder. The proposal studies will define how these processes are mediated by thyroid hormone and identify those actions specific for TR isoforms. These studies should also indicate how TR defects produce the abnormalities seen in RTH and provide a model to assess the response to treatment with thyroid hormone and its analogs. The phenotype of RTH can result from complete absence of the TR beta gene or by point mutations in the TR beta carboxy terminus, which act as dominant negative inhibitors of thyroid hormone action. Homologous recombination techniques have been used to target and inactivate the TR beta gene in mice, creating a TR beta deletion model of RTH. In addition to studying these mice, Dr. Brent will create mice with a point mutation in the TR beta gene that will produce a dominant negative receptor typical of the other genotype producing RTH. He will analyze both lines of mice, focusing on the role of TR in the regulation of nervous system development and function, cardiac function, metabolism and the dynamics of fat storage. Additionally, a TR beta isoform exclusively expressed in the brain and retina, TR beta 2 will be selectively inactivated and the resultant mice analyzed. Abnormalities in brain development and thyroid hormone regulation of pituitary hormones will be studied. Each targeted embryonic stem cell line will be used to create whole animals and will also be studied in an in vitro model in which both alleles are inactivated. Embryonic stem cells, under defined conditions, can be differentiated into a variety of cell types including erythrocytes, cardiac myocytes and neurons. This in vitro system will complement the in vivo studies and provide a model to study tissue specific gene regulation under more defined conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK043714-07
Application #
2414811
Study Section
Endocrinology Study Section (END)
Program Officer
Margolis, Ronald N
Project Start
1992-02-01
Project End
2000-04-30
Budget Start
1997-09-01
Budget End
1998-04-30
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Ribeiro, Miriam O; Bianco, Suzy D C; Kaneshige, Masahiro et al. (2010) Expression of uncoupling protein 1 in mouse brown adipose tissue is thyroid hormone receptor-beta isoform specific and required for adaptive thermogenesis. Endocrinology 151:432-40
Langton, Joanne E; Brent, Gregory A (2002) Nonthyroidal illness syndrome: evaluation of thyroid function in sick patients. Endocrinol Metab Clin North Am 31:159-72
Ribeiro, M O; Carvalho, S D; Schultz, J J et al. (2001) Thyroid hormone--sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoform--specific. J Clin Invest 108:97-105
Gouveia, C H; Schultz, J J; Bianco, A C et al. (2001) Thyroid hormone stimulation of osteocalcin gene expression in ROS 17/2.8 cells is mediated by transcriptional and post-transcriptional mechanisms. J Endocrinol 170:667-75
Li, Q L; Jansen, E; Brent, G A et al. (2001) Regulation of prohormone convertase 1 (PC1) by thyroid hormone. Am J Physiol Endocrinol Metab 280:E160-70
Kogai, T; Curcio, F; Hyman, S et al. (2000) Induction of follicle formation in long-term cultured normal human thyroid cells treated with thyrotropin stimulates iodide uptake but not sodium/iodide symporter messenger RNA and protein expression. J Endocrinol 167:125-35
Brent, G A (2000) Tissue-specific actions of thyroid hormone: insights from animal models. Rev Endocr Metab Disord 1:27-33
Li, Q L; Jansen, E; Brent, G A et al. (2000) Interactions between the prohormone convertase 2 promoter and the thyroid hormone receptor. Endocrinology 141:3256-66
Brent, G A (1999) Maternal hypothyroidism: recognition and management. Thyroid 9:661-5
Motomura, K; Brent, G A (1998) Mechanisms of thyroid hormone action. Implications for the clinical manifestation of thyrotoxicosis. Endocrinol Metab Clin North Am 27:1-23

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