The overall goal of this proposal is to gain a better understanding of the central regulation of the hypothalamic- pituitary-thyroid axis (HPT axis) by thyroid hormones (T4 and T3) and thyrotropin-releasing hormone (TRH). Thyroid stimulating hormone (TSH also known as thyrotropin) is a heterodimeric protein, which is synthesized and secreted from the thyrotroph and is essential for activating thyroid hormone (TH) synthesis in the thyroid. THRB isoforms (principally the THRB2 isoform) mediates T3 negative feedback at the level of the hypothalamus and pituitary thyrotroph based on elevated TH and TSH levels in THRB isoform KO mice. In contrast, THRA1 KO mice actually display slightly reduced TH levels associated with slightly elevated TSH levels. These findings suggest that THRA1 has no role in negative T3 regulation of the HPT axis in the euthyroid state. However, THRA1 must play some role since KO of all THR isoforms (THRA1, THRB1 and THRB2) markedly elevates both TSH and TH levels above those observed in THRB KO mice. What explains this THR isoform difference? We hypothesize that THRB isoforms bind preferentially to a negative thyroid response element(s) (nTREs) in the Tshb gene to mediate negative T3 regulation. In the absence of T3, other workers have suggested that TRH and TSH production are maximal, and that the unliganded THRs play no direct role in activating the axis. Our in vitro studies and studies in KO mice challenge this model. We have demonstrated, for example, that the N-terminus of THRB2 contains a potent trans-activation domain and that both THRB2 and hypothalamic TRH are necessary for full activation of Tsh subunit gene expression in the hypothyroid state in vivo. We hypothesize that specific THR isoforms mediate an increase in histone acetylation on the Tshb gene, which underlies the mechanism by which the unliganded THRB2 activates basal gene expression. Finally, we have characterized a unique, permanent mouse thyrotroph cell line (T?T1.1) that displays physiological T3 negative regulation of the Tshb gene. We find that acute changes in histone methylation of the proximal Tshb gene occur after T3 treatment. We hypothesize that liganded THRs recruit a histone demethylase to Tshb resulting in a decrease in histone methylation and T3- inhibition of gene expression.

Public Health Relevance

The overall goal of this proposal is to gain a better understanding of how thyroid hormone production is regulated by pituitary thyrotropin (TSH) and hypothalamic thyrotropin-releasing hormone (TRH). Understanding how genes are regulated by thyroid hormones will elucidate mechanisms responsible for development, growth and metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK049126-15A1
Application #
8438581
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
1995-08-01
Project End
2016-10-31
Budget Start
2012-12-03
Budget End
2013-10-31
Support Year
15
Fiscal Year
2013
Total Cost
$352,350
Indirect Cost
$134,850
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Aninye, Irene O; Matsumoto, Shunichi; Sidhaye, Aniket R et al. (2014) Circadian regulation of Tshb gene expression by Rev-Erb? (NR1D1) and nuclear corepressor 1 (NCOR1). J Biol Chem 289:17070-7
Ortiga-Carvalho, Tânia M; Sidhaye, Aniket R; Wondisford, Fredric E (2014) Thyroid hormone receptors and resistance to thyroid hormone disorders. Nat Rev Endocrinol 10:582-91
Wondisford, Fredric E (2011) A new medical therapy for Cushing disease? J Clin Invest 121:4621-3
Richter, Claus-Peter; Munscher, Adrian; Machado, Danielle Santana et al. (2011) Complete activation of thyroid hormone receptor ýý by T3 is essential for normal cochlear function and morphology in mice. Cell Physiol Biochem 28:997-1008
Machado, Danielle S; Sabet, Amin; Santiago, Leticia A et al. (2009) A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo. Proc Natl Acad Sci U S A 106:9441-6
Applebury, M L; Farhangfar, F; Glosmann, M et al. (2007) Transient expression of thyroid hormone nuclear receptor TRbeta2 sets S opsin patterning during cone photoreceptor genesis. Dev Dyn 236:1203-12
Nikrodhanond, Amisra A; Ortiga-Carvalho, Tania M; Shibusawa, Nobuyuki et al. (2006) Dominant role of thyrotropin-releasing hormone in the hypothalamic-pituitary-thyroid axis. J Biol Chem 281:5000-7
Hashimoto, Koshi; Cohen, Ronald N; Yamada, Masanobu et al. (2006) Cross-talk between thyroid hormone receptor and liver X receptor regulatory pathways is revealed in a thyroid hormone resistance mouse model. J Biol Chem 281:295-302
Ortiga-Carvalho, Tania M; Shibusawa, Nobuyuki; Nikrodhanond, Amisra et al. (2005) Negative regulation by thyroid hormone receptor requires an intact coactivator-binding surface. J Clin Invest 115:2517-23
Ortiga-Carvalho, Tania M; Hashimoto, Koshi; Pazos-Moura, Carmen C et al. (2004) Thyroid hormone resistance in the heart: role of the thyroid hormone receptor beta isoform. Endocrinology 145:1625-33

Showing the most recent 10 out of 24 publications