Interferon gamma (IFNg) has been implicated with contradictory results in the pathogenesis of autoimmune thyroid diseases. To investigate this issue, we have made transgenic mice that express IFNg in the thyroid gland under control of the thyroglobulin promoter. The thyr-IFNg transgenic mice present signs of hypothyroidism, which results from a profound inhibition of the expression of the sodium iodide symporter gene. The thyroid pathology is characterized by extensive loss of follicular architecture, maturation delay in the remaining follicles, and a mild mononuclear cell infiltration. The thyr-IFNg transgenic mice provide a model to study how the local production of IFNg in thyroid autoimmunity affects thyroid structure and function. We have structured this application with three specific aims.
Specific aim 1 tests, by crossing thyr-IFNg transgenic mice to RAG-2 knock out mice, whether the observed morphologic and functional thyroid changes are mediated lymphocytes or, instead, by a direct effect of IFNg on thyrocytes.
Specific aim 2 defines, by genetic tools and transfection assays, the mechanisms through which IFNg causes suppression of the expression of the sodium iodide symporter gene, leading to hypothyroidism.
Specific aim 3 compares, by serial analysis of gene expression, the thyroid transcriptome of normal and thyr-IFNg transgenic thyrocytes, with the goals to quantitatively measure the genes in the IFNg signaling and thyroid hormone synthetic pathways; and to discover new thyroid-specific genes. The long-term objectives of this proposal are to characterize the role of IFNg in relation to inflammation and cell damage in thyroiditis. The health-relatedness of the project stems from the high prevalence of autoimmune thyroid diseases in humans. Furthermore, the understanding of the pathogenesis can open new avenues for diagnosis, prognosis, and treatment of these and other organ-specific autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055670-04
Application #
6635147
Study Section
Endocrinology Study Section (END)
Program Officer
Akolkar, Beena
Project Start
2000-04-01
Project End
2004-02-28
Budget Start
2003-03-01
Budget End
2004-02-28
Support Year
4
Fiscal Year
2003
Total Cost
$231,738
Indirect Cost
Name
Johns Hopkins University
Department
Pathology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Caturegli, Patrizio; De Remigis, Alessandra; Chuang, Kelly et al. (2013) Hashimoto's thyroiditis: celebrating the centennial through the lens of the Johns Hopkins hospital surgical pathology records. Thyroid 23:142-50
Zheng, Gang; Chaux, Alcides; Sharma, Rajni et al. (2013) LMP2, a novel immunohistochemical marker to distinguish renal oncocytoma from the eosinophilic variant of chromophobe renal cell carcinoma. Exp Mol Pathol 94:29-32
Iwama, Shintaro; De Remigis, Alessandra; Bishop, Justin A et al. (2012) Hurthle cells predict hypothyroidism in interferon-ýý transgenic mice of different genetic backgrounds. Endocrinology 153:4059-66
Guaraldi, F; Zang, G; Dackiw, A P et al. (2011) Oncocytic mania: a review of oncocytic lesions throughout the body. J Endocrinol Invest 34:383-94
Hutfless, Susan; Matos, Peter; Talor, Monica V et al. (2011) Significance of prediagnostic thyroid antibodies in women with autoimmune thyroid disease. J Clin Endocrinol Metab 96:E1466-71
Marsili, A; Zavacki, A M; Harney, J W et al. (2011) Physiological role and regulation of iodothyronine deiodinases: a 2011 update. J Endocrinol Invest 34:395-407
Suzuki, Koichi; Kimura, Hiroaki; Wu, Huhehasi et al. (2010) Excess iodide decreases transcription of NIS and VEGF genes in rat FRTL-5 thyroid cells. Biochem Biophys Res Commun 393:286-90
Wang, George C; Talor, Monica V; Rose, Noel R et al. (2010) Thyroid autoantibodies are associated with a reduced prevalence of frailty in community-dwelling older women. J Clin Endocrinol Metab 95:1161-8
Caturegli, Patrizio; Kimura, Hiroaki (2010) A nonclassical model of autoimmune hypothyroidism. Thyroid 20:3-5
Kimura, Hiroaki J; Rocchi, Roberto; Landek-Salgado, Melissa A et al. (2009) Influence of signal transducer and activator of transcription-1 signaling on thyroid morphology and function. Endocrinology 150:3409-16

Showing the most recent 10 out of 28 publications