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.
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