ROLE OF INTERFERON GAMMA IN THYROIDITIS

干扰素γ（IFNg）在自身免疫性甲状腺疾病的发病机制中具有相互矛盾的结果。 为了研究这个问题，我们制作了在甲状腺球蛋白启动子控制下在甲状腺中表达IFNg的转基因小鼠。thyr-IFNg转基因小鼠存在甲状腺功能减退症的迹象，这是由于钠碘转运体基因表达的严重抑制。 甲状腺病理学的特征是滤泡结构的广泛丧失，剩余滤泡的成熟延迟和轻度单核细胞浸润。Thyr-IFNg转基因小鼠为研究甲状腺自身免疫中IFNg的局部产生如何影响甲状腺结构和功能提供了模型。 我们构建了这个应用程序有三个具体目标。 具体目标1通过将thyr-IFNg转基因小鼠与RAG-2敲除小鼠杂交来测试所观察到的甲状腺形态和功能变化是淋巴细胞介导的还是IFNg对甲状腺细胞的直接作用。 具体目标2通过遗传工具和转染测定来定义IFNg引起钠碘同向转运体基因表达抑制从而导致甲状腺功能减退的机制。 具体目标3通过基因表达的系列分析比较正常和thyr-IFNg转基因甲状腺细胞的甲状腺转录组，目的是定量测量IFNg信号传导和甲状腺激素合成途径中的基因;并发现新的甲状腺特异性基因。该提案的长期目标是描述IFNg在甲状腺炎炎症和细胞损伤中的作用。该项目与健康有关，因为人类自身免疫性甲状腺疾病的发病率很高。此外，对发病机制的理解可以为这些和其他器官特异性自身免疫性疾病的诊断、预后和治疗开辟新的途径。

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.