ROLE OF INTERFERON GAMMA IN THYROIDITIS

γ 干扰素在甲状腺炎中的作用

• 批准号: 6363047
• 负责人: PATRIZIO CATUREGLI
• 金额: $ 22.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6363047
• 关键词: 3T3 cells; B lymphocyte; T lymphocyte; autoimmune disorder; biological signal transduction; fibroblasts; gene expression; gene targeting; genetic promoter element; genetic transcription; genetically modified animals; hormone biosynthesis; hypothyroidism; interferon gamma; laboratory mouse; membrane transport proteins; nucleic acid sequence; pathologic process; polymerase chain reaction; thyroglobulin; thyroid function; thyroid hormones; thyroiditis; transfection

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.

干扰素γ (IFNg)在自身免疫性甲状腺疾病的发病机制中与相互矛盾的结果有关。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转基因小鼠表现出甲状腺功能减退的迹象，这是由于碘化钠同转运体基因的表达受到严重抑制。甲状腺的病理特征是滤泡结构的广泛丧失，剩余滤泡的成熟延迟，以及轻微的单核细胞浸润。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。我们为这个应用程序构建了三个特定的目标。特异性目的1通过将甲状腺素-IFNg转基因小鼠与RAG-2敲除小鼠杂交，检验观察到的甲状腺形态学和功能变化是由淋巴细胞介导的，还是由IFNg对甲状腺细胞的直接作用引起的。特异性目标2通过遗传工具和转染测定，定义了IFNg抑制碘化钠同转运体基因表达的机制，从而导致甲状腺功能减退。特异性目的3：通过对正常和转甲状腺素-IFNg的甲状腺细胞的基因表达序列分析，比较其甲状腺转录组，定量测定IFNg信号通路和甲状腺激素合成通路中的基因；并发现新的甲状腺特异性基因。本提案的长期目标是表征IFNg在甲状腺炎炎症和细胞损伤中的作用。该项目的健康相关性源于人类自身免疫性甲状腺疾病的高患病率。此外，了解其发病机制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。