ROLE OF INTERFERON GAMMA IN THYROIDITIS

γ 干扰素在甲状腺炎中的作用

• 批准号: 6635147
• 负责人: PATRIZIO CATUREGLI
• 金额: $ 23.17万
• 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/6635147
• 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）与自身免疫性甲状腺疾病的发病机理有关。 为了研究这个问题，我们制造了在甲状腺球蛋白启动子控制下表达甲状腺中表达IFNG的转基因小鼠。三iFNG转基因小鼠表现出甲状腺功能减退症的迹象，这是由于对碘化钠共物基因表达的深刻抑制作用而引起的。 甲状腺病理学的特征是卵泡结构的广泛丧失，剩余的卵泡中的成熟延迟以及轻度的单核细胞浸润。 Thy-IFNG转基因小鼠提供了一个模型，以研究甲状腺自身免疫性中IFNG的局部产生如何影响甲状腺结构和功能。 我们已经以三个特定的目标构建了此应用程序。 特定的目标1测试是，通过将三个IFNG转基因小鼠跨到rag-2敲除小鼠，无论观察到的形态学和功能性甲状腺变化是否是介导的淋巴细胞，还是通过ifng对甲状腺细胞的直接作用。 特定的目标2通过遗传工具和转染测定法定义了IFNG导致碘化钠分类基因表达的机制，从而导致甲状腺功能减退症。 特定的目标3通过对基因表达的序列分析，正常和三型转基因甲状腺细胞的甲状腺转录组与甲状腺转录组的序列分析，以及在量化IFNG信号传导和甲状腺激素合成途径中定量测量基因的目标。并发现新的甲状腺特异性基因。该提案的长期目标是表征IFNG在甲状腺炎中炎症和细胞损伤方面的作用。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流行。此外，对发病机理的理解可以为这些和其他特定器官特定的自身免疫性疾病开辟新的途径，以进行诊断，预后和治疗。