Using Genomics to Understand Autoimmune Diabetes

描述（由申请人提供）：非肥胖糖尿病（NOD）小鼠为1型糖尿病（T1DM）提供了极好的模型。多项证据表明 T1DM 是 Th1 自身免疫反应的结果。例如，我们小组和其他人的研究表明，胰岛反应性 Th1（产生干扰素 (IFN)-gamma）T 细胞会转移糖尿病，而胰岛反应性 Th2（产生白细胞介素 (IL)-4）T 细胞则不会。这些和其他数据支持 T1DM 发展与 Th1 反应相关的观点。然而，与其他器官特异性自身免疫性疾病一样，T1DM 的发病机制显然不仅仅涉及产生 IFN-γ 的淋巴细胞的发育。事实上，IFN-γ 和 IFN-γ 受体缺陷的 NOD 小鼠都会患上 T1DM。 因此，对 T1DM 的免疫发病机制建立更深入、更机制的理解至关重要。为此，我们利用胰岛特异性 T 细胞受体 (TCR) 转基因 NOD 小鼠亚系所表现出的疾病谱，利用功能基因组学技术分析体内疾病的分子进化。这些研究的一般假设是：(a) NOD 小鼠的糖尿病是一种 Th1 相关疾病； (b) NOD小鼠中的疾病表达不依赖于IFN-γ的表达或活性，IFN-γ是Th1反应的表面表型标志物； (c) 疾病和组织特异性基因表达的整体特征将有助于更全面地了解 NOD 小鼠糖尿病的发病机制。这些研究中正在测试的具体假设是，对分子发病机制进行仔细的功能基因组学方法将允许详细描述对于 NOD 小鼠疾病发病机制真正重要的 Th1 相关炎症反应的那些方面。为此，我们的目标是： 目标 1：建立一组有限且经过验证的基因，其表达模式可直接分期并预测 NOD 小鼠自发疾病进展的过程。 目标 2：阐明 IFN-γ 和 IFN-γ 受体缺陷型 NOD 小鼠在缺乏干扰素-γ 活性的情况下自发形成 T1DM 的遗传机制。 目标 3：建立胰岛反应性 Th1 和 Th2 T 细胞 NOD 受体中与疾病进展和抵抗相关的差异基因表达模式。

DESCRIPTION (provided by applicant): The non-obese diabetic (NOD) mouse provides an excellent model for e type 1 diabetes mellitus (T1DM). Several lines of evidence suggest that T1DM results from a Th1 autoimmune response. For example, studies by our group and others have shown that islet-reactive Th1 (interferon (IFN)-gamma producing) T cells transfer diabetes, while islet-reactive Th2 (interleukin (IL)-4 producing) T cells do not. These and other data support the notion that T1DM development correlates with a Th1 response. However, the pathogenesis of T1DM, like that of other organ-specific autoimmune diseases, clearly involves more than the development of IFN-gamma producing lymphocytes. Indeed, both IFN-gamma- and IFN-gamma receptor-deficient NOD mice develop T1DM. Therefore, it is critical that a deeper, more mechanistic understanding of the immunopathogenesis of T1DM be established. To this end, we have taken advantage of the spectrum of disease exhibited by sub-lines of our islet-specific T cell receptor (TCR) transgenic NOD mice to analyze the molecular evolution of disease in vivo, using the technique of functional genomics. The general hypotheses underlying these studies are: (a) that diabetes in NOD mice is a Th1-associated disease; (b) that disease expression in the NOD mouse is not dependent upon the expression or activity of IFN-gamma, the superficial phenotype marker of a Th1 response; and (c) that global characterization of disease- and tissue-specific gene expression will allow for a more complete understanding of the pathogenesis of diabetes in the NOD mouse. The specific hypothesis being tested in these studies is that a careful, functional genomics approach to molecular pathogenesis will allow for the detailed delineation of those aspects of the Th1-associated inflammatory response that are truly essential for disease pathogenesis in the NOD mouse. To this end, we aim: Aim 1: To establish a limited and verified set of genes whose expression patterns directly stage and predict the course of spontaneous disease progression in NOD mice. Aim 2: To delineate the genetic mechanism by which IFN-gamma- and IFN-gamma receptor-deficient NOD mice develop spontaneous T1DM in the absence of interferon-gamma activity. Aim 3: To establish the differential gene expression pattern associated with disease progression and resistance in NOD recipients of islet-reactive Th1 and Th2 T cells.