Using Genomics to Understand Autoimmune Diabetes

描述（由申请方提供）：非肥胖糖尿病（NOD）小鼠为1型糖尿病（T1 DM）提供了极好的模型。几条证据表明，T1 DM是由Th 1自身免疫反应引起的。例如，我们小组和其他人的研究表明，胰岛反应性Th 1（产生干扰素（IFN）-γ）T细胞会转移糖尿病，而胰岛反应性Th 2（产生白细胞介素（IL）-4）T细胞不会。这些和其他数据支持T1 DM的发展与Th 1应答相关的观点。然而，与其他器官特异性自身免疫性疾病一样，T1 DM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受体缺陷型NOD小鼠均发生T1 DM。 因此，建立对T1 DM免疫发病机制的更深入、更机械的理解至关重要。为此，我们利用胰岛特异性T细胞受体（TCR）转基因NOD小鼠的亚系所表现出的疾病谱，使用功能基因组学技术分析体内疾病的分子演变。作为这些研究基础的一般假设是：（a）NOD小鼠中的糖尿病是一种Th 1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Th 1应答的表面表型标志物;以及（c）疾病和组织的全球特征，特异性基因表达将允许更完整地理解NOD小鼠中糖尿病的发病机制。在这些研究中正在测试的具体假设是，一个仔细的，功能基因组学的分子发病机制的方法将允许详细描绘的那些方面的Th 1相关的炎症反应，是真正必要的疾病的发病机制在NOD小鼠。为此，我们的目标是： 目标1： 建立一个有限的和经过验证的基因组，其表达模式直接分期和预测NOD小鼠自发性疾病进展的过程。 目标二： 描述IFN-γ和IFN-γ受体缺陷NOD小鼠在缺乏干扰素-γ活性的情况下发生自发性T1 DM的遗传机制。 目标3： 目的建立胰岛反应性Th 1和Th 2 T细胞NOD受者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.