Using Genomics to Understand Autoimmune Diabetes

描述(申请人提供)：非肥胖糖尿病(NOD)小鼠为e型糖尿病(T1 DM)提供了一个很好的模型。一些证据表明，T1 DM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(干扰素)-伽马)T细胞可以转移糖尿病，而胰岛反应性Th2(产生白介素4)T细胞不能。这些和其他数据支持T1 DM发育与Th1反应相关的概念。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干扰素-γ的淋巴细胞的发育。事实上，干扰素-γ和干扰素-γ受体缺陷的NOD小鼠都会患上T1 DM。因此，建立对T1 DM免疫发病机制的更深层次、更机械性的理解是至关重要的。为此，我们利用胰岛特异性T细胞受体(TCR)转基因NOD小鼠亚系表现出的疾病谱，利用功能基因组学技术，分析了疾病在体内的分子进化。这些研究的基本假设是：(A)NOD小鼠的糖尿病是一种Th1相关疾病；(B)NOD小鼠的疾病表达不依赖于Th1反应的表面表型标记物--干扰素-γ的表达或活性；以及(C)疾病和组织特异性基因表达的全球特征将有助于更全面地了解NOD小鼠糖尿病的发病机制。在这些研究中检验的具体假设是，仔细的、功能基因组学方法对分子发病机制将允许详细描述Th1相关炎症反应的那些方面，这些方面对于NOD小鼠的疾病发病机制确实是必不可少的。为此，我们的目标是： 目的1：建立一组有限的、经过验证的基因，其表达模式直接预测NOD小鼠的自发性疾病进展过程。 目的：探讨干扰素-γ及其受体缺陷的NOD小鼠在干扰素-γ缺乏活性的情况下发生自发性T1 DM的遗传机制。 目的：建立NOD受者胰岛反应性Th1和Th2T细胞与疾病进展和耐药相关的差异基因表达谱。

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.