GENETICS AND PATHOLOGY OF NON-OBESE DIABETIC (NOD) MICE

该项目的长期目标是鉴定染色体 控制糖尿病发病机制的基因的位置和功能 NOD/Lt小鼠。 NOD/Lt小鼠的胰岛素依赖型糖尿病是多基因遗传的 控制并反映免疫系统失调的发展， 自身反应性T细胞既不被胸腺内删除，也不被抑制 外围的 主要组织相容性复合体（MHC）内的基因是 基因易感性的重要组成部分;然而，非MHC 易感基因与致糖尿病的MHC基因座相互作用， 糖尿病发病机制 遗传分析将集中在NOR/Lt，一种NOD- 相关的无糖尿病股票 该原种在MHC上含有NOD等位基因， 大多数其他非MHC基因座分型，但包含4条染色体的片段 来源于C57 BL/KsJ菌株。 糖尿病抗性在NOR股票是 伴随着重建的同系混合淋巴细胞反应（SMLR）， NOD/Lt中不存在外周T细胞应答。因此， 作为一个有价值的免疫表型标记， 分析NOR/Lt中的C57 BL/KsJ基因消除糖尿病发病机制， 将它们与免疫表型标记联系起来。 这将通过 开发与携带染色体片段同源的NOD原种 糖尿病耐药等位基因 第二个目的是分析 遗传隔离发病机制-易感MHC单倍型如何相互作用 与致糖尿病非MHC基因（在第一个目标中定义）介导 通过干扰免疫调节系统的发病机制。 第三个目标 是开发单克隆抗体，以允许表征Mrt-6， 小鼠基因定位于Chr 7，与大鼠中的RT 6同源。 RT 6是T 大鼠中定义的细胞表面分化抗原; RT 6 + T亚群 细胞具有免疫调节功能， 糖尿病在迄今为止的抵抗大鼠。 北方印迹分析显示 与糖尿病抗性小鼠相比，NOD中的Mrt-6 RNA表达较低， 这表明Mrt-6也可以作为免疫调节的标志物， NOD小鼠中的亚群。 第四个目标是研究潜在的 胰腺β细胞表达内源性 Emy-30基因定位于NOD的Chr 11，在NOD中缺失。 抗糖尿病NOR股票。 我们将建立分子基础 对于这种内源性逆转录病毒在NOD β细胞中的差异表达， 与来自相关但耐糖尿病的种群的β细胞相比。 结果 这些研究将指导遗传学家寻找非MHC 与人类中的糖尿病易感基因相关并增强 了解它们与致糖尿病MHC基因的相互作用。

The long term goal of this project is identification of the chromosomal locations and functions of genes controlling diabetes pathogenesis in NOD/Lt mice. Insulin dependent diabetes in NOD/Lt mice is under polygenic control and reflects development of a dysregulated immune system in which autoreactive T cells are neither deleted intrathymically nor suppressed peripherally. Genes within the major histocompatibility complex (MHC) are important components of the genetic susceptibility; however, non-MHC susceptibility genes interact with the diabetogenic MHC loci to initiate diabetes pathogenesis. Genetic analysis will be centered on NOR/Lt, a NOD- related, diabetes-free stock. This stock contains NOD alleles at MHC and most other non-MHC loci typed, but contains segments of 4 chromosomes derived from the C57BL/KsJ strain. Diabetes resistance in the NOR stock is accompanied by a reconstituted syngeneic mixed lymphocyte reaction (SMLR), a peripheral T cell response absent in NOD/Lt. Thus, presence or absence of SMLR activity serves as a valuable immunophenotypic marker to segregate analysis the C57BL/KsJ genes in NOR/Lt abrogating diabetes pathogenesis and relate them to immunophenotypic markers. This will be accomplished by development of NOD stocks congenic for chromosomal segments carrying diabetes resistance alleles from NOR. The second aim is to analyze by genetic segregation how pathogenesis-predisposing MHC haplotypes interact with diabetogenic non-MHC genes (defined in the first aim) to mediate pathogenesis via perturbation of immunoregulatory systems. The third aim is to develop monoclonal antibodies to permit characterization of Mrt-6, a mouse gene we mapped to Chr 7 and homologous to RT6 in the rat. RT6 is a T cell surface differentiation antigen defined in rats; a subset of RT6+ T cells possess immunoregulatory function since their depletion elicits diabetes in heretofore resistant rats. Northern blot analysis reveals lower Mrt-6 RNA expression in NOD compared to diabetes-resistant mice, indicating that Mrt-6 may also serve as a marker for immunoregulatory subsets in the NOD mouse. The fourth aim is to investigate the potential pathogenic significance of pancreatic beta cell expression of an endogenous ecoptropic proviral gene, Emy-30, located on Chr 11 of NOD and absent in the diabetes resistant NOR stock. We will establish the molecular basis for differential expression of this endogenous retrovirus in NOD beta cells versus beta cells from related but diabetes-resistant stocks. Results from these proposed studies will guide geneticists in their search for non-MHC linked diabetogenic susceptibility genes in humans and enhance understanding of their interactions with diabetogenic MHC genes.