GENETICS AND PATHOLOGY OF NONOBESE DIABETIC (NOD) MICE

NOD小鼠自身免疫性胰岛素依赖型糖尿病（IDDM）的发展涉及固有的糖尿病性MHC和许多非MHC基因之间复杂的相互作用。虽然已经确定了许多非mhc胰岛素依赖型糖尿病（Idd）基因的染色体位置，但它们的实际身份和精确功能仍然未知。分离这些非mhc Idd基因座并确定其在免疫发病机制中的作用的策略是使NOD小鼠的基因群携带Idd基因座上的抗性等位基因。本研究的目的是将小鼠遗传学和功能基因组学结合起来，确定控制自身反应性CD4和CD8 T细胞外周积累的基因（“T淋巴积累”），并更准确地确定能够延缓糖尿病发生过程的调节性T细胞的性质。将L-选择素基因的靶向破坏引入NOD/Lt小鼠，以验证该标记物识别外周t调节细胞的假设。为了鉴定能够调节或限制胰岛积累T细胞激活的非mhc基因，研究人员提出了在hh2g7 -相同的NOR/Lt菌株中建立IDDM抗性的遗传基础。NOR小鼠表现出T效应细胞活化迟缓，部分原因可能是巨噬细胞群更为正常。将基因中断的Caspase 1 （IL-1 β转换酶）基因引入NOR中表达IL-1等位基因的糖尿病抵抗性chr2基因库中，以测试IL-1基因复合物的候选性。NOD/Lt在Chr 9上拥有NON/Lt衍生抗性位点的同源基因（表现T淋巴积聚，但阻滞效应激活），而NOcCB-1是一种新的重组同源菌株，将分别用于鉴定控制CD4和CD4 T细胞积聚的NOD基因。所提出的方法组合不仅应该允许主要的非mhc相关IDDM易感基因的分子鉴定，而且还应该在细胞水平上建立它们的致病作用。

Development of autoimmune insulin dependent diabetes mellitus (IDDM) in NOD mice entails a complex interaction between an inherently daibetogenic MHC and numerous non-MHC genes. Although chromosomal locations for a number of the non-MHC insulin dependent diabetes (Idd) genes have been established, their actual identities and precise functions remain unknown. The strategy employed to isolate these non-MHC Idd loci and to establish their contribution to immunopathogenesis has been to make congenic stocks of NOD mice carrying resistance alleles at Idd loci. The objectives of this proposal are to combined mouse genetics and function genomics to identify genes that control peripheral accumulation of autoreactive CD4 and CD8 T cells ("T-lymphoaccumulation") and to identify more precisely the nature of regulatory T cells capable of retarding the diabetogenic process. A targeted disruption of the L- selectin gene will be introduced into NOD/Lt mice to test the hypothesis that this marker identifies peripheral T-regulatory cells. To identify non-MHC genes that function either to regulate activation of islet- accumulation T cells or to limit their accumulation, studies are proposed to establish the genetic basis for IDDM resistance in the H2g7- identical NOR/Lt strain. NOR mice show a retarded activation of T- effector cells that may, in part, be a consequence of a more normal macrophage population. A genetically disrupted Caspase 1 (IL-1beta converting enzyme) gene will be introduced into diabetes-resistant Chr.2 congenic stocks expressing IL-1 alleles from NOR to test the candidacy of the IL-1 gene complex. NOD/Lt stocks congenic for NON/Lt-derived resistance loci on Chr 9 (exhibiting T-lymphoaccumulation, but retarded effector activation), and NOcCB-1, a new recombinant congenic strain, will be used to identify NOD genes controlling CD4 and CD4 T cell accumulation respectively. The combination of approaches proposed should permit not only molecular identification of major non-MHC associated IDDM susceptibility genes, but also establishment of their pathogenic contributions at a cellular level.