Costimulation Genes and Pathways in Type 1 Diabetes

这项应用的总体目标是了解1型糖尿病(T1D)和其他自身免疫性疾病的遗传基础。这些知识随后可以应用于他们的治疗、治愈和最终预防。在T1D的情况下，几个动物模型的获得，特别是NOD小鼠，补充了人类基因定位的努力，并表明一些相同的基因，例如那些编码MHC II类分子和共刺激分子CTLA-4的基因，在两个物种中都以一种主要的、引起TID的方式与TID有关。越来越多的证据表明，包括T1D、自身免疫性甲状腺疾病和多发性硬化症(MS)在内的自身免疫性疾病很可能受到一些相同基因的影响。例如，CTLA-4分子的变异影响人类Graves病和T1D的病程，以及小鼠T1D和EAE的病程。第一个目标是确定额外的共享基因 控制T1D在人和小鼠体内的发育。Idd10和Idd18.2有助于NOD小鼠T1D的遗传控制，可能与MS重叠。Idd10的主要候选基因是 编码B7H4和CD101以及Idd18.2、CD2和IgSFS的多态基因。利用新的小鼠同基因品系以及比较序列和表达研究，将测试这些基因的候选能力。由Idd10和Idd18.2区域定义的候选基因的影响将在T1D中使用分阶段基因分型策略在家族集合(748个家系)和新的病例对照集合(&gt；4,000个T1D病例和4,000个对照)中进行评估。第二个目标集中在人类CTLA-4基因遗传变异的后果上。来自基因分型的正常人和T1D患者的外周血细胞将被用来研究CTLA-4的可溶性异构体的调节。在第三个目标中，CD101是一种共刺激分子，其表达受到CTLA4基因的影响，将在人类外周血细胞和基因敲除小鼠模型中进行研究。

The overall goal of this application is to understand the genetic basis of type 1 diabetes (T1D) and other autoimmune diseases. This knowledge can then be applied to their treatment, cure, and eventual prevention. In the case of T1D, the availability of several animal models, especially the NOD mouse, has complemented the efforts to localize human genes and has shown that some of the same genes, e.g. those encoding MHC class II molecules and the costimulatory molecule CTLA-4, are associated with TID in both species in a primary, causative way. There is also growing evidence that autoimmune diseases including T1D, autoimmune thyroid disease and multiple sclerosis (MS) are likely to be influenced by some of the same genes. For example, variation in the CTLA-4 molecule affects the course of both Graves' disease and T1D in humans and T1D and EAE in the mouse. The first aim is to determine if additional shared genes control the development of T1D in humans and mice. Idd10 and Idd18.2 contribute to the genetic control of T1D in NOD mice and may overlap with MS. The primary candidates in Idd10 are the polymorphic genes encoding B7H4 and CD101 and for Idd18.2, CD2 and IgSFS. Using novel congenic strains of mice and comparative sequence and expression studies, the candidacy of these genes will be tested. The influence of candidate genes defined by the Idd10 and Idd18.2 regions will be assessed in T1D using a staged genotyping strategy in a family collection (748 families) and a new case-control collection (> 4,000 T1D cases and 4,000 controls). The second aim focuses on the consequences of genetic variation in the human CTLA-4 gene. Peripheral blood cells from genotyped individuals, normal and patients with T1D, will be used to study the regulation of the soluble isoform of CTLA-4. In the third aim, the function of CD101, a costimulatory molecule whose expression is influenced by the CTLA4 genotype, will be studied in human peripheral blood cells and in a knockout mouse model.