Costimulation Genes and Pathways in Type 1 Diabetes

本申请的总体目标是了解1型糖尿病（T1 D）和其他自身免疫性疾病的遗传基础。这些知识可以应用于他们的治疗，治愈和最终预防。在T1 D的情况下，几种动物模型的可用性，特别是NOD小鼠，补充了定位人类基因的努力，并表明一些相同的基因，例如编码MHC II类分子和共刺激分子CTLA-4的基因，与两个物种中的T1 D以主要的致病方式相关。还有越来越多的证据表明，自身免疫性疾病，包括T1 D，自身免疫性甲状腺疾病和多发性硬化症（MS）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T1 D以及小鼠T1 D和EAE的病程。第一个目标是确定是否有额外的共享基因 控制人类和小鼠T1 D的发展。Idd 10和Idd18.2有助于NOD小鼠中T1 D的遗传控制，并且可能与MS重叠。 编码B7 H4和CD 101的多态性基因以及编码Idd18.2、CD 2和IgSFS的多态性基因。使用新的同类品系的小鼠和比较序列和表达研究，这些基因的候选人将进行测试。将在一个家族集合（748个家族）和一个新的病例对照集合（> 4，000例T1 D病例和4，000例对照）中使用分阶段基因分型策略评估由Idd 10和Idd18.2区域定义的候选基因在T1 D中的影响。第二个目标集中在人类CTLA-4基因遗传变异的后果。来自基因分型个体、正常个体和T1 D患者的外周血细胞将用于研究CTLA-4的可溶性同种型的调节。在第三个目标中，将在人外周血细胞和基因敲除小鼠模型中研究CD 101（一种其表达受CTLA 4基因型影响的共刺激分子）的功能。

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.