Costimulation Genes and Pathways in Type 1 Diabetes

1 型糖尿病的共刺激基因和通路

• 批准号: 7310153
• 负责人: Linda S. Wicker
• 金额: $ 32.12万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7310153
• 关键词: CD antigens; CD28 molecule; NOD mouse; T lymphocyte; diabetes mellitus genetics; family genetics; genetic polymorphism; genetic susceptibility; genetically modified animals; human subject; insulin dependent diabetes mellitus; laboratory mouse; leukocyte activation /transformation; patient oriented research; protein structure function

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.

该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。然后，这些知识可以应用于他们的治疗，治愈和最终预防。就T1D而言，几种动物模型的可用性，尤其是点头小鼠，已经补充了定位人类基因的努力，并表明某些相同的基因，例如那些编码MHC II类分子和共刺激分子CTLA-4的人与两种物种的TID相关。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可能受到某些相同基因的影响。例如，CTLA-4分子的变化会影响人类的坟墓疾病和T1D的过程，而T1D和EAE在小鼠中都会影响。第一个目的是确定是否其他共享基因 控制人类和小鼠T1D的发展。 IDD10和IDD18.2有助于NOD小鼠T1D的遗传控制，并且可能与MS重叠。 IDD10中的主要候选人是 编码B7H4和CD101以及IDD18.2，CD2和IGSF的多态性基因。使用小鼠的新型相对菌株和比较序列和表达研究，将测试这些基因的候选性能。 IDD10和IDD18.2区域定义的候选基因的影响将在T1D中使用家庭收集中的分阶基因分型策略（748个家庭）和新的病例控制收集（> 4,000 T1D病例和4,000个控制）评估。第二个目的侧重于人CTLA-4基因遗传变异的后果。来自基因分型个体，正常和T1D患者的外周血细胞将用于研究CTLA-4可溶性同工型的调节。在第三个目标中，将在人的外周血细胞和基因敲除小鼠模型中研究CD101的功能，CD101的表达受CTLA4基因型影响。