Genetic and molecular mechanisms dysregulating CD4 T cell tolerance in organ-specific autoimmunity

该项目将分析调节CD4 T细胞的机制，并通常防止免疫系统攻击我们自己的身体部位。T细胞控制中的未知错误导致自身免疫性疾病，如1型糖尿病，多发性硬化症，阿狄森氏病和甲状腺疾病，其中T细胞损伤或破坏重要器官。为了开发治疗和预防这些疾病的合理，具体的方法，有必要确定和理解通常控制T细胞对自身成分反应的遗传和生化机制，以及遗传缺陷如何导致这些机制被破坏。该项目的重点是定义CD4 T细胞调节如何在一个已建立但知之甚少的多基因遗传性自身免疫性疾病易感性的例子中被破坏。多基因疾病是指易感性以复杂的方式遗传，涉及许多不同的基因共同作用或相互作用，这种遗传的分子基础特别不清楚。该项目将通过分析糖尿病易感基因在负责自身免疫攻击的特定T细胞水平上的直接作用以及失调的T细胞内的生化途径来分析这种遗传模式的基础。通过识别自身免疫性疾病中失调的机制和生化途径，该项目的结果将为理解和诊断自身免疫性疾病以及开发新的药物或疫苗以防止T细胞损伤重要器官并治愈这些疾病提供概念和目标。

This project will analyse mechanisms that regulate CD4 T cells and normally prevent the immune system from attacking parts of our own body. Unknown errors in the control of T cells result in autoimmune diseases such as Type 1 diabetes, multiple sclerosis, Addison s disease and thyroid disease, where T cells damage or destroy vital organs. In order to develop rational, specific methods for treating and preventing these diseases, it is necessary to identify and understand the genetic and biochemical mechanisms that normally control T cell responses to self components, and how inherited defects lead these mechanisms to break down. The project focuses on defining how CD4 T cell regulation breaks down in a well established but poorly understood example of polygenic inherited susceptibility to autoimmune disease. Polygenic diseases are those where susceptibility is inherited in a complex way involving many different genes either acting together or in opposition, and the molecular basis for this kind of inheritance is particularly poorly understood. The project will analyse the basis for this kind of inheritance pattern by analysing the direct action of diabetes susceptibility genes at the level of the specific T cells responsible for autoimmune attack and in terms of the biochemical pathways within the T cells that are dysregulated. By identifying the mechanisms and biochemical pathways that are dysregulated in autoimmune disorders, the results of this project will concepts and targets for understanding and diagnosing autoimmune diseases and for developing new drugs or vaccines to prevent T cells damaging vital organs and cure these diseases.