Project 2: STAT3 as a trigger for T1D

项目摘要/摘要 与1型糖尿病的发展密切相关的单基因疾病一直是 为解开控制这种疾病的关键途径提供了信息。成功使用此功能的示例 方法包括对AIRE和FOXP3的研究，它们对于识别AIR和FOXP3的通路具有重要意义。 胸腺和T调节细胞，控制1型糖尿病。在这里，我们将利用最新的知识 STAT3功能突变(GOF)的获得与1型糖尿病的发生密切相关 通过建立一种健壮的综合症动物模型。 我们的具体目标是： 目的1：在一种新的自身免疫性糖尿病小鼠模型中建立STAT3GOF的作用模型 (NOD.STAT3K392R/) 目的2：鉴定和鉴定NOD.STAT3K392R/缺陷的关键免疫细胞群 模型和具有相似STAT3 GOF突变的患者 目标3：确定STAT3 GOF模型中中心耐受性可能发生的变化 这些研究将与PPG项目1(库珀)和项目3(马森)密切合作进行，并将 帮助我们更好地理解STAT3是如何控制免疫耐受的，以及免疫耐受是如何改变的 这种分子可以激发1型雏菊。

Project Summary/Abstract Monogenic diseases that have a close association with the development of type 1 diabetes have been informative for unraveling critical pathways that keep this disease in check. Examples of success using this approach include the study of AIRE and FOXP3 which have been informative for identifying pathways in the thymus and T regulatory cells that keep type 1 diabetes in check. Here, we will leverage the recent knowledge that gain of function mutations (GOF) in STAT3 are tightly associated with the development of type 1 diabetes by developing a robust animal model of the syndrome. Our specific aims are: Aim 1: Model the effects of STAT3 GOF in a novel mouse model of autoimmune diabetes (NOD.STAT3K392R/+) Aim 2: Identify and characterize key immune cell populations that are defective in the NOD.STAT3K392R/+ model and in patients with similar STAT3 GOF mutations Aim 3: Identify how central tolerance is potentially altered in STAT3 GOF models These studies will be performed in close collaboration with PPG projects 1 (Cooper) and 3 (Marson) and will help improve our understanding of how the immune tolerance is controlled by STAT3 and how alterations in this molecule can provoke type 1 daibetes.