Project 2: STAT3 as a trigger for T1D

项目 2：STAT3 作为 T1D 的触发因素

• 批准号: 10576386
• 负责人: Mark S Anderson
• 金额: $ 17.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-17 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576386
• 关键词: Acceleration; Adoptive Transfer; Alleles; Animal Model; Animals; Antigens; Autoantibodies; Autoimmune; Autoimmune Diabetes; Autoimmunity; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Survival; Cell surface; Cells; Clinical; Collaborations; Critical Pathways; Defect; Development; Diabetes Mellitus; Disease; Engineering; Epithelium; FOXP3 gene; Family member; Gene Activation; Gene Expression; Genes; Genetic; Genetic Transcription; Hormones; Human; Human Genetics; Immune; Immune Tolerance; Immune system; Inbred NOD Mice; Infiltration; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-6; Knock-in Mouse; Knowledge; Link; MHC Class II Genes; Maps; Mediating; Mendelian disorder; Missense Mutation; Modeling; Mus; Mutation; Natural Immunity; Organ; Pathway interactions; Patients; Phenotype; Phosphorylation; Play; Population; Predisposition; Proliferating; Regulatory T-Lymphocyte; Reporting; Research Personnel; Role; Signal Transduction; Stat3 protein; Study models; Syndrome; T-Lymphocyte; Thymic epithelial cell; Thymus Gland; Time; Tissues; Transcription Factor 3; Validation; Variant; Work; adaptive immunity; central tolerance; cytokine; cytopenia; exome sequencing; gain of function; gain of function mutation; improved; insight; insulin dependent diabetes mellitus onset; insulitis; islet; lymphadenopathy; mouse model; novel; peripheral blood; peripheral tolerance; success; synergism; transcription factor; transmission process

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.

项目总结/摘要 与1型糖尿病发展密切相关的单基因疾病已经被发现， 为解开控制这种疾病的关键途径提供了信息。成功使用此 方法包括AIRE和FOXP 3的研究，这些研究为确定 胸腺和T调节细胞，保持1型糖尿病的检查。在这里，我们将利用最近的知识， STAT 3中的功能获得突变（GOF）与1型糖尿病的发生密切相关， 通过开发一个强大的综合症动物模型。 我们的具体目标是： 目的1：在新型自身免疫性糖尿病小鼠模型中模拟STAT 3 GOF的作用 （NOD.STAT3K392R/+） 目的2：鉴定和表征NOD.STAT3K392R/+缺陷的关键免疫细胞群体 模型和具有相似STAT 3 GOF突变的患者中 目的3：确定在STAT 3 GOF模型中中枢耐受性是如何潜在改变的 这些研究将与PPG项目1（库珀）和3（Marson）密切合作进行，并将 有助于我们更好地理解免疫耐受是如何由STAT 3控制的，以及STAT 3基因的改变是如何影响免疫耐受的。 这种分子可以刺激1型糖尿病。