Project 2: STAT3 as a trigger for T1D

项目 2：STAT3 作为 T1D 的触发因素

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要与 1 型糖尿病的发生密切相关的单基因疾病已被证实为揭示控制这种疾病的关键途径提供了信息。使用此方法的成功示例方法包括对 AIRE 和 FOXP3 的研究，这些研究为确定胸腺和 T 调节细胞可控制 1 型糖尿病。在这里，我们将利用最新的知识 STAT3 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该综合征的稳健动物模型。我们的具体目标是：目标 1：在新型自身免疫性糖尿病小鼠模型中模拟 STAT3 GOF 的作用 (NOD.STAT3K392R/+) 目标 2：识别和表征 NOD.STAT3K392R/+ 中存在缺陷的关键免疫细胞群模型和具有类似 STAT3 GOF 突变的患者目标 3：确定 STAT3 GOF 模型中中心耐受性如何可能发生改变这些研究将与 PPG 项目 1（Cooper）和 3（Marson）密切合作进行，并将有助于提高我们对 STAT3 如何控制免疫耐受以及如何改变免疫耐受的理解该分子可以激发 1 型糖尿病。