STAT3 variants as a rheostat of immune tolerance

项目概要/摘要（总体） 免疫系统的失调可能对健康和福祉产生严重后果。虽然这是 通常是一个复杂的过程，人类遗传学的最新进展允许识别单个基因 与免疫失调密切相关的变异。在这个项目中， 互补的团队将共同努力，进一步揭示杂合突变如何导致获得 STAT3基因的功能活性（GOF）的降低可强烈地易感疾病。此外，通过我们的努力， 我们希望发现潜在的新方法来扭转这一缺陷。该项目将有三个高度 由Megan库珀、Mark安德森和Alex Marson博士领导的协作和互动项目 沿着的还有两个科学核心。赠款的主要主题是： 1. STAT3 GOF患者免疫细胞功能障碍的更精确分析 2.使用最先进的动物建模方法来询问触发中的STAT3 GOF突变 皮肤炎症与1型糖尿病 3.利用最先进的CRISPR/Cas9方法来询问STAT3 GOF功能障碍 4.基因修复人类细胞中有缺陷的STAT3的建模方法 这项工作的长期目标是提高我们对STAT3如何作为可调 变阻器来控制免疫耐受和免疫失调。这些研究结果将有助于进一步 完善我们对自身免疫性炎症的理解，并帮助改善其治疗方法， 诊断.

Project Summary/Abstract (Overall) Dysregulation of the immune system can have severe consequences on health and wellbeing. Although this is often a complex process, recent progress in human genetics has allowed for the identification of single gene variants that are strongly associated with immune dysregulation. Here, in this program project grant three complementary teams will be working together to further unravel how heterozygous mutations that lead to gain of function activity (GOF) of the STAT3 gene can strongly predispose to disease. Moreover, through our efforts we hope to discover potential new methods to reverse this defect. This program project will have three highly collaborative and interactive projects headed by Drs. Megan Cooper, Mark Anderson, and Alex Marson along with two scientific cores. The major themes of the grant are: 1. More refined analysis of the immune cell dysfunction in STAT3 GOF patients 2. Using state of the art animal modeling approaches to interrogate STAT3 GOF mutations in triggering skin inflammation and type 1 diabetes 3. Utilizing state of the art CRISPR/Cas9 methods to interrogate STAT3 GOF dysfunction 4. Modeling methods to genetically repair defective STAT3 in human cells The long-term objectives of this work are to improve our understanding of how STAT3 can serve as a tunable rheostat to control immune tolerance and immune dysregulation. Results of these studies will help further refine our understanding of autoimmunity inflammation and help improve methods for its treatment and diagnosis.