Project 1: Functional consequences of STAT3 GOF on immune cell signaling

项目总结/摘要 原发性免疫失调综合征是一组罕见的影响免疫耐受的单基因疾病 并导致早发性免疫缺陷、自身免疫和恶性肿瘤的风险。STAT 3功能增益 (GOF)综合征最近被描述为一种原发性免疫失调综合征， 多种自身免疫和淋巴增生。虽然我们对STAT 3的遗传基础有了很好的了解， GOF综合征，免疫失调的潜在机制和相关的细胞类型，应该是 用于治疗疾病的靶点不太清楚。我们假设STAT 3 GOF中T细胞的失调导致了 这是一种可以作为治疗靶点的相关细胞类型。我们将调查这一假设 与安德森博士和马森博士合作，通过深入询问患者的免疫反应， STAT 3 GOF和使用新的疾病小鼠模型。这个项目的长期目标是了解如何 STAT 3 GOF使免疫耐受丧失，以更好地理解免疫耐受的机制 并为治疗这种和其他罕见的免疫性疾病提供个性化和精确的治疗。 儿童疾病。在这个项目中，我们将研究免疫失调的机制：1）识别 STAT 3中改变功能和询问被STAT 3 GOF改变的免疫细胞信号的变体 使用测序技术使用来自STAT 3 GOF的鼠模型的原代患者样品和细胞; 2） 使用基础广泛的方法从患者样品中鉴定新的自身抗体;和3）研究 在STAT 3 GOF小鼠中建立皮肤炎症模型以确定疾病模型中的相关细胞类型， 询问对JAK抑制的反应。

Project Summary/Abstract Primary immune dysregulation syndromes are group of rare monogenic disorders affecting immune tolerance and leading to early-onset immunodeficiency, autoimmunity, and risk of malignancy. STAT3 gain-of-function (GOF) syndrome was recently described as a primary immune dysregulation syndrome causing early-onset polyautoimmunity and lymphoproliferation. While we have a good understanding of the genetic basis of STAT3 GOF syndrome, the underlying mechanisms of immune dysregulation and relevant cell types that should be targeted for therapy of disease are less clear. We hypothesize that dysregulation of T cells in STAT3 GOF leads to disease and that this is a relevant cell type that can be targeted for therapy. We will investigate this hypothesis in collaboration with Drs. Anderson and Marson by deeply interrogating the immune response in patients with STAT3 GOF and using new mouse models of disease. The long-term goals of this project are to understand how immune tolerance is lost with STAT3 GOF to gain a better understanding of mechanisms of immune tolerance in humans and provide personalized and precision therapy for the treatment of this and other rare immunologic diseases of childhood. In this project we will investigate mechanisms of immune dysregulation by: 1) identifying the variants in STAT3 that alter function and interrogating immune cells signals that are altered by STAT3 GOF using primary patient samples and cells from murine models of STAT3 GOF using sequencing techniques; 2) Identifying novel autoantibodies from patient samples using a broad-based approach; and 3) Investigating a model of skin inflammation in STAT3 GOF mice to determine relevant cell types in a disease model and interrogate the response to JAK inhibition.