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

项目 1：STAT3 GOF 对免疫细胞信号传导的功能影响

基本信息

批准号：
10328101
负责人：
MEGAN Anne COOPER
金额：
$ 39.38万
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/10328101
关键词：
Affect Animals Antibodies Autoantibodies Autoimmune Autoimmunity B-Lymphocytes Binding Sites CD4 Positive T Lymphocytes CTLA4 gene Celiac Disease Cell physiology Cells ChIP-seq Child Childhood Code Collaborations Cytometry Data Defect Disease Disease model FOXP3 gene Gene Expression Profile Genes Genetic Genetic Transcription Goals Human Human Genetics Imiquimod Immune Immune System Diseases Immune Tolerance Immune response Immunologic Deficiency Syndromes Immunological Models Immunologics Impairment Inflammation Institution Interleukin-17 Janus kinase Laboratories Lead Malignant Neoplasms Mature B-Lymphocyte Mendelian disorder Modeling Molecular Mus Neutrophil Infiltration Pathway interactions Patients Peripheral Peripheral Blood Mononuclear Cell Phage Display Phage ImmunoPrecipitation Sequencing Pharmaceutical Preparations Phenotype Population Precision therapeutics Predisposition Production Proteome Psoriasis Regulatory T-Lymphocyte Risk STAT3 gene Sampling Signal Transduction Skin Syndrome System T cell response T-Lymphocyte Techniques Thymus Gland Variant Work adaptive immune response base cancer risk cell type cytopenia early onset exome sequencing gain of function high dimensionality interest interleukin-22 kinase inhibitor loss of function mouse model novel organ growth peripheral blood personalized medicine response single-cell RNA sequencing targeted treatment treatment comparison

项目摘要

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.

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。