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：
10576382
负责人：
MEGAN Anne COOPER
金额：
$ 40.37万
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/10576382
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 Heterozygote Human Human Genetics IL17 gene Imiquimod Immune Immune System Diseases Immune Tolerance Immune response Immunologic Deficiency Syndromes Immunological Models Immunologics Impairment Inflammation Institution Janus kinase Laboratories 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 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 synergism 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.

项目摘要/摘要原发性免疫失调综合征是影响免疫耐受性的罕见单基因疾病并导致早期发作的免疫缺陷，自身免疫性和恶性肿瘤的风险。 STAT3功能收益（GOF）综合征最近被描述为一种原发性免疫失调综合征，引起早发作聚自动免疫和淋巴增生。虽然我们对Stat3的遗传基础有很好的了解 GOF综合征，免疫失调和相关细胞类型的潜在机制应为针对疾病治疗的目标还不太清楚。我们假设STAT3 GOF引线中T细胞的失调失调疾病，这是一种可用于治疗的相关细胞类型。我们将研究这一假设与Drs合作。安德森和马森通过深入询问患者的免疫反应 STAT3 GOF并使用新的小鼠疾病模型。该项目的长期目标是了解如何 STAT3 GOF失去免疫耐受性，以更好地了解免疫耐受的机制在人类中，并提供个性化和精确的治疗，以治疗这种和其他罕见的免疫学童年的疾病。在这个项目中，我们将通过以下方式研究免疫失调的机制 STAT3中改变功能和询问的免疫细胞信号的变体，该信号由STAT3 GOF改变使用测序技术利用STAT3 GOF的鼠模型中的主要患者样品和细胞； 2）使用广泛的方法从患者样品中识别出新的自身抗体； 3）调查 STAT3 GOF小鼠皮肤炎症的模型，以确定疾病模型中相关细胞类型和询问对JAK抑制的反应。