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Role of the transcription factor Ikaros in development of autoimmune disease

转录因子 Ikaros 在自身免疫性疾病发展中的作用

基本信息

批准号：
10408036
负责人：
Seth E Frietze
金额：
$ 39.54万
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：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408036
关键词：
Affect Age American Antibodies Antigens Antinuclear Antibodies Autoantibodies Autoimmune Autoimmune Diseases Autoimmune Process Autoimmunity B-Cell Activation B-Lymphocytes Biological Assay Cell Lineage Cell Maturation Cells Chronic DNA Binding Data Defect Development Disease Ensure Environmental Risk Factor Epigenetic Process Etiology Exons Flow Cytometry Future Gene Expression Genes Genetic Predisposition to Disease Genetic Transcription Goals Health Human Immune Immune Tolerance Investigation Knowledge Lead Link LoxP-flanked allele Mature B-Lymphocyte Mediating Modeling Molecular Mus Mutant Strains Mice Mutate Mutation Pathogenesis Patients Phenotype Proteins Regulator Genes Reporting Research Research Design Role Serum Signal Pathway Signal Transduction Specificity Symptoms System TNFSF5 gene Testing United States Zinc Fingers autoreactive B cell autoreactivity cell type central tolerance chronic autoimmune disease clinically relevant epigenetic regulation gene repression genetic variant genome wide association study genomic locus improved in vivo insight mouse model mutant mutant mouse model novel prevent programs public health relevance response targeted treatment tool transcription factor transcriptomics

项目摘要

ABSTRACT Autoimmune diseases are chronic and often disabling illnesses that affect millions of Americans. Current treatments help to prevent the symptoms of autoimmune disease, but there are no cures. Autoimmune disease is thought to be due to a combination of genetic predispositions and environmental factors, but the etiology is not fully understood. In order to develop new and improved treatments, and to potentially find a cure, a better understanding of the underlying molecular mechanisms of autoimmune disease is essential. Using a newly established strain of mutant mice, we found that a small targeted deletion in the gene encoding the transcription factor Ikaros, resulted in a profound defect in immune tolerance, with high levels of autoreactive antibodies in the serum of very young mice. Antibodies are produced by B cells, and the presence of autoreactive antibodies indicates that Ikaros is necessary to control how B cells respond to antigen and to ensure tolerance to self. A role for Ikaros in human autoimmune disease is supported by recent genome-wide association studies (GWAS), where genetic variants in the Ikaros gene locus (IKZF1) have been linked to several autoimmune diseases. Furthermore, recent studies have reported patients with autoimmune disease that carry IKZF1 mutations. We propose to employ our Ikaros-mutant mice as a new model of autoimmunity to investigate the molecular mechanisms underlying the break of tolerance in Ikaros-mutated B cells. We have preliminary data suggesting that Ikaros regulates two distinct stages of B-cell maturation that are critical for proper tolerance: The central tolerance checkpoint and the requirement for costimulatory signal upon Ag encounter in the periphery. We will use this mouse model to directly test the hypothesis that Ikaros limits autoreactive B cells by enforcing central tolerance and establishing a requirement for the “second signal” (indicating danger) through epigenetic mechanisms. Accordingly, our study design is focused on an understanding of central tolerance and B-cell autoreactivity, using a combination of in vivo and ex vivo approaches. to directly assess the gene expression, epigenetic and signaling pathways associated with proper versus aberrant B cell activation. Specifically, we will investigate the role of Ikaros in BCR signaling and establishment of central tolerance (Aim 1). We will employ our Ikaros-mutant model to investigate the role of Ikaros in the molecular mechanisms regulating mature B-cell response to antigen (Aim 2). Lastly, we will examine the B-cell intrinsic, as well as the relative extrinsic contributions and roles of different immune cell lineages in the observed break of B-cell tolerance (Aim 3).

摘要