Low density neutrophils and lupus

低密度中性粒细胞和狼疮

基本信息

批准号：
10743175
负责人：
Carol F Webb
金额：
$ 36.25万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
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：
2022-12-08 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10743175
关键词：
ATAC-seq Affect Antigen-Antibody Complex Autoantibodies Autoimmune Autoimmune Diseases B-Cell Development B-Lymphocytes Binding Sites Blood Cells Cell Line Cells Characteristics Chemotaxis Chromatin Clinical Clinical Trials Co-Immunoprecipitations Complex Cytokine Signaling DNA-Binding Proteins Data Dendritic Cells Development Disease Epigenetic Process Exhibits Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Goals Growth Factor Heterogeneity Human Herpesvirus 4 Immune response Impairment Individual Inflammatory Interferon alpha Kidney Knowledge Laboratories Lupus Maintenance Mass Spectrum Analysis Mediator MicroRNAs Pathogenesis Pathogenicity Pathway interactions Patients Phagocytosis Phenotype Predisposition Production Proteins Publishing Receptor Signaling Regulatory Pathway Sorting Symptoms Systemic Lupus Erythematosus Technology Testing Tissue-Specific Gene Expression Transgenic Mice Treatment Protocols Validation body system constitutive expression cytokine density differential expression effective therapy experimental study extracellular granulocyte indexing individual patient inhibitor neutrophil new therapeutic target novel overexpression pathogen posttranscriptional protein expression success therapeutic target transcriptome sequencing

ATAC-seq Affect Antigen-Antibody Complex Autoantibodies Autoimmune Autoimmune Diseases B-Cell Development B-Lymphocytes Binding Sites Blood Cells Cell Line Cells Characteristics Chemotaxis Chromatin Clinical Clinical Trials Co-Immunoprecipitations Complex Cytokine Signaling DNA-Binding Proteins Data Dendritic Cells Development Disease Epigenetic Process Exhibits Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Goals Growth Factor Heterogeneity Human Herpesvirus 4 Immune response Impairment Individual Inflammatory Interferon alpha Kidney Knowledge Laboratories Lupus Maintenance Mass Spectrum Analysis Mediator MicroRNAs Pathogenesis Pathogenicity Pathway interactions Patients Phagocytosis Phenotype Predisposition Production Proteins Publishing Receptor Signaling Regulatory Pathway Sorting Symptoms Systemic Lupus Erythematosus Technology Testing Tissue-Specific Gene Expression Transgenic Mice Treatment Protocols Validation body system constitutive expression cytokine density differential expression effective therapy experimental study extracellular granulocyte indexing individual patient inhibitor neutrophil new therapeutic target novel overexpression pathogen posttranscriptional protein expression success therapeutic target transcriptome sequencing

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项目摘要

Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organ systems and for which current treatments are toxic and impair immune responses to pathogens, so new treatment regimens are needed. Identification of new therapeutic targets is complicated by a lack of understanding of the mechanisms that cause SLE. ARID3a is a DNA-binding protein that can alter gene expression both at the transcription level, and by contributing to epigenetic landscapes. We found that ARID3a protein is expressed in low density neutrophils (LDNs) of SLE patients, but not in LDNs from healthy controls, and ARID3a expression was associated with production of the inflammatory cytokine, interferon alpha (IFNα) in the same cells. Surprisingly, increased numbers of ARID3a+ LDNs are more significantly associated with increased disease activity indices (SLEDAI scores; R2=0.65) in SLE patients than were numbers of IFNα-producing LDNs. These data suggest that ARID3a-expressing LDNs contribute to disease activity in SLE through other mechanisms than IFNα production. Our previous data suggested that ARID3a protein expression was associated with differential gene expression patterns in LDNs. We hypothesize that ARID3a-associated gene dysregulation contributes to SLE disease pathogenesis. Therefore, our first aim is to define binding sites for ARID3a near differentially expressed genes and accessible epigenetic domains in SLE. The second specific aim will directly test known functions of LDNs to define which of those functions require ARID3a expression and which may be inhibited with ARID3a-specific inhibitors. Finally, we found that ARID3a expression in LDNs is not regulated at the level of transcription, perhaps explaining why ARID3a has not been previously identified through elegant RNA-seq studies as potential driver of pathogenesis in SLE LDNs. Our third aim will determine how ARID3a protein expression is induced in LDNs. Our published and preliminary data support the idea that ARID3a contributes to, or is a consequence of, disease activity in SLE and that inhibition of ARID3a decreases autoimmune symptoms. These experiments will fill important gaps in our understanding of how ARID3a is associated with SLE and will define functions and genetic pathways that may serve as new therapeutic targets for this devastating disease.

抽象的全身性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，影响多器官系统并且目前的治疗是有毒的，并且会损害病原体的免疫调查，因此新治疗需要方案。由于缺乏了解引起SLE的机制。 ARID3A是一种DNA结合蛋白，可以改变基因表达转录水平，以及有助于表观遗传景观。我们发现ARID3A蛋白在 SLE患者的低密度嗜中性粒细胞（LDN），而不是来自健康对照的LDN和ARID3A表达与同一细胞中炎症细胞因子，干扰素α（IFNα）的产生有关。令人惊讶的是，增加的ARID3A+ LDN数量与疾病增加更明显 SLE患者的活性指数（SLEDAI评分； R2 = 0.65）比产生IFNα的LDN的数量。这些数据表明，表达ARID3A的LDN通过其他机制有助于SLE的疾病活动比IFNα产生。我们先前的数据表明ARID3A蛋白表达与 LDN中的差异基因表达模式。我们假设ARID3A相关的基因失调有助于SLE疾病发病机理。因此，我们的第一个目的是在附近定义ARID3A的绑定位点 SLE中差异表达的基因和可访问的表观遗传结构域。第二个特定目标将直接测试LDN的已知功能以定义哪些功能需要ARID3A表达，哪些可能是用ARID3A特异性抑制剂抑制。最后，我们发现LDN中的ARID3A表达不受调节转录水平，也许解释了为什么以前尚未通过优雅识别ARID3A RNA-seq研究是SLE LDN中发病机理的潜在驱动力。我们的第三个目标将决定ARID3A如何蛋白表达在LDN中诱导。我们已发布和初步数据支持ARID3A的想法促成SLE中疾病活性的贡献，并且抑制ARID3A的抑制作用下降自身免疫性症状。这些实验将填补我们对ARID3A的理解的重要空白与SLE相关并将定义可能用作新治疗靶标的功能和遗传途径对于这种毁灭性疾病。