Low density neutrophils and lupus

低密度中性粒细胞和狼疮

• 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
• 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

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.

摘要 系统性红斑狼疮是一种累及多器官系统的复杂自身免疫性疾病 目前的治疗方法是有毒的，会损害对病原体的免疫反应，因此新的治疗方法 需要有治疗方案。新治疗靶点的鉴定由于缺乏对靶点的了解而变得复杂。 导致SLE的机制。ARID 3a是一种DNA结合蛋白，可以改变基因表达， 转录水平，并有助于表观遗传景观。我们发现ARID 3a蛋白在大肠杆菌中表达， SLE患者的低密度中性粒细胞（LDN），而不是来自健康对照的LDN， 与相同细胞中炎性细胞因子干扰素α（IFNα）的产生有关。 令人惊讶的是，ARID 3a + LDN数量的增加与疾病的增加更显著相关。 活动指数（SLEDAI评分; R2=0.65）高于IFNα产生LDN的数量。这些 数据表明，表达ARID 3a的LDN通过其他机制促进SLE的疾病活动 比IFNα产量高。我们以前的数据表明，ARID 3a蛋白表达与 LDN中的差异基因表达模式。我们假设ARID 3a相关基因失调 有助于SLE疾病的发病机制。因此，我们的第一个目标是确定ARID 3a的结合位点， SLE中的差异表达基因和可及表观遗传结构域。第二个具体目标将直接 测试LDN的已知函数，以定义这些函数中的哪些需要ARID 3a表达式，哪些可以 用ARID 3a特异性抑制剂抑制。最后，我们发现ARID 3a在LDNs中的表达在 转录水平，也许可以解释为什么ARID 3a以前没有通过优雅的 RNA-seq研究是SLE LDN发病机制的潜在驱动因素。我们的第三个目标将决定ARID 3a 在LDN中诱导蛋白表达。我们发表的和初步的数据支持ARID 3a的想法， 有助于SLE的疾病活动性，或者是SLE疾病活动性的结果，并且ARID 3a的抑制降低 自身免疫症状这些实验将填补我们理解ARID 3a是如何 与SLE相关，并将定义可能作为新治疗靶点的功能和遗传途径 这种毁灭性的疾病。