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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

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.

摘要