A Novel Long Noncoding RNA Associated with Systemic Lupus Erythematosus Pathogenesis

一种与系统性红斑狼疮发病机制相关的新型长非编码RNA

• 批准号: 10725130
• 负责人: Ruxiao Tian
• 金额: $ 4.77万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725130
• 关键词: 3' Untranslated Regions; Acceleration; Address; Affect; Alleles; Alternative Splicing; Animal Model; Antinuclear Antibodies; Antisense RNA; Autoantigens; B-Cell Activation; B-Cell Development; B-Lymphocytes; Binding; Biological Markers; Body Weight Changes; CRISPR/Cas technology; Cell Culture Techniques; Cell Line; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Complementary DNA; Complex; Coupled; DNA sequencing; Development; Disease; Disease Progression; Disease model; Dominant-Negative Mutation; Drug Targeting; Enzyme-Linked Immunosorbent Assay; Etiology; Exons; Family; Flare; Flow Cytometry; Gene Expression; Genes; Genetic Transcription; Haplotypes; Histology; Human; Immune system; Immunoprecipitation; Infiltration; Inflammation; Inflammatory; Investigation; Investments; Island; Knockout Mice; Knowledge; Life; Link; Maps; Mass Spectrum Analysis; Mature B-Lymphocyte; Mediating; Messenger RNA; Molecular Probes; Monitor; Mus; Names; Organ; Pathogenesis; Patients; Physiological; Plasma Cells; Population; Predisposition; Production; Protein Isoforms; Proteins; RNA; RNA Splicing; Raji Cell; Regulation; Regulatory Element; Reporting; Repression; Research; Risk; Role; Single Nucleotide Polymorphism; Single-Stranded DNA; Site; Small Interfering RNA; Spliceosomes; Structure of germinal center of lymph node; Symptoms; Systemic Lupus Erythematosus; Therapeutic; Tissue-Specific Gene Expression; Transcript; Transcriptional Regulation; Untranslated RNA; Variant; Western Blotting; Zinc Fingers; autoreactive B cell; chronic autoimmune disease; chronic graft versus host disease; conditional knockout; cytokine; design; drug development; experience; genetic risk factor; genome wide association study; genomic locus; improved; in vivo; knock-down; lymphoblastoid cell line; member; mortality; mouse model; new therapeutic target; novel; overexpression; peripheral blood; promoter; recruit; transcription factor

PROJECT SUMMARY/ABSTRACT Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multi-organ inflammation, resulting from loss of tolerance to self-antigens and production of anti-nuclear antibodies by activated, autoreactive B cells. To date, the exact etiology of SLE has not been well characterized. There is no cure for SLE and current treatments focus on controlling symptoms and minimizing flare-ups. Identification of new targets for therapy could greatly improve the therapeutic landscape for a disease for which little progress has been made in decades. In recent years, genome-wide association studies (GWAS) have been used to identify genetic risk factors for SLE. Interestingly, most single nucleotide polymorphisms (SNPs) identified through GWAS reside in non-coding regions, with some found in the poorly understood regulatory elements known as long-noncoding RNAs (lncRNAs). Our lab has significant experience in identifying and characterizing lncRNAs associated with human inflammatory diseases, and in the current study, we propose to characterize a novel SLE-associated lncRNA, that we have named as lnc12. Our preliminary studies have shown that lnc12 is highly expressed in germinal center B cells and appears to regulate a subset of genes known to be dysregulated during SLE progression. As determined by GWAS, lnc12 overlaps with a haplotype block of SNPs associated with SLE, including a highly associated SNP, rs4917014, which has been linked to susceptibility, cytokine levels, and clinical features in SLE. The rs4917014 SNP has been studied by other groups for potential effects on a neighboring gene, Ikaros family zinc finger 1(IKZF1), which encodes the critical B cell transcription factor, Ikaros. Increased expression of IKZF1 has been reported in patients with SLE, and interestingly, we have observed that lnc12 can bind to the gene promoter and 3’UTR of IKZF1, as well as members of the transcription machinery and spliceosome complex. We hypothesize that lnc12 regulates gene expression in B cells through its effects on IKZF1, and that changes in lnc12 expression, e.g. due to the SLE-associated rs4917014 SNP, may dysregulate IKZF1 expression and contribute to SLE pathogenesis. In Aim 1, we will probe the molecular mechanisms by which human lnc12 affects IKZF1 activity. In Aim 2, we will examine the physiological roles of lnc12 in B cell development and activation in vivo in a mouse model of SLE.

项目摘要/摘要 全身性红斑狼疮（SLE）是一种以多器官为特征的慢性自身免疫性疾病 炎症是由于对自我抗原的耐受性丧失以及抗核抗体产生而引起的 激活的自动反应性B细胞。迄今为止，SLE的确切病因尚未得到很好的特征。没有 治愈SLE和当前处理的目的是控制符号并最大程度地减少爆炸。识别 治疗的新靶标可以大大改善这种疾病的治疗景观 几十年来已经制造了。 近年来，全基因组关联研究（GWAS）已被用来确定遗传风险因素 sle。有趣的是，通过GWAS鉴定的大多数单一核苷酸多态性（SNP）都存在于非编码中 区域，其中一些在较了解的调节元件中发现，称为长期编码RNA （lncrnas）。我们的实验室在识别和表征与人相关的lncRNA方面具有丰富的经验 炎症性疾病，在当前的研究中，我们建议表征一种新型SLE相关的LNCRNA， 我们命名为LNC12。我们的初步研究表明，LNC12在生发中高度表达 中心B细胞，似乎调节了SLE进展过程中已知失调的基因子集。作为 由GWAS确定，LNC12与与SLE相关的单倍型SNP重叠，包括高度 相关的SNP，RS4917014，与SLE的易感性，细胞因子水平和临床特征有关。 RS4917014 SNP已由其他组研究，以对邻近基因，Ikaros家族进行潜在影响 锌指1（IKZF1），它编码临界B细胞转录因子Ikaros。 IKZF1的表达增加 已经报道了SLE患者，有趣的是，我们已经观察到LNC12可以与基因结合。 IKZF1的启动子和3'Utr，以及转录机械和剪接体综合体的成员。 我们假设LNC12通过其对IKZF1的作用来调节B细胞中的基因表达，并改变 在LNC12表达中，例如由于SLE相关的RS4917014 SNP，可能会使IKZF1的表达失调，并且 有助于SLE发病机理。在AIM 1中，我们将探测人类LNC12影响的分子机制 IKZF1活动。在AIM 2中，我们将检查LNC12在B细胞发育和激活中的物理作用 SLE鼠标模型中的体内。