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.

项目总结/摘要 系统性红斑狼疮（SLE）是以多器官损害为特征的慢性自身免疫性疾病 炎症，由于对自身抗原的耐受性丧失和抗核抗体的产生， 激活的自身反应性B细胞。迄今为止，SLE的确切病因尚未得到很好的表征。没有 目前的治疗集中在控制症状和最大限度地减少突然发作。鉴定 新的治疗靶点可以极大地改善这种疾病的治疗前景， 已经有几十年了。 近年来，全基因组关联研究（GWAS）已被用于确定遗传风险因素， SLE。有趣的是，通过GWAS鉴定的大多数单核苷酸多态性（SNP）位于非编码区。 区域，其中一些发现于知之甚少的调节元件，称为长非编码RNA （lncRNA）。我们的实验室在鉴定和表征与人类相关的lncRNA方面有着丰富的经验。 炎症性疾病，在目前的研究中，我们提出了一种新的SLE相关lncRNA的特征， 我们命名为lnc 12我们的初步研究表明，lnc 12在germ中高表达， 中心B细胞，并似乎调节已知在SLE进展期间失调的基因子集。作为 通过GWAS确定，lnc 12与SLE相关的SNP单倍型块重叠，包括高度的 相关SNP，rs 4917014，其与SLE的易感性、细胞因子水平和临床特征相关。 rs 4917014 SNP已被其他研究小组研究，以研究其对邻近基因Ikaros家族的潜在影响。 锌指1（IKZF 1），其编码关键的B细胞转录因子Ikaros。IKZF 1表达增加 在SLE患者中有报道，有趣的是，我们观察到lnc 12可以与该基因结合， IKZF 1的启动子和3 'UTR，以及转录机制和剪接体复合物的成员。 我们假设lnc 12通过对IKZF 1的影响调节B细胞中的基因表达， 在lnc 12表达中，例如由于SLE相关的rs 4917014 SNP，可能失调IKZF 1表达， 有助于SLE发病机制。在目标1中，我们将探索人类lnc 12影响的分子机制 IKZF 1活性。在目的2中，我们将研究lnc 12在B细胞发育和活化中的生理作用， 在SLE的小鼠模型中体内。