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 系统性红斑狼疮(SLE)是一种以多器官为特征的慢性自身免疫性疾病 由于对自身抗原失去耐受性和产生抗核抗体而引起的炎症 激活的、自身反应的B细胞。到目前为止，SLE的确切病因还没有得到很好的描述。没有 治疗系统性红斑狼疮和目前的治疗方法侧重于控制症状和最大限度地减少突发事件。身份识别 新的治疗靶点可以极大地改善这种进展甚微的疾病的治疗格局。 是几十年来制造出来的。 近年来，全基因组关联研究(GWAS)已被用来识别遗传风险因素 SLE。有趣的是，通过GWAS鉴定的大多数单核苷酸多态(SNPs)位于非编码区 区域，其中一些发现在知之甚少的调控元件中，称为长非编码RNA (LncRNAs)。我们的实验室在鉴定和鉴定与人类相关的lncRNA方面有丰富的经验。 炎症性疾病，在本研究中，我们建议鉴定一种与SLE相关的新的lncRNA， 我们已将其命名为lnc12。我们的初步研究表明，lnc12在生殖细胞中高表达。 以B细胞为中心，似乎调节在SLE进展过程中已知的失调基因的子集。AS 由Gwas确定，lnc12与与系统性红斑狼疮相关的SNP的单倍型块重叠，包括高度 相关的SNP，rs4917014，它与SLE的易感性、细胞因子水平和临床特征有关。 Rs4917014 SNP已经被其他研究小组研究过，以研究对邻近基因Ikaros家族的潜在影响 锌指蛋白1(IKZF1)，编码关键的B细胞转录因子Ikaros。IKZF1基因的高表达 已经在系统性红斑狼疮患者中被报道，有趣的是，我们观察到lnc12可以与该基因结合。 IKZF1的启动子和3‘非编码区，以及转录机制和剪接体复合体的成员。 我们假设lnc12通过对IKZF1的作用来调节B细胞中的基因表达，并且这种变化 在LNC12表达中，例如由于SLE相关的rs4917014 SNP，可能会失调IKZF1的表达，并 参与系统性红斑狼疮的发病。在目标1中，我们将探索人类lnc12影响的分子机制。 IKZF1活动。在目标2中，我们将研究lnc12在B细胞发育和激活中的生理作用。 在系统性红斑狼疮小鼠模型上进行体内实验。