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.

项目概要/摘要 系统性红斑狼疮（SLE）是一种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而导致 迄今为止，SLE 的确切病因尚未明确。 SLE 的治愈方法和当前的治疗方法侧重于控制症状和最大限度地减少发作。 新的治疗目标可以极大地改善这种进展甚微的疾病的治疗前景 已经几十年了。 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 不为人所知，大多数通过 GWAS 鉴定的单核苷酸多态性 (SNP) 存在于非编码区。 区域，其中一些发现于人们知之甚少的调控元件中，称为长非编码 RNA （lncRNA）。我们的实验室在识别和表征与人类相关的 lncRNA 方面拥有丰富的经验。 炎症性疾病，在当前的研究中，我们建议表征一种新的 SLE 相关 lncRNA， 我们将其命名为lnc12。我们的初步研究表明lnc12在生发细胞中高度表达。 中心 B 细胞，似乎调节已知在 SLE 进展过程中失调的基因子集。 通过 GWAS 确定，lnc12 与 SLE 相关的 SNP 单倍型块重叠，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。 其他小组已经研究了 rs4917014 SNP 对邻近基因 Ikaros 家族的潜在影响 锌指 1 (IKZF1)，编码关键的 B 细胞转录因子 Ikaros。IKZF1 表达增加。 已在 SLE 患者中报道过，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’UTR，以及转录机制和剪接体复合体的成员。 我们热切地希望 lnc12 通过对 IKZF1 的影响来调节 B 细胞中的基因表达，这会改变 lnc12 表达中，例如由于 SLE 相关的 rs4917014 SNP，可能会失调 IKZF1 表达 在目标 1 中，我们将探讨人类 lnc12 影响的分子机制。 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。 体内系统性红斑狼疮小鼠模型。