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/文摘