Exploring the role of a novel autoimmune disease-associated lncRNA in Treg biology

探索一种新型自身免疫性疾病相关 lncRNA 在 Treg 生物学中的作用

基本信息

批准号：
10598708
负责人：
Sankar Ghosh
金额：
$ 24.53万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-10 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10598708
关键词：
Affect Alleles Animals Anti-Inflammatory Agents Antisense RNA Autoimmune Autoimmune Diseases Binding Sites Biological Process Biological Response Modifiers Body Weight decreased Bone Marrow Cell Separation Cell physiology Cells Cellular biology Chimera organism Chromatin Chronic Clinical Colitis Complement Coupled Crohn&apos s disease DNA sequencing Data Development Disease Disease Progression Exhibits Functional disorder Gene Expression Profile Genes Homeostasis Human Immune Immune system Immunity Immunologics Immunosuppression Impairment Inflammation Inflammatory Interleukin-10 Intestines Knockout Mice Lamina Propria Link Maps Mass Spectrum Analysis Modeling Molecular Monitor Mucous Membrane Mus Names Pathology Pattern Phenotype Physiological Predisposition Proliferating Property Proteins RNA Rag1 Mouse Regulatory T-Lymphocyte Role Single Nucleotide Polymorphism Spleen Synteny T-Cell Development T-Lymphocyte T-Lymphocyte Subsets Testing Time Tissue-Specific Gene Expression Tissues Transcript Ulcerative Colitis Untranslated RNA clinically significant cytokine design dextran sulfate sodium induced colitis differential expression effector T cell experimental study genome wide association study gut inflammation human disease in vivo knock-down lymph nodes mouse model new therapeutic target novel novel therapeutic intervention overexpression selective expression transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT Long non-coding RNAs (lncRNAs) are now established as important regulators of diverse biological processes. Tens of thousands of non-coding transcripts have been detected by RNA sequencing, yet only a minute fraction of these have been functionally characterized. LncRNAs are of potential clinical significance, as they are increasingly considered as targets for the development of novel therapeutic approaches. We have established a systematic approach to specifically identify lncRNAs that are likely to be functional regulators of the immune system and that may be involved in inflammatory and autoimmune diseases. This discovery pipeline integrates information from genome-wide association studies (GWAS), evolutionary conservation between mice and humans, and differential expression patterns in immune cells. Using this approach, we have identified a previously unknown human lncRNA, which we have named lnc15. Lnc15 is present in mice and humans, and overlaps with a single-nucleotide polymorphism that has been linked to Crohn’s disease and ulcerative colitis, two severe intestinal auto-immune pathologies. Importantly, we have found that lnc15 is present at high levels in regulatory T cells (Tregs) but only at low levels in other T-cell subsets. We have generated lnc15 knockout mice and, intriguingly, have observed that these animals exhibit exacerbated disease progression in a model of intestinal inflammation. Additionally, Tregs isolated from lnc15-deficient mice are less effective at suppressing the proliferation of naive T cells, whereas overexpression of lnc15 enhances expression of IL-10, an important effector cytokine of Tregs. Based on these observations, we hypothesize that lnc15 is a novel regulator of Treg function. The experiments proposed here will explore this hypothesis by determining how lnc15 affects the Treg transcriptome and identifying its protein and chromatin interaction partners. To evaluate the physiological relevance of lnc15 in vivo, we further propose to utilize Treg-specific models of intestinal inflammation and determine the effect of lnc15 deficiency on T-cell development, differentiation and homeostasis.

项目摘要/摘要长期非编码RNA（LNCRNA）现在被确定为潜水生物学过程的重要调节剂。通过RNA测序检测到数万个非编码转录本，但只有一分钟的分数 LNCRNA具有潜在的临床意义，因为它们是越来越多地被视为开发新型治疗方法的目标。我们已经建立了一种系统的方法，用于识别可能是免疫功能调节剂的LNCRNA 系统，这可能涉及炎症和自身免疫性疾病。该发现管道集成了全基因组关联研究（GWAS）的信息，小鼠与小鼠之间的进化保守性人类和免疫细胞中的差异表达模式。使用这种方法，我们已经确定了以前未知的人类lncRNA，我们将其命名为LNC15。 LNC15存在于小鼠和人类中，以及与克罗恩病和溃疡性结肠炎有关的单核苷酸多态性的重叠，两种严重的肠自身免疫性病理。重要的是，我们发现LNC15高水平存在在调节性T细胞（TREG）中，但仅在其他T细胞子集中低水平。我们已经产生了LNC15淘汰赛小鼠，有趣的是，这些动物在一个模型中表现出恶化的疾病进展肠炎。另外，从LNC15缺乏小鼠中分离出的Tregs在抑制中的有效性较小天真T细胞的增殖，而LNC15的过表达增强了IL-10的表达，这是一个重要的 Tregs的效应细胞因子。基于这些观察结果，我们假设LNC15是Treg的新调节剂功能。这里提出的实验将通过确定LNC15如何影响Treg来探讨这一假设转录组并鉴定其蛋白质和染色质相互作用伙伴。评估生理 LNC15在体内的相关性，我们进一步建议利用Treg特异性肠道注入和确定LNC15缺乏对T细胞发育，分化和稳态的影响。