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.

项目概要/摘要长非编码 RNA (lncRNA) 现在已被确定为多种生物过程的重要调节因子。 RNA测序已检测到数以万计的非编码转录本，但只有一小部分其中的 LncRNA 已得到功能表征，具有潜在的临床意义。我们已经越来越多地将其视为开发新治疗方法的目标。一种专门识别可能成为免疫系统功能调节因子的 lncRNA 的系统方法该发现管道整合了可能涉及炎症和自身免疫性疾病的系统。来自全基因组关联研究（GWAS）、小鼠和小鼠之间的进化保守性的信息使用这种方法，我们已经确定了人类和免疫细胞中的差异表达模式。以前未知的人类lncRNA，我们将其命名为lnc15，存在于小鼠和人类中，并且与与克罗恩病和溃疡性结肠炎有关的单核苷酸多态性重叠，重要的是，我们发现 lnc15 的水平很高。在调节性 T 细胞 (Treg) 中存在，但在其他 T 细胞亚群中仅存在低水平。我们已经产生了 lnc15 敲除。有趣的是，我们观察到这些动物在小鼠模型中表现出加剧的疾病进展此外，从 lnc15 缺陷小鼠中分离出的 Tregs 在抑制肠道炎症方面效果较差。幼稚 T 细胞的增殖，而 lnc15 的过表达会增强 IL-10 的表达，IL-10 是一种重要的细胞因子。基于这些观察，我们发现lnc15是Treg的新型调节因子。这里提出的实验将通过确定 lnc15 如何影响 Treg 来探索这一假设。转录组并鉴定其蛋白质和染色质相互作用伙伴以评估生理学。 lnc15在体内的相关性，我们进一步建议利用肠道炎症的Treg特异性模型确定 lnc15 缺陷对 T 细胞发育、分化和稳态的影响。