Exploring a novel lncRNA regulator of T-cell function

探索 T 细胞功能的新型 lncRNA 调节因子

基本信息

批准号：
10303748
负责人：
Sankar Ghosh
金额：
$ 24.3万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-11 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10303748
关键词：
Adaptive Immune System Alleles Antisense Oligonucleotides Antisense RNA Attention Autoimmune Diseases Backcrossings Binding Binding Sites Biological Biological Process Biology CCL3 gene CRISPR/Cas technology Cell Proliferation Cell physiology Cells Chromatin Code Consumption Coupled Cytokine Gene DNA DNA purification Development Disease Elements Embryonic Development Exhibits Funding Funding Opportunities Genes Genetic Transcription Genome HIV Health Human IL2 gene IL8 gene Immune Immune response Individual Infection Interferon Type II Knock-out Knowledge Maps Mass Spectrum Analysis Mediating Methods Modeling Molecular Mus Nuclear Orthologous Gene Phenotype Physiological Process Production Proteins RNA RNA-Protein Interaction Regulation Role Spleen T-Cell Activation T-Lymphocyte TNF gene Testing Time Transcript Untranslated RNA Update Viral Virus Diseases Virus Replication combat comparative conditional knockout cytokine design experimental study immune activation in vivo in vivo Model interest knock-down lymph nodes mRNA Stability mouse model new therapeutic target novel overexpression prevent scaffold tool transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT Once thought to be a rare exception, it has become apparent over the past decade that long non-coding RNAs (lncRNAs) are quite common. Simply defined as RNA transcripts of more than 200 nt that do not encode proteins, lncRNAs have been shown to be important regulators of a plethora of biological processes, ranging from cellular proliferation to embryonic development. Initial studies have revealed that lncRNAs exert their functions through remarkably diverse mechanisms, acting as molecular scaffolds, guides, decoys and sequestration hubs. Tens of thousands of lncRNAs have been identified in the human and murine genome, but only a comparatively small number of them have been explored functionally. Indeed, it remains unclear how many of these lncRNAs carry out biological functions and how many are mere by-products of regulatory DNA elements. The identification and mechanistic analysis of biologically active lncRNAs is of considerable significance for human health, as such lncRNAs have the inherent potential to become novel therapeutic targets in the treatment of a variety of diseases, including viral infections and auto-immune disorders. The expression levels of thousands of lncRNAs are altered when immune cells are activated or virally infected, but their role in these processes has been investigated only in few instances. This application proposes to define the molecular mechanism that allows an HIV-responsive lncRNA to act as a selective regulator of cytokine levels in activated T cells. This will include a thorough characterization of the cytokine genes regulated by the lncRNA, as well as the identification of its DNA, RNA and protein interaction partners that mediate this function. The results from these experiments will be integrated into an updated model of cytokine regulation during T-cell activation. Additionally, a mouse carrying a conditional knockout allele of a previously unrecognized murine ortholog will be created and used to validate the role of this lncRNA in the function of primary T cells.

项目概要/摘要长链非编码 RNA 曾经被认为是一种罕见的例外，但在过去十年中，这一点已变得显而易见。 (lncRNA) 相当常见。简单定义为超过200 nt的RNA转录本，不编码蛋白质， lncRNA 已被证明是多种生物过程的重要调节因子，从细胞增殖至胚胎发育。初步研究表明，lncRNA 通过以下方式发挥其功能：机制非常多样化，充当分子支架、导向器、诱饵和隔离中心。十人类和小鼠基因组中已鉴定出数千种 lncRNA，但只有相对较小的其中许多已在功能上进行了探索。事实上，目前尚不清楚这些 lncRNA 有多少携带生物学功能以及有多少仅仅是 DNA 调控元件的副产品。身份识别和生物活性lncRNA的机制分析对于人类健康具有重要意义 lncRNA具有成为治疗多种疾病的新治疗靶点的内在潜力，包括病毒感染和自身免疫性疾病。当免疫细胞被激活或病毒感染时，数千个lncRNA的表达水平会发生改变，但它们在这些过程中的作用仅在少数情况下得到研究。本申请建议定义允许 HIV 响应性 lncRNA 作为细胞因子水平的选择性调节剂的分子机制在活化的T细胞中。这将包括对 lncRNA 调节的细胞因子基因的全面表征，以及介导该功能的 DNA、RNA 和蛋白质相互作用伙伴的鉴定。这这些实验的结果将被整合到 T 细胞过程中细胞因子调节的更新模型中激活。此外，携带先前未被识别的小鼠的条件性敲除等位基因的小鼠将创建直向同源物并用于验证该 lncRNA 在原代 T 细胞功能中的作用。