Exploring a novel lncRNA regulator of T-cell function

项目总结/摘要 曾经被认为是一个罕见的例外，在过去的十年里，长非编码RNA （lncRNA）是非常常见的。简单定义为不编码蛋白质的超过200 nt的RNA转录物， lncRNA已被证明是多种生物过程的重要调节剂，从细胞内的细胞凋亡到细胞外的细胞凋亡。 增殖到胚胎发育。初步研究表明，lncRNA通过以下途径发挥其功能： 它们具有非常多样的机制，充当分子支架、向导、诱饵和隔离中心。几十 在人类和小鼠基因组中已经鉴定出数千种lncRNA，但只有相对较小的lncRNA。 其中一些已经在功能上进行了探讨。事实上，目前还不清楚这些lncRNA中有多少携带 有多少生物学功能以及有多少仅仅是调节DNA元件的副产品。确定和 生物活性lncRNA的机制分析对于人类健康具有相当大的意义， lncRNA具有成为治疗多种疾病的新型治疗靶点的固有潜力， 包括病毒感染和自身免疫紊乱。 当免疫细胞被激活或病毒感染时，数千种lncRNA的表达水平发生改变， 但它们在这些过程中的作用仅在少数情况下得到调查。本申请建议定义 允许HIV应答性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细胞中这将包括由lncRNA调节的细胞因子基因的彻底表征， 以及鉴定其介导该功能的DNA、RNA和蛋白质相互作用伙伴。的 这些实验的结果将被整合到T细胞增殖过程中细胞因子调节的更新模型中。 activation.此外，携带先前未识别的鼠基因的条件性敲除等位基因的小鼠， 将产生直系同源物并用于验证该lncRNA在原代T细胞功能中的作用。

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.