LncRNA regulation of Type I IFN signaling in intestinal epithelium

摘要 粘膜表面的上皮细胞为宿主抵御病原体感染提供了第一线的防御 胃肠道(GI)。这些上皮细胞是高度受调控的 一种通讯网络，可以将必要的信号传输到胃肠道粘膜下的细胞，进而， 作为粘膜免疫介质的靶标。肠上皮细胞如何协调胃肠道粘膜 防御措施仍然没有完全被理解。LncRNAs是最近发现的长的非编码转录本，可以 通过它们与其他效应分子的相互作用来调节基因转录。我们最近确认了 一组在微生物攻击后在胃肠道上皮细胞中上调的lncRNA。特定的lncRNA 对I型干扰素控制的胃肠道上皮细胞基因转录有显著抑制作用 细胞。有趣的是，一些lncRNA的诱导是由I型干扰素信号控制的。鉴于新兴的 LncRNAs在调节先天和获得性免疫反应中的意义，以及关键 I型干扰素信号在调节胃肠道稳态中的作用，我们推测lncRNAs可能是重要的 胃肠道生理学和病理生理学中的调节剂。在这项研究中，我们假设lncRNA提供 抑制I型干扰素控制基因对I型干扰素信号的负反馈调节 转录，从而有助于微调上皮细胞对微生物的天然防御 感染。我们将使用体外，体外和体内感染模型和补充生化， 用分子和形态方法阐明lncRNAs调控的分子机制 I型干扰素介导的胃肠道上皮细胞基因转录(AIM 1)及确定lncRNA-1的作用 I型干扰素介导的基因转录在胃肠道上皮固有防御(AIM)中的中介反馈调节 2)。因此，这一应用将为lncRNAs调节胃肠粘膜固有功能提供新的机制。 豁免权。阐明lncRNAs对胃肠道上皮细胞关键信号通路的调控可能揭示新的 对胃肠道的分子免疫学和免疫病理学的见解。

Summary Epithelial cells along the mucosal surface provide the front line of host defense against pathogen infection in the gastrointestinal (GI) tract. These epithelial cells represent an integral component of a highly regulated communication network that can transmit essential signals to cells in the underlying GI mucosa that, in turn, serve as targets of mucosal immune mediators. How intestinal epithelial cells orchestrate GI mucosal defense is still not fully understood. LncRNAs are recently identified long non-coding transcripts that can regulate gene transcription through their interactions with other effect molecules. We have recently identified a panel of lncRNAs that are upregulated in GI epithelial cells following microbial challenge. Specific lncRNAs display a significant suppressive effect on Type I interferon (IFN)-controlled gene transcription in GI epithelial cells. Interestingly, induction of some lncRNAs is controlled by Type I IFN signaling. Given the emerging significance of lncRNAs in regulation of both innate and adaptive immune responses, coupled with the key role of Type I IFN signaling in regulating GI homeostasis, we speculate that lncRNAs may be important regulators in GI physiology and pathophysiology. In this study, we hypothesize that lncRNAs provide negative feedback regulation of Type I IFN signaling through suppression of Type I IFN-controlled gene transcription, consequently contributing to fine-tuning of epithelial cell innate defense against microbial infection. We will use in vitro, ex vivo and in vivo infection models and complementary biochemical, molecular, and morphologic approaches to elucidate the molecular mechanisms by which lncRNAs modulate Type I IFN-mediated gene transcription in GI epithelial cells (Aim 1) and determine the role of lncRNA- mediated feedback regulation of Type I IFN-mediated gene transcription in GI epithelial innate defense (Aim 2). Therefore, this application will explore a novel mechanism for lncRNAs in regulating GI mucosal innate immunity. Elucidating the regulation of key signal pathways in GI epithelial cells by lncRNAs may reveal new insights into the molecular immunology and immunopathology of the GI tract.