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LncRNA regulation of Type I IFN signaling in intestinal epithelium

LncRNA 对肠上皮 I 型 IFN 信号传导的调节

基本信息

批准号：
10321685
负责人：
Xian-Ming Chen
金额：
$ 19.63万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-23 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321685
关键词：
Address Anti-Inflammatory Agents Biochemical Biochemistry Biological Response Modifiers Biology Cell physiology Cells Cellular biology Communication Coupled Cryptosporidium parvum DNA Data Development Effector Cell Epithelial Epithelial Cells Family Feedback Foundations Functional disorder Future Gastrointestinal Physiology Gastrointestinal tract structure Genes Genetic Transcription Goals Health Homeostasis Host Defense Human Immune Immune response Immunity In Vitro Infection Inflammatory Inflammatory Response Injury Interferon Type I Interferon-alpha Interferons Investigation Ligation Mediating Modeling Molecular Molecular Immunology Molecular Virology Morphology Mucosal Immunity Mucous Membrane Mus Natural Immunity Orthologous Gene Outcome Parasites Pathogenicity Play Production Proteins RNA Regulation Research Role Series Signal Pathway Signal Transduction Site Surface Transcript Untranslated RNA adaptive immune response antimicrobial autocrine chemokine cytokine experience gastrointestinal gastrointestinal epithelium immunopathology immunoreaction in vivo insight intestinal epithelium intestinal homeostasis microbial novel novel therapeutic intervention pathogen receptor response

项目摘要

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.

总结沿着粘膜表面的上皮细胞提供宿主防御病原体感染的前线，胃肠道（GI）。这些上皮细胞代表了一个高度调节的通信网络，可以将基本信号传输到下面的GI粘膜中的细胞，反过来，作为粘膜免疫介质的靶点。肠上皮细胞如何协调GI粘膜防御还没有完全理解。lncRNA是最近鉴定的长非编码转录物，通过与其他效应分子的相互作用来调节基因转录。我们最近发现一组在微生物攻击后在GI上皮细胞中上调的lncRNA。特异性lncRNA 对GI上皮中I型干扰素（IFN）控制的基因转录显示出显著的抑制作用细胞有趣的是，一些lncRNA的诱导受I型IFN信号传导控制。鉴于新兴的 lncRNA在调节先天性和适应性免疫应答中的重要性， 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提供了通过抑制I型IFN控制基因的负反馈调节I型IFN信号传导转录，因此有助于微调上皮细胞对微生物的先天防御感染我们将使用体外，离体和体内感染模型和互补的生化，分子和形态学方法来阐明lncRNA调节的分子机制，胃肠道上皮细胞中I型干扰素介导的基因转录（目的1）并确定lncRNA-的作用 I型IFN介导的基因转录在GI上皮先天防御中的反馈调节（目的 2）的情况。因此，本申请将探索lncRNA在调节GI粘膜先天性免疫应答中的新机制。免疫力阐明lncRNA对GI上皮细胞中关键信号通路的调节可能揭示新的深入了解胃肠道的分子免疫学和免疫病理学。