Deciphering Post-transcriptional gene regulatory networks in cellular stress and innate immunity

破译细胞应激和先天免疫中的转录后基因调控网络

• 批准号: 9141899
• 负责人: Manuel Ascano
• 金额: $ 38.5万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9141899
• 关键词: Affect; Antiviral Response; Autoimmune Diseases; Biological; Biology; Cells; Cellular Stress; Collection; DNA; DNA-Binding Proteins; Detection; Development; Disease; Employee Strikes; Event; Gene Expression; Gene Expression Regulation; Genome; Goals; Health; Human; Immune; Immune response; Immune system; Immunologic Monitoring; Immunologics; Infection; Interferon Type I; Interferons; Knowledge; Laboratories; Lead; Messenger RNA; Mission; Natural Immunity; Nature; Nucleic Acids; Pathway interactions; Pharmaceutical Preparations; Process; Property; Protein Biochemistry; RNA; RNA Viruses; RNA methylation; RNA-Binding Proteins; Reagent; Regulator Genes; Research; Research Proposals; Shapes; Signal Transduction; Staging; Stimulus; Stress; Therapeutic; Training; Up-Regulation; Viral; cytokine; fitness; immune activation; immunogenic; interest; pathogen; prevent; programs; response; scaffold; sensor; small molecule; tool; tumor

PROJECT SUMMARY It is the long-term mission of my lab to decipher the critical regulatory networks that govern post-transcriptional gene regulation during innate immunity with the goal that such knowledge significantly contributes to our scientific understanding of human health and disease. The innate immune system is comprised of a collection of environmental sensors and downstream signaling components that orchestrate a response to cellular insults and stress. A hallmark of innate immune activation is the transcriptional upregulation of the type-I interferons triggered by the sensing of pathogen-associated or damage-associated molecules. Research on innate immunity has traditionally focused on understanding the initiating triggers and signal transduction events that ultimately modulate the expression of a central set of interferons and cytokines. However, much less is known about the post-transcriptional gene regulatory layer, which acts to refine innate immune activation at the RNA level – shaping gene expression to allow for a robust but finite host response while simultaneously preventing aberrant or pathogen-associated gene expression. This is a striking gap in our understanding given that many aspects of host-pathogen interactions have at its core the detection and suppression of foreign nucleic acids. It is becoming increasingly clear that RNA-binding proteins (RBPs) can pre-program the sensitivity of cells to immunogenic stimuli, as well as being essential factors in the anti- viral response. In part, much of the challenge has been an inability to query this layer of gene regulation in a comprehensive and systematic way, a necessary prerequisite when it comes to studying RBP biology. My training and expertise in RNA/DNA binding protein biochemistry and –omic scale biology has allowed me to develop the necessary tools and reagents that I have now established in my laboratory to deeply understand post-transcriptional gene regulation in innate immunity. We are interested in pursuing the following major biological questions: 1)How do RNA-binding proteins regulate gene expression of their targets during an innate immune response? 2)What is the nature and impact of RNA methylation on mRNAs upon interferon/cGAMP stimulation? And how do such changes affect RBP assembly and function? 3) How are the genomes of RNA viruses deployed during the early stages of infection, and what host- or viral-encoded RNA-binding proteins facilitate this process? 4) What are the regulatory co-factors required for the activating or repressing cGAS-STING signaling? and can we identify small molecule compounds for the development of experimental probes and pre- therapeutic scaffolds?

项目摘要 我实验室的长期使命是破译控制转录后的关键调控网络， 先天免疫过程中的基因调控，目标是这些知识显着有助于我们 对人类健康和疾病的科学认识。先天免疫系统由一系列 环境传感器和下游信号组件，协调对细胞损伤的反应， 和压力。先天免疫激活的一个标志是I型干扰素的转录上调 由病原体相关或损伤相关分子的感应触发。先天性研究 免疫学传统上集中于理解起始触发器和信号转导事件， 最终调节一组中心干扰素和细胞因子的表达。然而， 已知转录后基因调控层，其作用是改善先天免疫 在RNA水平上激活-塑造基因表达，以允许强大但有限的宿主反应 同时防止异常或病原体相关的基因表达。这是一个惊人的 鉴于宿主-病原体相互作用的许多方面的核心是检测， 和抑制外源核酸。越来越清楚的是，RNA结合蛋白（RBP） 可以预先编程细胞对免疫原性刺激的敏感性，以及作为抗- 病毒反应在某种程度上，大部分的挑战是无法查询这一层的基因调控， 全面、系统的研究方法，是研究RBP生物学的必要前提。 我在RNA/DNA结合蛋白生物化学和组学规模生物学方面的训练和专业知识 使我能够开发出必要的工具和试剂，我现在已经在我的实验室里建立了， 了解先天免疫中的转录后基因调控。我们有兴趣追求 主要的生物学问题： 1)RNA结合蛋白在先天免疫过程中如何调节靶基因的表达 回应？ 2)干扰素/cGAMP刺激后RNA甲基化对mRNA的性质和影响是什么？和 这些变化如何影响RBP的组装和功能？ 3)在感染的早期阶段，RNA病毒的基因组是如何部署的？ 病毒编码的RNA结合蛋白促进了这一过程？ 4)激活或抑制cGAS-STING信号传导所需的调节辅因子是什么？和 我们能否识别小分子化合物，用于开发实验探针和预处理， 治疗支架