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

项目总结 破译管理转录后基因的关键调控网络是我的实验室的长期使命。 先天免疫过程中的基因调控，其目标是这些知识对我们的 对人类健康和疾病的科学认识。先天免疫系统由一个集合组成 环境传感器和下游信号组件协调对细胞侮辱的反应 和压力。先天免疫激活的一个标志是I型干扰素转录上调。 由病原体相关或损伤相关分子的感应触发。关于先天的研究 传统上，免疫侧重于理解启动触发和信号转导事件 最终调节一组干扰素和细胞因子的表达。然而，更少的是 已知转录后基因调节层，它起到完善先天免疫的作用 RNA水平的激活-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。这是一个引人注目的 我们理解上的差距，因为宿主-病原体相互作用的许多方面都以检测为核心 和抑制外源核酸。越来越清楚的是，RNA结合蛋白(RBPs) 可以预先编程细胞对免疫原性刺激的敏感性，也是抗 病毒反应。在某种程度上，挑战很大程度上是无法质疑这一层的基因调控 全面系统的方法，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基因组规模生物学方面的培训和专业知识 使我能够开发必要的工具和试剂，我现在已经在我的实验室建立了深入的 了解先天免疫中转录后基因的调控。我们有兴趣追求 以下是主要的生物学问题： 1)在先天免疫过程中，rna结合蛋白如何调节靶基因的表达？ 有什么反应？ 2)在干扰素/cGAMP刺激下，RNA甲基化对mRNAs的性质和影响是什么？和 这样的变化如何影响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，以及什么宿主-或 病毒编码的RNA结合蛋白促进了这一过程吗？ 4)激活或抑制cGAS-STING信号需要哪些调节辅助因子？和 我们能否识别小分子化合物以用于开发实验探针和预 治疗性脚手架？

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?