Characterizing gene regulatory networks that control gut-associated immunity

表征控制肠道相关免疫的基因调控网络

• 批准号: RGPIN-2017-06427
• 负责人: Rast, Jonathan
• 金额: $ 1.89万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=681398
• 关键词: Characterizing; gene; regulatory; networks; control

We have analyzed immune diversity in genome sequences from a variety of animal phyla and find that different organisms have evolved a wide range of solutions to the problem of immune control. These diverse immune systems interface with shared gene regulatory circuitry structure. Characterizing the integration of these rapidly evolving recognition and effector systems with the more conserved core developmental gene regulatory networks, and the functional feedback between the two that maintains immune homeostasis is the focus of our laboratory. ******Rationale: An intact animal model with simple morphology provides a means to address these interactions. The purple sea urchin embryo/larva is a leading model for gene regulatory network biology and provides specific advantages for immune studies. The sea urchin is more closely related to vertebrates than other common invertebrate genetic models and shares an important genetic heritage with vertebrates. Sea urchin larvae are morphologically simple and transparent, which offers an unparalleled ability to visualize immune response at the resolution of individual cells. Furthermore, the transgenesis and gene perturbation techniques that are necessary for regulatory investigations can be performed with high efficiency.******Background: We have developed a novel model for characterization of the gut-associated immune response. After exposure to Vibrio diazotrophicus, larvae exhibit a robust, organism-wide response that involves the gut epithelium, immune cells and other tissues. The system returns to a quiescent state once bacteria are removed, allowing the study of both initiation and resolution of response. These events are accompanied by extensive changes in gene activity that we have thoroughly profiled using RNA-Seq. This model provides opportunities to mechanistically address problems of relevance to vertebrate inflammation, lineage-specific immune innovations and more general questions of immune system evolution. Here we will address the gene regulatory network connections that coordinate the larval gut-associated immune response, and how these feed into systems that maintain and renew immune cells.******PROJECT AIMS***1. Immune gene activity in the gut epithelium and control of IL17 in the initiation of response. ***2. Analysis of parallel and downstream regulatory inputs across response genes.******Significance and impact: A highly detailed understanding of animal immunity has only been achieved in vertebrates and arthropods. This work will lead towards a comprehensive view of the immune system in a third phylum. In doing so, it will broaden our view of animal immunology and identify regulatory interactions among gene homologs with direct relevance to vertebrates. In addition it will contribute to several areas of practical import such as aquaculture and the discovery of novel evolutionary innovations in microbial control strategies.

我们分析了来自各种动物门的基因组序列中的免疫多样性，发现不同的生物体已经进化出了广泛的免疫控制问题的解决方案。这些不同的免疫系统与共享的基因调控电路结构相互作用。表征这些快速发展的识别和效应系统与更保守的核心发育基因调控网络的整合，以及两者之间维持免疫稳态的功能反馈是我们实验室的重点。** 依据：具有简单形态的完整动物模型提供了解决这些相互作用的方法。紫海胆胚胎/幼虫是基因调控网络生物学的领先模型，为免疫研究提供了特定的优势。海胆与脊椎动物的关系比其他常见的无脊椎动物遗传模型更密切，并与脊椎动物共享重要的遗传遗产。海胆幼虫的形态简单而透明，这提供了一种无与伦比的能力，可以在单个细胞的分辨率下可视化免疫反应。此外，可以高效地进行监管调查所需的转基因和基因干扰技术。**背景：我们已经开发了一种新的模型来表征肠道相关的免疫反应。在暴露于重氮营养弧菌后，幼虫表现出强烈的，涉及肠道上皮，免疫细胞和其他组织的生物体范围内的反应。一旦细菌被去除，系统返回到静止状态，允许研究响应的启动和解决。这些事件伴随着基因活性的广泛变化，我们已经使用RNA-Seq进行了彻底的分析。该模型提供了机会，以机械地解决与脊椎动物炎症，谱系特异性免疫创新和免疫系统进化的更一般的问题。在这里，我们将讨论协调幼虫肠道相关免疫反应的基因调控网络连接，以及这些如何进入维持和更新免疫细胞的系统。项目目标 *1.肠上皮中的免疫基因活性和IL 17在应答起始中的控制。***2。跨反应基因的平行和下游调控输入的分析。**意义和影响：对动物免疫的高度详细了解仅在脊椎动物和节肢动物中实现。这项工作将导致对第三门免疫系统的全面看法。这样做，它将拓宽我们的动物免疫学的视野，并确定与脊椎动物直接相关的基因同源物之间的调控相互作用。此外，它将有助于几个实际进口领域，如水产养殖和发现新的微生物控制策略的进化创新。