Systems Approach to Immunity and Inflammation

免疫和炎症的系统方法

基本信息

批准号：
10291571
负责人：
Richard J Ulevitch
金额：
$ 188.73万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2020-11-24 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10291571
关键词：
Antiviral Response Architecture Bioinformatics C-Type Lectins Cells Collaborations Communicable Diseases Communities Complex Computer Analysis Data Disease Gene Proteins Genes Genomics Goals Host Defense Human Immune Immune response Immune signaling Immune system Immunity Immunologic Receptors Individual Infection Inflammation Inflammatory Influenza Informatics Innate Immune Response Interferon Type I Interferons Invaded Knowledge Laboratories Ligands Link Mediating Molecular Multiplexed Ion Beam Imaging Mus Mutant Strains Mice Orthologous Gene Output Pathogenesis Pathway interactions Pattern recognition receptor Pharmaceutical Preparations Proteomics Reagent Receptor Signaling Regulation Regulator Genes Resources Role Signal Pathway Signal Transduction Streptococcus pneumoniae System Systems Biology Toll-like receptors Ursidae Family Vaccine Design Work combat data management epigenomics forward genetics genetic approach human disease immunoregulation in vivo innate immune function large scale data macrophage member microorganism molecular phenotype new technology novel strategies pathogen phenotypic data program dissemination programs receptor response single cell analysis superinfection tool transcriptomics

项目摘要

Summary The innate immune response is a double-edged sword; it is absolutely required for host defense, but unregulated, causes inflammatory disease. Diverse and potent mechanisms have evolved to recognize and counter invading microorganisms. These include a variety of pattern recognition receptors, including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), Nod-like receptors (NLRs) and C-type lectin like receptors (CLRs) that recognize conserved molecular motifs on pathogens. While significant progress has been made in identifying the ligands detected by these receptors and the signaling cascades that they activate, a number of critical questions regarding the mechanisms that appropriately tailor the outputs of these pathways remain unanswered. Furthermore, the immune response to live pathogens is shaped by the interaction of multiple receptors and their cognate signaling pathways. The aggregate response is complex and cannot be predicted from analysis of each pathway in isolation; however, it is tractable using the tools of systems biology and forward genetics. Over the past 15 years members of this U19 consortium have collaborated using cross-disciplinary approaches to define the molecular mechanisms underlying the regulation of immune receptors and pathways. Their genetic approaches have also linked the pathways to pathogenesis and to immunity in vivo. These studies have also generated a significant body of work demonstrating cross-regulation between innate immune receptors. This U19 consists of two interrelated Projects that probe the innate immune response to infection. In Project 1, the Beutler laboratory will work in close collaboration with the Aderem, Nolan, and Ulevitch laboratories, taking a highly automated forward genetic approach to the analysis of innate immune signaling. In Project 2, the Aderem laboratory will determine mechanisms by which the TLR and type I interferon pathways cross-regulate each other. The Projects will be supported by three scientific Cores: The Signaling Core, will bring to bear several novel technologies for highly multiplexed molecular phenotyping of immune cells. The Data Management and Bioinformatics Core will support the individual Projects as well as the overall goals of the program through integrated computational analysis of all large-scale datasets. The Human Correlation Core will examine the relevance of mouse genes, demonstrated in Projects 1 and 2 to mediate innate immune functions, in the analogous human pathways.

概括先天免疫反应是一把双刃剑。这对于宿主防御来说是绝对必要的，但是不受调节，导致炎症性疾病。已经发展出多种有效的机制来识别和对抗入侵的微生物。其中包括多种模式识别受体，包括 Toll 样受体受体 (TLR)、RIG-I 样受体 (RLR)、Nod 样受体 (NLR) 和 C 型凝集素样受体（CLR）识别病原体上的保守分子基序。虽然已经取得了重大进展识别这些受体检测到的配体以及它们激活的信号级联，许多关于适当调整这些途径的输出的机制的关键问题仍然存在无人回答。此外，对活病原体的免疫反应是由多种受体和他们的同源信号通路。总体响应很复杂，无法通过分析进行预测每个路径都是孤立的；然而，使用系统生物学和正向遗传学工具可以轻松处理它。在过去 15 年里，这个 U19 联盟的成员使用跨学科方法进行合作定义免疫受体和途径调节的分子机制。他们的遗传方法还将这些途径与发病机制和体内免疫联系起来。这些研究还开展了大量工作，证明先天免疫之间的交叉调节受体。该 U19 由两个相互关联的项目组成，旨在探索对感染的先天免疫反应。在项目1中， Beutler 实验室将与 Aderem、Nolan 和 Ulevitch 实验室密切合作，用于分析先天免疫信号的高度自动化的正向遗传方法。在项目2中， Aderem 实验室将确定 TLR 和 I 型干扰素途径交叉调节的机制彼此。这些项目将得到三个科学核心的支持：信号核心，将发挥作用几种用于免疫细胞高度多重分子表型分析的新技术。数据管理和生物信息学核心将支持各个项目以及项目的总体目标通过对所有大规模数据集的综合计算分析来编程。人类关联核心将检查项目 1 和 2 中演示的小鼠基因与介导先天免疫的相关性功能，在类似的人类途径中。