Systems Approach to Immunity and Inflammation

免疫和炎症的系统方法

基本信息

批准号：
8893876
负责人：
Richard J Ulevitch
金额：
$ 632.44万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8893876
关键词：
Agonist Animals Biological Response Modifiers Breeding Cells Code Communicable Diseases Communities Complex DNA Sequence Data Data Set Defect Dendritic Cells Discipline Disease Ethylnitrosourea Genes Genetic Goals Host Defense Human Immune Immune response Immune system Immunity Immunologist In Vitro Induced Mutation Infection Inflammation Inflammatory Influenza Investments Joints Knowledge Link Listeria Methodology Methods Mouse Pox Virus Mus Mutagenesis Mutant Strains Mice Mutate Mutation National Institute of Allergy and Infectious Disease Natural Immunity Other Genetics Pathway interactions Pharmaceutical Preparations Phenotype Play Proteins Regulation Regulator Genes Research Research Personnel Role Salmonella Set protein Signal Transduction System Systems Analysis Systems Biology Techniques Technology Time Vaccine Design Work adaptive immunity combat cost exome sequencing forward genetics gene discovery genetic approach genetic pedigree in vivo influenzavirus macrophage member mouse model mutant new technology new therapeutic target next generation sequencing novel novel strategies pathogen programs public health relevance response screening success web site

项目摘要

DESCRIPTION (provided by applicant): The immune response is a double-edged sword; it is absolutely required for host defense, but unregulated, causes inflammatory disease. A number of critical questions regarding the mechanisms that appropriately tailor these pathways remain unanswered. This proposal seeks to uncover novel regulatory mechanisms that control critical aspects of the innate and adaptive response to NIAID priority pathogens. This U19 proposes a novel and fully integrated approach to immunological research that we have termed Systems-Guided Forward Genetics. Here, we combine traditional forward genetics and systems biology methodologies, retaining the advantages of each strategy while eliminating several previous obstacles. The result of this synergy is a significant increase in both the scope and pace of gene discovery and of subsequent mechanistic studies. This program is enabled by the rapid advances in next-generation sequencing technology, which have transformed forward genetics by allowing the identification of ENU-induced mutations prior to phenotypic screening, and by new systems biology approaches that allow contextualization of the mutations within gene regulatory and signaling networks. The multiple Cores within this integrated U19 program will enable and support three complementary Projects that probe the immune system in several orthogonal directions. The UTSW group will conduct an unbiased screen for defective immune responses to a variety of PAMPs that are components of multiple NIAID Priority pathogens. This group will use knowledge of the mutations present in each pedigree to accelerate the identification of genes identified in these screens. The ANU group will selectively enrich the colony of mice to be screened for mutations in genes that have been predicted by systems biology analyses to play a role in adaptive immune responses, and analyze the role of these genes during infection with the NIAID Priority pathogens influenza and ectromelia viruses. The Seattle BioMed group will comprehensively screen macrophages and dendritic cells for in vitro defects in response to a wide-range of innate immune agonists. This group will focus on mice identified by exome sequencing to have ENU induced mutations in genes predicted by systems analysis to be critical regulators of immune ceil networks and will establish the role of these genes in the immune response to the NIAID Priority pathogens Salmonella, Listeria, and influenza.

描述（申请人提供）：免疫反应是一把双刃剑；它是宿主防御所必需的，但如果不受调节，会导致炎症性疾病。有关适当调整这些途径的机制的许多关键问题仍未得到解答。该提案旨在揭示新的调控机制，控制对 NIAID 优先病原体的先天和适应性反应的关键方面。该 U19 提出了一种新颖且完全集成的免疫学研究方法，我们将其称为系统引导的正向遗传学。在这里，我们结合了传统的正向遗传学和系统生物学方法，保留了每种策略的优点，同时消除了之前的一些障碍。这种协同作用的结果是基因发现和后续机制研究的范围和速度显着增加。该计划得益于下一代测序技术的快速进步，该技术通过允许在表型筛选之前识别 ENU 诱导的突变，改变了正向遗传学，并且通过新的系统生物学方法，允许在基因调控和基因调控中对突变进行背景化。信令网络。该集成 U19 计划中的多个核心将启用并支持三个互补项目，这些项目在多个正交方向上探测免疫系统。 UTSW 小组将对作为多种 NIAID 优先病原体组成部分的各种 PAMP 进行公正的筛查，以发现有缺陷的免疫反应。该小组将利用每个谱系中存在的突变知识来加速对这些筛选中发现的基因的识别。澳大利亚国立大学小组将选择性地富集小鼠群体，筛选通过系统生物学分析预测在适应性免疫反应中发挥作用的基因突变，并分析这些基因在 NIAID 优先病原体流感和流感病毒感染期间的作用。节肢动物病毒。西雅图生物医学小组将全面筛查巨噬细胞和树突状细胞的体外缺陷，以应对各种先天免疫激动剂。该小组将重点关注通过外显子组测序鉴定出的小鼠，其基因中存在 ENU 诱导突变，系统分析预测这些基因是免疫细胞网络的关键调节因子，并将确定这些基因在对 NIAID 优先病原体沙门氏菌、李斯特菌、和流感。