Systems Approach to Immunity and Inflammation

免疫和炎症的系统方法

基本信息

批准号：
8717568
负责人：
Richard J Ulevitch
金额：
$ 633.95万
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 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8717568
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 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（由申请人提供）：免疫反应是双刃剑；宿主防御绝对需要，但不受管制会引起炎症性疾病。关于适当调整这些途径的机制的许多关键问题仍未得到答复。该提案试图揭示新的调节机制，这些机制控制了对NIAID优先病原体的先天和适应性反应的关键方面。该U19提出了一种新型且完全整合的方法，用于我们称之为系统引导遗传学的免疫学研究。在这里，我们结合了传统的前瞻性遗传学和系统生物学方法论，保留了每种策略的优势，同时消除了以前的几个障碍。这种协同作用的结果是，基因发现的范围和速度和随后的机械研究的范围和速度都显着提高。下一代测序技术的快速进步可以实现该程序，这些技术通过在表型筛选之前识别ENU诱导的突变以及新的系统生物学方法，从而改变了eNU诱导的突变，从而改变了前向遗传学，从而允许在基因调节和信号网络中进行情境化突变的新系统生物学方法。该集成的U19程序中的多个核心将启用并支持三个互补项目，这些项目以多个正交方向探测免疫系统。 UTSW组将进行无偏见的筛查，以使对多种NIAID优先病原体组成的各种弹丸的免疫反应有缺陷。该组将使用每个血统中存在的突变的知识来加速这些筛选中鉴定的基因的识别。 ANU组将有选择地富集小鼠的群，以筛选以通过系统生物学分析预测的基因中的突变，以在自适应免疫反应中发挥作用，并分析这些基因在NIAID优先病原体感染过程中的作用，而这些基因的作用。西雅图生物群体将全面筛选巨噬细胞和树突状细胞，以响应广泛的先天免疫激动剂，以使体外缺陷。该组将重点放在外显子组测序中确定的小鼠，以使通过系统分析预测的基因中的突变是免疫CEIL网络的关键调节剂，并将确定这些基因在对NIAID优先病原体病原体沙门氏菌，李斯特菌和流感的免疫反应中的作用。