Systems Approach to Immunity and Inflammation

免疫和炎症的系统方法

基本信息

批准号：
10159667
负责人：
Richard J Ulevitch
金额：
$ 36.66万
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：
2020-06-11 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159667
关键词：
2019-nCoV Administrative Supplement Animal Model Antibodies Biochemical Biological Blood COVID-19 Cells Chemicals Coronavirus Data Disease Drug Modelings Evaluation Family Foundations Funding Genes Genetic Genetic Variation Heart Human Image Immune Immunity Immunologics Infection Inflammasome Inflammation Innate Immune Response Intestines Knockout Mice Libraries Lung Modeling Molecular Molecular Profiling Mus Pathogenesis Pathology Pathway Analysis Pathway interactions Pharmacology Proteins Publishing Role Running Sampling Seminal Series Signal Transduction Spleen System Technology Testing Therapeutic Intervention Therapeutic Uses Tissue imaging Tissues Viral Virulent Virus Work antibody libraries base biomarker panel disease phenotype draining lymph node drug action experience extracellular genetic approach human tissue imaging approach in vivo inhibitor/antagonist innovation macrophage man member mouse model novel nucleic acid detection programs small molecule inhibitor success tool ubiquitin-protein ligase

项目摘要

This proposal represents a highly innovative and perhaps unique approach to lay the foundation for understanding the pathogenesis of COVID19-driven pathologies in man. Here we bring three distinct scientific approaches together in a novel and coordinated fashion to analyze key steps in innate immune response to COVID-19 infection. The fundamental studies of the NLRP3 inflammasome pathway is both deep and broad given the nearly 20-year experience of the Ulevitch lab in studying various members of the NLR family at the level of pathway analysis. While drawing on information from studies in murine cells (genetic, biochemical and cell biologic) the focus here is on human Mϕ where the Ulevitch lab has built a broad approach with immunologic, cell biologic and genetic approaches. The Nolan lab has pioneered the use of high content imaging approaches for analyzing cells and tissues. The high parameter technologies maximize the breadth of immune features analyzed in samples for rapid discovery. CyTOF gives 42-channel info for millions of cells in blood. CODEX spatially resolves single cells in tissues with >60 parameters, while ViralMIBI brings viral nucleic acid detection to antibody-based multiparameter imaging defining cellular niches of infection. Combining these technologies with SARS-CoV2 challenge models and the Collaborative Cross will also result in the identification of mouse models that most closely match the disease phenotypes and molecular signatures of COVID-19 disease in humans. If deemed useful we can also use information and/or murine strains derived from forward genetic efforts in the Beutler lab. The latter has been an integral part of the Scripps U19 program since the initial funding in 2001/2002.

该提案代表了一种高度创新且也许是独特的方法，为以下方面奠定了基础：在这里，我们带来了三种不同的科学知识，以了解新冠病毒引起的人类疾病的发病机制。以一种新颖且协调的方式共同分析先天免疫反应的关键步骤 COVID-19 感染的基础研究既深入又广泛。鉴于 Ulevitch 实验室在研究 NLR 家族的各个成员方面拥有近 20 年的经验同时利用小鼠细胞研究的信息（遗传、生化和细胞生物学）这里的重点是人类 Mphi，Ulevitch 实验室已经建立了一种广泛的方法诺兰实验室率先使用了高含量的免疫学、细胞生物学和遗传学方法。用于分析细胞和组织的成像方法最大化了分析范围。 CyTOF 分析样本中的免疫特征，提供数百万个细胞的 42 通道信息。 CODEX 以超过 60 个参数对组织中的单个细胞进行空间解析，而 ViralMIBI 则带来病毒。核酸检测到基于抗体的多参数成像定义感染的细胞生态位。将这些技术与 SARS-CoV2 挑战模型和协作交叉相结合也将产生鉴定与疾病表型和分子最接近的小鼠模型如果认为有用，我们还可以使用信息和/或小鼠的 COVID-19 疾病特征。菌株源自 Beutler 实验室的正向遗传工作，后者是该实验室不可分割的一部分。斯克里普斯 U19 项目自 2001/2002 年首次资助以来。