Signaling Core

信令核心

• 批准号: 10181124
• 负责人: GARRY P NOLAN
• 金额: $ 21.52万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 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/10181124
• 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

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 M? 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-CoV-2 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.

这一建议是一种高度创新的、也许是独特的方法，为以下方面奠定了基础： 了解COVID 19驱动的人类病理的发病机制。在这里，我们带来了三个不同的科学 以一种新的和协调的方式一起分析先天免疫反应的关键步骤， COVID-19感染NLRP 3炎性体通路的基础研究既深入又广泛 鉴于Ulevitch实验室在研究NLR家族的各种成员方面近20年的经验， 路径分析水平。虽然利用来自小鼠细胞研究的信息（遗传、生物化学和生物化学）， 细胞生物学）这里的重点是人类M？Ulevitch实验室已经建立了一个广泛的方法， 免疫学、细胞生物学和遗传学方法。诺兰实验室率先使用高含量的 用于分析细胞和组织的成像方法。高参数技术最大限度地扩大了 分析样品中的免疫特征以快速发现。CyTOF为数百万个细胞提供42通道信息， 血CODEX空间分辨组织中的单个细胞，参数>60个，而ViralMIBI将病毒 从核酸检测到基于抗体的多参数成像，定义了感染的细胞小生境。 将这些技术与SARS-CoV-2挑战模型和协作交叉相结合， 在鉴定与疾病表型和分子生物学特征最匹配的小鼠模型中， COVID-19疾病的特征。如果认为有用，我们也可以使用信息和/或鼠 这些菌株来自Beutler实验室的遗传学研究。后者一直是《公约》的组成部分， Scripps U19计划自2001/2002年首次资助以来。