Stanford/UNC Biomimetic U19 Research Center

斯坦福大学/北卡罗来纳大学仿生 U19 研究中心

基本信息

批准号：
10191934
负责人：
MANUEL R AMIEVA
金额：
$ 155.93万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10191934
关键词：
2019-nCoV 3-Dimensional Acute Adult Respiratory Distress Syndrome Air Alveolar Apical Bacteria Bacterial Infections Basic Science Binding Biology Biomimetics COVID-19 COVID-19 pandemic CRISPR interference CRISPR screen Cell Communication Cells Chiroptera Chronic Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Communicable Diseases Coronavirus Digestion Disease Distal Enteral Epidemic Epithelial Epitopes Escherichia coli Etiology Exhibits Experimental Models Functional disorder Gastrointestinal Diseases Gastrointestinal tract structure Genes Genetic Screening Glycoproteins Goals Growth Helicobacter pylori Human Immune Immune response Immunity In Vitro Incubators Infection Influenza Influenza A Virus, H1N1 Subtype Intestines Investigation Investigational Therapies Lead Liquid substance Lung Lung infections M cell Mediating Methods Middle East Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Mission Modeling Monoclonal Antibodies Morbidity - disease rate Myelogenous National Institute of Allergy and Infectious Disease Norovirus North Carolina Organoids Outcome Pathogenesis Pathogenicity Play Pneumonia Population Predisposition Prevention Recurrence Research Research Personnel Research Project Grants Resistance Respiratory Failure Respiratory Mucosa Respiratory Therapy Respiratory Tract Infections Role Rotavirus Route SARS coronavirus SARS-CoV-2 inhibitor Salmonella Salmonella typhi Salmonella typhimurium Severe Acute Respiratory Syndrome Sinus Stomach Structure of respiratory epithelium Surface System Terminal Bronchiole Testing Therapeutic Time Tissue Engineering Tissues Tumor-infiltrating immune cells Universities Viral Virulence Virus Virus Diseases Zoonoses absorption adaptive immune response base cell type comparative cytokine release syndrome emerging pathogen enteric infection gastric organoids gastrointestinal gastrointestinal epithelium gastrointestinal infection genetic manipulation global health human coronavirus human disease human model improved mortality multidisciplinary multiplexed imaging mutant neutralizing monoclonal antibodies novel novel coronavirus pathogen pathogenic virus permissiveness preservation reconstitution respiratory respiratory pathogen reverse genetics screening single-cell RNA sequencing small molecule inhibitor socioeconomics synergism therapeutic candidate therapeutic development therapeutic evaluation three dimensional cell culture vaccine development virus tropism zoonotic coronavirus

项目摘要

Stanford/UNC Biomimetic U19 Research Center PROJECT SUMMARY/ABSTRACT – CENTER OVERVIEW Infectious diseases continue to pervasively afflict global health and socioeconomic stability despite substantial prevention and treatment initiatives. Respiratory and gastrointestinal pathogens rank amongst the most intractable infectious diseases, particularly notable for recurrent waves of zoonotic coronaviruses and the recent COVID-19 pandemic, engendered by SARS-CoV-2. Overall, an urgent need exists for improved in vitro experimental models of human disease to study pathogenesis and to validate therapeutics. The central mission of the Stanford/UNC Biomimetic U19 Research Center is thus to deploy novel 3-dimensional organoid culture models to elucidate the biology and therapy of respiratory and gastrointestinal infectious pathogens. Our application is a renewal of our prior Stanford NAMSED U19 Research Center and is comprised of two Cores and three research Projects, leveraging complementary and synergistic expertise of our investigators at Stanford University and the University of North Carolina. The Center continues to be led by the Multi-PIs, Calvin Kuo and Manuel Amieva, who also co-lead Core A (Administrative Core). Core B (Organoid Core) is led by Calvin Kuo and provides novel capabilities for lung and GI organoid culture, gene editing and multiplexed screening. The three Projects extensively utilize organoid biomimetics for exploration of GI and respiratory pathogens. Project 1, (PI, Manuel Amieva) investigates H. pylori and Salmonella colonization, competition and invasion in the GI tract, while Project 2 (PI, Harry Greenberg) investigates rotavirus host range, neutralization, and M cell interactions in enteric biomimetics. Project 3 (PI, Ralph Baric) is a new addition and extensively uses organoids to model SARS-CoV-2, other closely related epidemic and pre-epidemic emerging coronaviruses and 1918 H1N1 influenza to reveal common and unique host networks associated with severe pulmonary outcomes. The activities of the Stanford/UNC Biomimetic U19 Research Center reside within three overarching Aims. In Aim 1, our Center performs organoid modeling of the epithelium-pathogen interface to investigate pathogenesis, susceptibility and host range restriction. This employs robust reverse genetics and CRISPR screens to systematically manipulate host versus viral/bacterial compartments, within novel apical-basal polarity modulated distal lung/alveolar, nasal sinus, stomach and intestinal organoid systems. Aim 2 defines how SARS- CoV-2, pre-epidemic coronaviruses, rotavirus and Salmonella can perturb reciprocal cross-talk between tissue epithelium and resident immune cells. This exploits a unique 3D air-liquid interface organoid method preserving GI and lung epithelium en bloc with diverse endogenous infiltrating immune cell types without artificial reconstitution. Lastly, Aim 3 performs organoid-based evaluation of therapeutic candidates against SARS-CoV- 2, pre-epidemic coronaviruses and rotavirus in medium- to high-throughput formats including epithelium and/or immune cells. Overall, the explorations of the Stanford/UNC Biomimetic U19 Research Center directly apply advanced organoid systems to the investigation and therapy of recalcitrant infectious pathogens.

斯坦福大学/北卡罗来纳大学仿生 U19 研究中心项目概要/摘要 – 中心概述尽管传染病已严重影响全球健康和社会经济稳定，但传染病仍然普遍困扰着全球健康和社会经济稳定。呼吸道和胃肠道病原体的预防和治疗举措名列前茅。难治性传染病，特别是人畜共患冠状病毒的反复发作和最近的由 SARS-CoV-2 引起的 COVID-19 大流行总体而言，迫切需要改进体外试验。人类疾病的实验模型研究发病机制并验证治疗方法。因此，斯坦福大学/北卡罗来纳大学仿生 U19 研究中心将部署新型 3 维类器官培养阐明呼吸道和胃肠道感染病原体的生物学和治疗的模型。我们的应用程序是我们之前的斯坦福 NAMSED U19 研究中心的更新，包括两个核心和三个研究项目，利用我们研究人员的互补和协同专业知识该中心继续由多位 PI 领导， Calvin Kuo 和 Manuel Amieva 共同领导了核心 A（行政核心）和核心 B（Organoid 核心）。由 Calvin Kuo 开发，为肺和胃肠道类器官培养、基因编辑和多重分析提供了新颖的功能这三个项目主要利用类器官仿生学来探索胃肠道和呼吸系统。项目 1（PI，Manuel Amieva）研究幽门螺杆菌和沙门氏菌的定殖、竞争和入侵胃肠道，而项目 2（PI，Harry Greenberg）研究轮状病毒宿主范围、中和、肠道仿生学中的 M 细胞和 M 细胞相互作用项目 3（PI，Ralph Baric）是一个新的补充和用途。用于模拟 SARS-CoV-2、其他密切相关的流行病和流行前新出现的冠状病毒的类器官 1918 年 H1N1 流感揭示了与严重肺部后果相关的常见和独特的宿主网络。斯坦福大学/北卡罗来纳大学仿生 U19 研究中心的活动分为三个总体范围在目标 1 中，我们中心对上皮-病原体界面进行类器官建模以进行研究。这利用了强大的反向遗传学和 CRISPR 来确定发病机制、易感性和宿主范围限制。在新颖的顶端-基底极性内系统地操纵宿主与病毒/细菌区室的筛选调节远端肺/肺泡、鼻窦、胃和肠道类器官系统的目标 2 定义了 SARS 的方式。 CoV-2、流行前冠状病毒、轮状病毒和沙门氏菌可以扰乱组织之间的相互串扰这利用了独特的 3D 气液界面类器官方法。胃肠道和肺上皮整体具有多种内源性浸润免疫细胞类型，无需人工最后，Aim 3 对 SARS-CoV 的候选治疗药物进行基于类器官的评估。 2、流行前冠状病毒和轮状病毒的中高通量形式，包括上皮细胞和/或总体而言，斯坦福大学/北卡罗来纳大学仿生U19研究中心的探索直接适用于免疫细胞。先进的类器官系统用于研究和治疗顽固性传染性病原体。