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Lung-on-a-Chip Disease Models for Efficacy Testing

用于功效测试的芯片肺疾病模型

基本信息

批准号：
9789494
负责人：
DONALD E INGBER
金额：
$ 141.38万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789494
关键词：
3-Dimensional Air Alveolus Antiviral Agents Antiviral Therapy Architecture Binding Sites Bioinformatics Biological Markers Blood Vessels Cell Line Cells Characteristics Chemicals Chronic Obstructive Airway Disease Clinical Coupled Coupling Cultured Cells Development Devices Disease Disease model Drug Targeting Drug usage Endothelial Cells Engineering Epithelial Cells Epithelium Exposure to Extracellular Matrix Functional disorder Goals Heterogeneity Human Immune Immune response In Vitro Individual Infection Inflammation Mediators Inflammatory Influenza Influenza A Virus, H1N1 Subtype Influenza A virus Influenza Therapeutic Inhalation Exposure Link Liquid substance Liver Lung Lung Inflammation Lung diseases Measures Mediator of activation protein Membrane Methods Microfluidic Microchips Microfluidics Modeling Molecular Molecular Target Organ Patients Perfusion Pharmaceutical Preparations Phase Physiological Production Pulmonary Edema Pulmonary alveolar structure Resolution Respiratory Tract Infections Safety Side Standardization Surface Therapeutic Therapeutic Uses Tissues Validation Variant Vascular Endothelium Viral Virus Virus Diseases Virus Replication Virus Shedding anti-influenza drug biomarker development clinically relevant cytokine drug discovery drug efficacy drug metabolism drug testing drug use screening efficacy study efficacy testing human disease human model in vitro Model in vivo influenzavirus insight instrument liver metabolism microchip microphysiology system mortality multiple omics new therapeutic target novel organ on a chip patient population preclinical efficacy real-time images recruit response safety testing therapeutic candidate therapeutic target therapy design treatment response

项目摘要

SUMMARY The goal of this proposal is to use Organs-on-Chips (Organ Chips) to develop clinically relevant in vitro models of influenza infection in humans that can be used to test efficacy of candidate therapeutics, explore variation in responses in different patient populations, and potentially develop anti-influenza drugs that target the host response to infection, rather than the virus itself. Our Organ Chips are 2-channel microfluidic culture devices that are lined by human organ-specific tissue cells and vascular endothelium grown in parallel microchannels separated by a porous extracellular matrix-coated membrane. We have previously created Lung Alveolus Chips as well as Small Airway Chips lined by bronchiolar epithelial cells from either normal donors or diseased patients, such as individuals with chronic obstructive pulmonary disease (COPD), and we showed that they faithfully recapitulate human pathophysiology observed in vivo, including lung inflammation and pulmonary edema In addition, we have created human Liver Chips that metabolize drugs in vitro, and engineered an instrument for automated culture and fluidic coupling of up to 10 human organ chips for up to 4 weeks, which can be used to link different Organ Chips in a physiological way. Importantly, in preliminary studies, we successfully infected these bronchiolar epithelium with H1N1 influenza A virus (IAV), identified molecular mediators of the host response to infection, and discovered a potential new antiviral therapeutic that targets these mediators. In the UG3 phase of this project, we will demonstrate that Lung Airway and Alveolus Chips lined by primary cells isolated from human healthy donors or COPD patients can be used to model clinical features of IAV infection and related lung disorders previously observed in human patients, including viral replication and shedding, release of characteristic inflammatory cytokines, recruitment of circulating immune cells, and pulmonary edema, all of which we will measured non-invasively. During the UH3 phase, we will conduct preclinical efficacy testing of existing antiviral drugs and use multi-omics analysis and bioinformatics approaches to define translatable biomarkers and identify new potential molecular targets. We also will leverage these insights to discover new potential therapeutics that target the host response to infection, rather than the virus itself. Our UG3 Specific Aims are 1) to develop models of influenza infection in human Lung Airway and Alveolus Chips lined by cells from healthy donors and COPD patients that recapitulate in vivo disease responses, and 2) to develop an integrated model for influenza drug testing by fluidically linking Lung Airway, Lung Alveolus Chips, and Liver Chips via their vascular channels. Our UH3 Aims include: 1) to use the integrated Organ Chip influenza model to measure efficacy and safety of known antiviral therapeutics, 2) to validate translatable biomarkers for influenza infection and therapeutic responses identified using the Organ Chip model by comparison with clinical measures in humans, and 3) to use the integrated Organ Chip influenza model to identify new antiviral therapeutics that target host responses to infection.

总结