A Microphysiological Mimicry of Human Lung-Bone Marrow Organ-Organ Crosstalk On-a-Chip

芯片上人体肺-骨髓器官-器官串扰的微生理模拟

• 批准号: 10468736
• 负责人: Kambez Hajipouran Benam
• 金额: $ 38.91万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468736
• 关键词: Acute; Address; Adult; Air; Amino Acid Sequence; Animals; Architecture; Benchmarking; Biochemical Genetics; Biomedical Research; Biomimetics; Birds; Blood Vessels; Bone Marrow; Breathing; CD8-Positive T-Lymphocytes; California; Cell Culture Techniques; Cells; Cessation of life; Chemicals; Clinic; Clinical; Clinical Data; Code; Communicable Diseases; Communication; Complex; Data; Devices; Disease; Disease Outbreaks; Engineering; Ensure; Epidemic; Epidemiology; Epithelial Cells; Generations; Genotype; Goals; Hemagglutinin; Hematopoietic; Human; Immune; Immunologics; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Lead; Length of Stay; Leukocytes; Life; Link; Liquid substance; Lower Respiratory Tract Infection; Lung; Lung infections; Mediating; Metabolic; Methods; Microfluidics; Modeling; Molecular; Morbidity - disease rate; Mus; Neutrophil Infiltration; Organ; Outcome; Pathogenicity; Pathology; Patients; Perfusion; Periodicity; Physiological; Physiology; Public Health; Reporting; Resolution; Respiratory System; Role; Security; Severities; Severity of illness; Shapes; Site; Smoking; System; Technology; Time; Tissues; Vietnam; Viral; Viral Hemagglutinins; Virulence; Virulence Factors; Virulent; Virus; Virus Diseases; aerosolized; airway epithelium; bioscaffold; cell type; drug development; efficacy testing; global health; human subject; human tissue; in vitro Model; in vivo; influenza infection; influenza virus strain; influenzavirus; innovation; lung development; mechanical signal; microchip; microphysiology system; microsystems; mimicry; monocyte; mortality; mouse model; neutrophil; new therapeutic target; novel; organ on a chip; pandemic disease; pandemic influenza; particle; patient population; precision drugs; real-time images; recruit; respiratory; respiratory virus; response; swine influenza; three dimensional cell culture; virology

PROJECT SUMMARY. Several new viral respiratory tract infectious diseases with epidemic potential that threaten global health security have emerged in the past 20 years. Influenza A viruses (IAVs) comprise 50% of the emerging respiratory viruses and can cause substantial morbidity and mortality. IAVs can infect a diversity of avian and mammalian species, including humans, and have the remarkable capacity to evolve and adapt to new hosts. Despite the tremendous progress made in virology and epidemiology, which subtype or strain of IAV will cause the next outbreak remains unpredictable. Importantly, there is no clinically simulating, pathophysiologically relevant, and readily available in vitro multi-organ system for predicting the pathogenicity of emerging and re-emerging influenza viruses in humans. Recent compelling evidence have revealed opposing roles for two major classes of bone marrow (BM)-produced innate immune cells in shaping the outcome of IAV infection, with neutrophils offering protection and increase in circulating monocytes being associated with increased pathology. Thus, selective mobilization of either of these two distinct cell types in response to pulmonary infection with IAV can indirectly reveal potential pathogenicity of a given viral strain. The overarching goal of this project is to develop a highly innovative, reductionist, yet advanced and complex, physiologically relevant in vitro model of influenza infection in humans utilizing Organ-on-Chip technology in order to predict virulence and infectivity of different IAV strains, by reproducing clinically and in vivo-observed immunological correlates of infection severity. More specifically, we will engineer a first-in-kind fluidically integrated multi- organ system that recreates BM-lung axis, using primary human-derived cells, for real-time analysis of inflammation and leukocyte mobilization in response to influenza challenge. Our central hypothesis is that this dynamic living microsystem can recapitulate differential immune cell mobilization and tissue pathology in response to high-pathogenicity vs. low-pathogenicity IAV infections in vitro. To address the hypothesis, we propose the following specific aims: (1) to engineer a living and hematopoietically active human BM-on-a-Chip and microfluidically link it to a human Lung Small Airway-on-a-Chip that our team has previously developed and characterize homeostatic physiology and organ-organ crosstalk; and (3) to challenge the BM-Lung microsystem with airborne IAVs under rhythmic breathing and reproduce differential leukocyte mobilization and tissue damage in response to distinctly pathogenic viral strains. Such a novel platform holds great potential in emulating and predicting pathogenicity of IAVs (e.g., during outbreaks, pandemics or when presence of a highly virulent strain is speculated), utilizing human cells isolated from desired donor/patient populations, and without needing to adapt the virus for host (as required for some animal studies). In addition, it can considerably accelerate drug development studies by enabling personalized drug efficacy testing and identification of new therapeutic targets.

项目摘要。 具有威胁全球卫生安全的流行潜力的几种新病毒呼吸道传染病 在过去的20年中出现了。流感病毒（IAVS）占新兴呼吸道病毒的50％，可以 引起大量的发病率和死亡率。 IAV可以感染各种各样的禽和哺乳动物，包括 人类，并具有出色的发展能力，可以发展和适应新宿主。尽管取得了巨大进展 病毒学和流行病学（IAV的亚型或菌株）将导致下一次爆发。 重要的是，没有临床模拟，病理生理学相关，并且在体外随时可用 多器官系统，用于预测人类出现和重新出现流感病毒的致病性。 最近有说服力的证据揭示了两种主要类别的骨髓（BM）生产的先天性的作用 免疫细胞塑造IAV感染的结果，中性粒细胞提供保护和循环增加 单核细胞与病理增加有关。因此，选择性动员这两个不同的细胞中的任何一个 响应IAV肺部感染的类型可以间接揭示给定病毒的潜在致病性 拉紧。该项目的总体目标是开发一个高度创新的，还原的，却是高级和复杂的， 在人类中使用器官芯片技术的人类感染流感感染与生理相关的体外模型 通过临床和体内的免疫学，预测不同IAV菌株的毒力和感染性 感染严重程度的相关性。更具体地说，我们将设计一项最初的流体集成的多元 使用原代人源细胞重新创建BM肺轴的器官系统，以实时分析 炎症和白细胞动员响应流感挑战。我们的中心假设是 动态生活微系统可以概括差异免疫细胞动员和组织病理学 在体外对高致病性与低致病性IAV感染的反应。为了解决该假设，我们 提出以下具体目的：（1）设计生命和造血活跃的人类BM片和 微流体将其链接到我们团队以前开发的人类肺部小气道，并且 表征体内稳态生理和有机器官串扰； （3）用 在节奏呼吸下的空中IAV和繁殖差异白细胞动员和组织损伤 对明显致病的病毒菌株的反应。这样一个新颖的平台在模拟和预测方面具有巨大的潜力 IAV的致病性（例如，在爆发，大流行期或猜测高毒性菌株的存在时）， 利用从所需的供体/患者种群中分离出的人类细胞，而无需适应宿主病毒 （根据某些动物研究的要求）。此外，它可以通过启用药物开发研究大大加速 个性化的药物疗效测试和新的治疗靶标的鉴定。