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

基本信息

批准号：
10237309
负责人：
Kambez Hajipouran Benam
金额：
$ 38.96万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10237309
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 Cues 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 Mechanics 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 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

项目摘要

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。几种具有流行潜力的新型病毒性呼吸道传染病威胁全球卫生安全是近20年来出现的。甲型流感病毒 (IAV) 占新出现的呼吸道病毒的 50%，可导致大量的发病率和死亡率。 IAV 可感染多种鸟类和哺乳动物物种，包括人类，具有非凡的进化和适应新宿主的能力。尽管取得了巨大进步就病毒学和流行病学而言，IAV 的哪种亚型或毒株将导致下一次爆发仍然无法预测。重要的是，目前还没有临床模拟的、病理生理学相关的、容易获得的体外模型。用于预测人类中新出现和重新出现的流感病毒的致病性的多器官系统。最近令人信服的证据揭示了骨髓 (BM) 产生的两种主要先天性物质的相反作用免疫细胞影响 IAV 感染的结果，其中中性粒细胞提供保护并增加循环单核细胞与病理增加有关。因此，这两种不同细胞的选择性动员对 IAV 肺部感染的反应类型可以间接揭示特定病毒的潜在致病性拉紧。该项目的总体目标是开发一种高度创新、简化但先进且复杂的、利用器官芯片技术建立人类流感感染的生理相关体外模型通过复制临床和体内观察到的免疫学结果，预测不同 IAV 毒株的毒力和传染性感染严重程度的相关性。更具体地说，我们将设计一种同类首创的流体集成多使用原代人源细胞重建骨髓-肺轴的器官系统，用于实时分析应对流感挑战的炎症和白细胞动员。我们的中心假设是，这动态活体微系统可以重现差异免疫细胞动员和组织病理学体外对高致病性与低致病性 IAV 感染的反应。为了解决这个假设，我们提出以下具体目标：（1）设计活的、具有造血活性的人类片上骨髓；通过微流体将其与我们团队之前开发的人类肺小气道芯片连接起来表征稳态生理学和器官间串扰； (3) 挑战 BM-Lung 微系统空气中的 IAV 在有节奏的呼吸下重现差异性白细胞动员和组织损伤对明显致病性病毒株的反应。这种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、大流行期间或推测存在高毒力菌株时），利用从所需的供体/患者群体中分离出的人类细胞，并且无需使病毒适应宿主（根据某些动物研究的要求）。此外，它还可以通过启用个性化药物疗效测试和新治疗靶点的识别。