Organs-on-Chips as a Platform for Studying Effects of Microgravity on Human Physiology: Blood-Brain Barrier-Chip in Health and Disease

器官芯片作为研究微重力对人体生理学影响的平台：血脑屏障芯片在健康和疾病中的应用

• 批准号: 9921513
• 负责人: Daniel Levner
• 金额: $ 89.3万
• 依托单位: EMULATE, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921513
• 关键词: ARNT gene; Address; Anti-Inflammatory Agents; Basic Science; Biochemical; Biological Models; Blood - brain barrier anatomy; Cell physiology; Cells; Characteristics; Clinical; Communities; Computer software; Data; Development; Disease; Drug Industry; Drug toxicity; Endothelial Cells; Endothelium; Environment; Epigenetic Process; Expression Profiling; Gene Expression; Goals; Government Agencies; Grant; Health; Homeostasis; Human; Human Biology; Hydrostatic Pressure; Hypergravity; Hypoxia; Image; Impact evaluation; In Vitro; Individual; Inflammatory; Inflammatory Response; Infrastructure; Institutes; International; Liquid substance; Malignant Neoplasms; Massachusetts; Mechanics; Microgravity; Modeling; Monitor; Morphology; Nerve Degeneration; Neurons; Organ; Outcome; Pathogenesis; Permeability; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Planet Earth; Positioning Attribute; Procedures; Protocols documentation; RNA; Request for Applications; Research Personnel; Sampling; Science; Series; Space Flight; Stimulus; Stromal Cells; System; Targeted Research; Technology; Time; Translational Research; Traumatic injury; United States Food and Drug Administration; United States National Aeronautics and Space Administration; United States National Institutes of Health; Universities; Work; base; blood-brain barrier function; clinically relevant; drug development; drug discovery; drug efficacy; experimental study; genomic profiles; human disease; in vivo; induced pluripotent stem cell; insight; instrumentation; microphysiology system; new technology; next generation; novel; organ on a chip; predictive modeling; protein profiling; prototype; remote control; research clinical testing; response; sample fixation; space station; stressor; temporal measurement; transcriptomics

Abstract In response to the National Institutes of Health (NIH), -Center for the Advancement of Science in Space (CASIS), -Request for Application (RFA), -Targeted Research (TR), -16-019 we propose to apply the Organ- Chip technology of Emulate Inc., to assess the effects of space flight in human organs in vitro. Emulate is a newly founded start-up based on technology developed at the Wyss Institute at Harvard University in Cambridge, Massachusetts. The proposed work focuses on the development of automated hardware for space to enable experiments in human, in vivo relevant microphysiological systems for understanding of the impact of microgravity and other space flight-imposed stressors on human physiology, disease development and response to drugs. The organ we will apply to all proposed studies is the blood-brain barrier (BBB)-Chip, both in normal and inflamed states, which causes a major compromise in the BBB and allows for evaluation of clinically relevant endpoints. In this proposal, we will first validate Emulate’s Organ-Chip technology, and the automated instrumentation to be developed together with implementation partners SpaceTango, in terrestrial experiments simulating the space flight protocols. Next, we will use the platform to conduct two separate organ-chip experiments on the International Space Station (ISS) to understand the effects of this unique environment on BBB physiology. Further, terrestrial experiments will assess the specific contribution of each of the individual, primary cell stressors in space that can be simulated on Earth. Imaging, biochemical, and transcriptomic data from all studies over different time points will be analyzed, compared and provide the inputs for building a model of the system. We believe that our integrative approach will reveal new aspects of the effects of microgravity on the BBB in normal and disease states, and provide insights into drug discovery for this critical organ that maintains homeostasis or propagates a number of serious diseases. Successful implementation of our space compatible hardware and our BBB-Chip findings will provide an in vivo relevant, in vitro platform available to the scientific community for the evaluation of the impact of microgravity in physiology and disease of a number of human organs, and support drug development in novel, clinically relevant ways.

摘要 回应美国国立卫生研究院(NIH)--空间科学促进中心 (CASIS)，-申请(RFA)，-目标研究(TR)，-16-019我们建议申请器官- 芯片技术，用于评估太空飞行对人体器官的体外影响。仿真是一种 年，基于哈佛大学怀斯研究所开发的技术的新成立的初创公司 马萨诸塞州剑桥市。拟议的工作重点是开发自动化硬件，以 能够在人体内进行空间实验，了解体内相关的微生理系统 微重力和其他空间飞行应激源对人体生理和疾病发展的影响 以及对药物的反应。我们将应用于所有拟议研究的器官是血脑屏障(BBB)芯片， 在正常和炎症状态下，这会导致血脑屏障的重大损害，并允许评估 临床上相关的终点。在这份提案中，我们将首先验证Eulate的器官芯片技术，以及 将与实施伙伴SpaceTango共同开发地面自动化仪器 模拟太空飞行协议的实验。接下来，我们将利用该平台分别进行两个 在国际空间站(ISS)进行器官芯片实验，以了解这种独特的 环境对血脑屏障生理的影响。此外，地面实验将评估每一个 太空中可以在地球上模拟的单个主要细胞应激源。成像、生化和 来自不同时间点的所有研究的转录数据将被分析、比较并提供 用于构建系统模型的输入。我们相信，我们的综合方法将揭示新的方面 微重力对正常和疾病状态下血脑屏障的影响，并为药物开发提供见解 对于这个维持体内平衡或传播一些严重疾病的关键器官来说。成功 实施我们的空间兼容硬件和我们的BBB芯片发现将提供体内相关的、 科学界可利用体外平台评估微重力对生理学的影响 并以新的、临床相关的方式支持药物开发。